tag:theconversation.com,2011:/global/topics/cells-2017/articlesCells – The Conversation2024-02-19T13:44:01Ztag:theconversation.com,2011:article/2235282024-02-19T13:44:01Z2024-02-19T13:44:01ZLung cancer: Predicting which patients are at high risk of recurrence to improve outcomes<figure><img src="https://images.theconversation.com/files/575433/original/file-20240205-29-abkjt8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chemotherapy is used to treat all lung cancer patients. Yet many would not need such invasive treatment if diagnosis of the risk of recurrence were more refined. A new technology could change all that.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Lung cancer <a href="https://cancer.ca/en/research/cancer-statistics/cancer-statistics-at-a-glance">is responsible for more deaths than breast, colon and prostate cancer combined</a>. </p>
<p>With advancements in lung cancer screening, it is expected that more patients will be diagnosed at earlier stages, enabling them to undergo surgery, the primary treatment modality for early-stage patients.</p>
<p>However, a significant proportion of patients will have a recurrence of their cancer after resection (surgery to remove the tumour). Unfortunately, current clinical guidelines cannot help predict which patients are at risk. Better knowledge of who is at risk has significant implications for systemic therapy selection such as chemotherapy for early-stage lung cancer patients after surgery. </p>
<p>To find solutions to this problem, our research group at McGill University launched a project in collaboration with Université Laval. <a href="https://www.nature.com/articles/s41586-022-05672-3#MOESM1">Preliminary results were published in <em>Nature</em></a>. In our work we discovered that the use of a new imaging technology, along with artificial intelligence, could improve outcomes for cancer patients.</p>
<h2>Too much or too little intervention</h2>
<p>This clinical dilemma has important implications for the choice of treatment, such as chemotherapy. For example, lung cancer patients who are cured by surgery could be spared the toxicity of chemotherapy. Patients at risk of their cancer recurring could benefit from additional therapeutic interventions.</p>
<p>The challenge of predicting recurrence for patients with early-stage lung cancer has important implications for the 31,000 Canadians who are diagnosed with this terrible disease every year.</p>
<h2>Mass cytometry imaging</h2>
<p>To address this clinical problem, we used <a href="https://www.mcgill.ca/gci/facilities/single-cell-imaging-and-mass-cytometry-analysis-platform-scimap">imaging mass cytometry</a> (IMC), a new technology that allows for a comprehensive characterization of the tumour microenvironment. </p>
<p>The tumour microenvironment is a complex ecosystem composed of interactions between tumour cells, immune cells, and various structural cells. IMC can be used to visualize up to 50 markers at the cell surface, significantly more than was previously possible. </p>
<p>This technology makes it possible to identify different types of cells and determine their spatial organization, i.e. how they interact. IMC produces images that can be analyzed to determine the frequency of cell subpopulations, their activation states, the other cell types with which they interact and their organization in cellular communities. </p>
<p>The results of our study, published in <em>Nature</em>, reveal that various cell types can interact in cellular communities, and that communities composed of B cells were strongly associated with prolonged survival in lung cancer patients. Our study highlights that beyond cellular frequency, cellular interactions and spatial organization also correlate strongly with important clinical outcomes such as survival.</p>
<h2>Using artificial intelligence to make better predictions</h2>
<p>Based on our initial results, we hypothesized that important spatial features embedded within IMC images, such as cellular interactions, could be important in predicting clinical outcomes. </p>
<p>Our dataset of 416 patients and over 1.6 million cells provided sufficient power to make predictions using artificial intelligence. We sought to predict which patients with early-stage lung cancer would have a recurrence of their cancer after surgery. </p>
<p>Using 1 mm2 tumour samples, material readily available from surgical resections or biopsies, we used artificial intelligence algorithms together with IMC images to make our predictions. Our algorithm was able to predict with 95 per cent accuracy which patients would experience a cancer recurrence by using the spatial information contained within the images. </p>
<h2>Six markers can make all the difference</h2>
<p>One of the challenges in applying our results in a clinical setting is that IMC is not readily available. Clinical pathologists typically use less complex technologies such as immunofluorescence, which are often limited to three or fewer markers. </p>
<figure class="align-center ">
<img alt="image obtained using immunofluorescence" src="https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Immunofluorescence image of a tumour treated with immunotherapy. This technology is often limited to the use of three or fewer markers at a time.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>To address this challenge, we sought to identify the minimum number of markers needed to make meaningful predictions about recurrence in lung cancer patients after surgery. By using six markers, we obtained an accuracy rate of 93 per cent, a result that is close to the 95 per cent accuracy rate obtained by using 35 markers. </p>
<p>These results suggest that by harnessing the power of artificial intelligence with existing technologies available in hospitals, we may be able to improve the post-surgical clinical management of patients with early-stage lung cancer. Our ultimate goal is to increase cure rates for those at high risk of cancer recurrence, while minimizing toxicity for those who can be cured by surgery.</p><img src="https://counter.theconversation.com/content/223528/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Sorin has received funding from the Fonds de recherche du Québec and Vanier Canada Graduate Scholarships.</span></em></p><p class="fine-print"><em><span>Logan Walsh has received funding from McGill University's Interdisciplinary Infection and Immunity Initiative, the Brain Tumour Funders' Collaborative, the Canadian Institutes of Health Research (CIHR; PJT-162137), the Canada Foundation for Innovation and holds the Rosalind Goodman Research Chair in Lung Cancer.</span></em></p>Treatment for lung cancer patients is the same for everyone, regardless of the risk of recurrence. The use of a new technology could refine diagnosis.Mark Sorin, Étudiant au MD-PhD, chercheur en cancer du poumon, McGill UniversityLogan Walsh, Assistant Professor, Department of Human Genetics, McGill UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2202782024-02-08T13:40:17Z2024-02-08T13:40:17ZSugary handshakes are how cells talk to each other − understanding these name tags can clarify how the immune system works<figure><img src="https://images.theconversation.com/files/570832/original/file-20240123-29-c6ob1s.png?ixlib=rb-1.1.0&rect=0%2C0%2C2880%2C1664&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Handshakes between glycans are one way cells recognize each other.</span> <span class="attribution"><span class="source">Kelvin Anggara</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Like the people they make up, cells communicate by bumping into one another and exchanging handshakes. Unlike people, cells perform these handshakes using the diverse range of sugar molecules coating their surface like trees covering a landscape. Handshakes between these <a href="https://doi.org/10.1093/glycob/cww086">sugar molecules, or glycans</a>, trigger cells to react in specific ways toward each other, such as escape, ignore or destroy.</p>
<p>Figuring out the “body language” of glycans during these handshakes can provide clues to how cancers, infections and immune systems work, as well as solutions to health and sustainability challenges society faces today.</p>
<h2>What are glycans?</h2>
<p>Each glycan molecule is made up of a network of individual sugar molecules bonded together. The vast number of possible glycan structures that can be built from connecting these sugar molecules together allows glycans to <a href="https://doi.org/10.1093/glycob/cww086">store rich information</a>.</p>
<p>Because all living cells are covered with sugars, glycans act like ID cards for cells. They display the cell’s identity, such as whether it’s a bacteria or human cell, and its state, such as whether it’s healthy or cancer, to the rest of the body and allow <a href="https://www.ncbi.nlm.nih.gov/books/NBK579984/">other cells to recognize</a> and respond to it. For example, these identifying signs allow our immune cells to recognize and clear out harmful bacteria and cancerous cells while leaving healthy cells in peace.</p>
<p>An example of how glycan-stored information is important to daily life is <a href="https://theconversation.com/what-are-blood-types-126002">your blood type</a>. Glycans are chemically bonded to proteins and lipids on the surface of red blood cells. Notably, the surface of type A red blood cells have glycans that differ from the glycans on the surface of type B and type O red blood cells. Knowing what blood type you have is important to avoid an unwanted immune response during blood transfusions.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing the glycan structures of types A, B and O red blood cells" src="https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=505&fit=crop&dpr=1 600w, https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=505&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=505&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=635&fit=crop&dpr=1 754w, https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=635&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/570449/original/file-20240120-22-n2v4b4.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=635&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Your blood type is determined by the types of glycans, depicted here in circles and triangles, on your red blood cells.</span>
<span class="attribution"><span class="source">Kelvin Anggara/Created with BioRender.com</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Proteins decorated with glycans, or glycoproteins, and lipids decorated with glycans, or glycolipids, are ubiquitous in nature. </p>
<p>For example, distinctive glycoproteins cover the surface of the viruses that cause <a href="https://doi.org/10.1021/acscentsci.0c01056">COVID-19</a>, <a href="https://doi.org/10.1016/j.cell.2016.04.010">HIV</a> and <a href="https://doi.org/10.1021/acscentsci.2c00981">H1N1 influenza</a> and help them <a href="https://theconversation.com/how-do-viruses-get-into-cells-their-infection-tactics-determine-whether-they-can-jump-species-or-set-off-a-pandemic-216139">infect cells</a>. Glycolipids also coat <a href="https://doi.org/10.1016%2Fj.cell.2019.12.006">many bacteria</a>, allowing them to stick to their hosts and protect them from viruses and immune cells.</p>
<p>More recently, researchers discovered pieces of <a href="https://doi.org/10.1016/j.cell.2021.04.023">genetic material decorated with glycans</a> on the surfaces of mammalian cells, challenging the long-standing notion that genetic material could be found only in the nucleus of cells and launching research to determine the functions of these glycans. One recent study showed that these molecules are vital in <a href="https://doi.org/10.1016/j.cell.2023.12.033">attracting immune cells</a> toward infected or injured tissues.</p>
<h2>How do cells read glycans?</h2>
<p>In addition to the rich biological information contained in glycans, their easily accessible locations on cell surfaces make them highly attractive targets in scientific research and drug development.</p>
<p>Cells sense glycans on the surfaces of other cells by using <a href="https://www.ncbi.nlm.nih.gov/books/NBK579947/">proteins called lectins</a>, among others. Each lectin has a unique area that allows it to bind to glycans with a specific matching sequence, triggering complex signals that lead to a biological action.</p>
<p>For example, a subfamily of lectins called <a href="https://doi.org/10.1038/nri2569">C-type lectins</a> are able to recognize the specific glycans on the outer walls of harmful viruses, fungi and bacteria. Found on surfaces of certain immune cells, these lectins deliver the glycans to proteins on other immune cells that can now selectively destroy any viruses or cells that carry that glycan. This process allows the immune system to clear the body of harmful pathogens. For example, these lectins recognize glycans on the <a href="https://doi.org/10.1093/glycob/cwy023">surfaces of cancer cells</a> and direct other immune cells to eliminate these cancer cells.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of a spherical influenza virus, with red and blue spikes studding its surface" src="https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/572940/original/file-20240201-25-cjkqvl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The spikes on the surface of the influenza virus are composed of glycoproteins.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/flu-virus-close-up-view-3d-illustration-royalty-free-image/1389473291">Dr_Microbe/iStock via Getty Images Plus</a></span>
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<p>Another type of <a href="https://doi.org/10.1146/annurev-immunol-102419-035900">lectin called siglecs</a> are found on surfaces of immune cells and help them distinguish self from nonself, that is, between the cells that make up the body and the cells that are foreign to the body. Because siglecs are involved in <a href="https://doi.org/10.1146/annurev-immunol-102419-035900">controlling how the immune system responds</a> to many cancers, allergies, autoimmune diseases and neurodegeneration, they offer an opportunity to treat these conditions.</p>
<p>The early success of glycan-based drugs is exemplified by <a href="https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5911a1.htm">Pfizer’s Prevnar vaccine</a> to prevent bacterial pneumonia, which was approved by the Food and Drug Administration in 2010. Prevnar contains glycans from various strains of <a href="https://doi.org/10.5863%2F1551-6776-21.1.27"><em>Streptococcus pneumoniae</em></a>, the leading cause of bacterial pneumonia in children and adults. The bacterial glycans in the vaccine trigger an immune response when immune cells recognize the glycans as foreign threats. Once immune cells learn how to neutralize the threat, the body becomes immune to future invasion by bacteria with the same glycans. </p>
<h2>Examining every sugar molecule</h2>
<p>Because scientists are still <a href="https://doi.org/10.1021/jacs.9b06406">unable to extract all the biological information</a> in glycans, their full potential as treatments has remained untapped. Comprehensively extracting all the information stored in glycans is very difficult because there isn’t currently technology able to analyze the complex and diverse structures of glycans. Researchers still don’t know what these “sugar codes” look like and how they function.</p>
<p>Individual glycans are composed of sugar molecules in unique arrangements, but current analytical tools can only <a href="https://doi.org/10.17226/13446">simultaneously analyze many glycans</a>. To see why this is a problem for analysis, imagine all the glycans in a cell as candies in a jar. Some of them are the same colors and some are not. It would be difficult to identify and quantify the color of every candy in the jar if you’re unable to pour them out to individually sort through each one of them.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Jar of colorful candy on a table" src="https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=404&fit=crop&dpr=1 600w, https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=404&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=404&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=508&fit=crop&dpr=1 754w, https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=508&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/570447/original/file-20240120-27-59622g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=508&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Can you identify the color of every candy and count how many there are of each color without opening the jar?</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/round-candies-in-clear-glass-jar-with-clamp-lid-lW25Zxpkln8">Clem Onojeghuo/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p><a href="https://anggara.science">My lab</a> <a href="https://scholar.google.ca/citations?user=1SkTHegAAAAJ&hl=en">is confronting</a> this challenge by developing imaging technology that can analyze the structure of glycans by <a href="https://doi.org/10.1126/science.adh3856">imaging each individual molecule</a>. Essentially, we’re developing a technique to open the jar and study every single candy one at a time.</p>
<p>In the long run, my team aspires to unveil how these glycans present themselves to the proteins that recognize them and, finally, reveal the very language that cells use to express themselves.</p><img src="https://counter.theconversation.com/content/220278/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kelvin Anggara works for the Max Planck Institute for Solid State Research and receives funding from the European Research Council under Project GlycoX (101075996).</span></em></p>Sugar molecules called glycans cover the surface of all cells, acting as ID cards that broadcast what they are to the rest of the body.Kelvin Anggara, Group leader in Single molecule imaging, Max Planck Institute for Solid State ResearchLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2196162024-02-01T03:06:45Z2024-02-01T03:06:45ZHow does cancer spread to other parts of the body?<figure><img src="https://images.theconversation.com/files/572081/original/file-20240130-21-o3plxl.jpg?ixlib=rb-1.1.0&rect=0%2C399%2C3953%2C2950&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.pexels.com/photo/happy-asian-woman-suffering-from-cancer-near-window-6798572/">Pexels/Michelle Leman</a></span></figcaption></figure><p>All cancers begin in a single organ or tissue, such as the lungs or skin. When these cancers are confined in their original organ or tissue, they are generally more treatable. </p>
<p>But a cancer that spreads is much more dangerous, as the organs it spreads to may be vital organs. A skin cancer, for example, might spread to the brain. </p>
<p>This new growth makes the cancer much more challenging to treat, as it can be difficult to find all the new tumours. If a cancer can invade different organs or tissues, it can quickly become lethal. </p>
<p>When cancer spreads in this way, it’s called metastasis. Metastasis is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745820/">responsible for</a> the majority (67%) of cancer deaths. </p>
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Read more:
<a href="https://theconversation.com/cancer-evolution-is-mathematical-how-random-processes-and-epigenetics-can-explain-why-tumor-cells-shape-shift-metastasize-and-resist-treatments-199398">Cancer evolution is mathematical – how random processes and epigenetics can explain why tumor cells shape-shift, metastasize and resist treatments</a>
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<h2>Cells are supposed to stick to surrounding tissue</h2>
<p>Our bodies are made up of trillions of tiny cells. To keep us healthy, our bodies are constantly replacing old or damaged cells. </p>
<p>Each cell has a specific job and a set of instructions (DNA) that tells it what to do. However, sometimes DNA can get damaged. </p>
<p>This damage might change the instructions. A cell might now multiply uncontrollably, or lose a property known as adherence. This refers to how sticky a cell is, and how well it can cling to other surrounding cells and stay where it’s supposed to be. </p>
<p>If a cancer cell loses its adherence, it can break off from the original tumour and travel through the bloodstream or lymphatic system to almost anywhere. This is how metastasis happens. </p>
<p>Many of these travelling cancer cells will die, but some will settle in a new location and begin to form new cancers. </p>
<figure class="align-center ">
<img alt="Cancer cells" src="https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=336&fit=crop&dpr=1 600w, https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=336&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=336&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=422&fit=crop&dpr=1 754w, https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=422&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/572086/original/file-20240130-21-vribgm.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=422&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Some cells settle in a new location.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/3d-rendered-medically-accurate-illustration-cancer-1176407554">Scipro/Shutterstock</a></span>
</figcaption>
</figure>
<p>Particular cancers are more likely to metastasise to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381616/">particular organs</a> that help support their growth. Breast cancers commonly metastasise to the bones, liver, and lungs, while skin cancers like melanomas are more likely to end up in the brain and heart. </p>
<p>Unlike cancers which form in solid organs or tissues, blood cancers like leukaemia already move freely through the bloodstream, but <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722462/">can escape</a> to settle in other organs like the liver or brain.</p>
<h2>When do cancers metastasise?</h2>
<p>The longer a cancer grows, the more likely it is to metastasise. If not caught early, a patient’s cancer may have metastasised even before it’s initially diagnosed. </p>
<p>Metastasis can also occur after cancer treatment. This happens when cancer cells are dormant during treatment – drugs may not “see” those cells. These invisible cells can remain hidden in the body, only to wake up and begin growing into a new cancer months or even years later. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-cancer-cells-move-and-metastasize-is-influenced-by-the-fluids-surrounding-them-understanding-how-tumors-migrate-can-help-stop-their-spread-195792">How cancer cells move and metastasize is influenced by the fluids surrounding them – understanding how tumors migrate can help stop their spread</a>
</strong>
</em>
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<hr>
<p>For patients who already have cancer metastases at diagnosis, identifying the location of the original tumour – called the “primary site” – is important. A cancer that began in the breast but has spread to the liver will probably still behave like a breast cancer, and so will respond best to an anti-breast cancer therapy, and not anti-liver cancer therapy. </p>
<p>As metastases can sometimes grow faster than the original tumour, it’s not always easy to tell which tumour came first. These cancers are called “cancers of unknown primary” and are the <a href="https://www.canceraustralia.gov.au/cancer-types/unknown-primary-cancer/statistics">11th most commonly diagnosed cancers in Australia</a>. </p>
<p>One way to improve the treatment of metastatic cancer is to improve our ways of detecting and identifying cancers, to ensure patients receive the most effective drugs for their cancer type. </p>
<h2>What increases the chances of metastasis and how can it be prevented?</h2>
<p>If left untreated, most cancers will eventually acquire the ability to metastasise.</p>
<p>While there are currently no interventions that specifically prevent metastasis, cancer patients who have their tumours surgically removed may also be given chemotherapy (or other drugs) to try and weed out any hidden cancer cells still floating around. </p>
<p>The best way to prevent metastasis is to diagnose and treat cancers early. Cancer screening initiatives such as Australia’s <a href="https://www.health.gov.au/our-work/national-cervical-screening-program">cervical</a>, <a href="https://www.health.gov.au/our-work/national-bowel-cancer-screening-program">bowel</a>, and <a href="https://www.health.gov.au/our-work/breastscreen-australia-program">breast</a> cancer screening programs are excellent ways to detect cancers early and reduce the chances of metastasis. </p>
<figure class="align-center ">
<img alt="Older woman has mammogram" src="https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=357&fit=crop&dpr=1 600w, https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=357&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=357&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=449&fit=crop&dpr=1 754w, https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=449&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/572089/original/file-20240130-29-3al4c0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=449&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The best way to prevent cancer spreading is to diagnose and treat them early.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/senior-woman-having-mammography-scan-hospital-1334759717">Peakstock/Shutterstock</a></span>
</figcaption>
</figure>
<p>New screening programs to detect cancers early are being researched for many types of cancer. Some of these are simple: CT scans of the body to look for any potential tumours, such as in England’s new <a href="https://theconversation.com/how-englands-new-lung-cancer-screening-could-save-thousands-of-lives-expert-qanda-208867">lung cancer screening program</a>. </p>
<p>Using artificial intelligence (AI) to help examine patient scans is also <a href="https://theconversation.com/ai-can-help-detect-breast-cancer-but-we-dont-yet-know-if-it-can-improve-survival-rates-210800">possible</a>, which might identify new patterns that suggest a cancer is present, and improve cancer detection from these programs. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/ai-can-help-detect-breast-cancer-but-we-dont-yet-know-if-it-can-improve-survival-rates-210800">AI can help detect breast cancer. But we don't yet know if it can improve survival rates</a>
</strong>
</em>
</p>
<hr>
<p>More advanced screening methods are also in development. The United States government’s Cancer Moonshot program is currently funding research into blood tests that could detect <a href="https://theconversation.com/a-blood-test-that-screens-for-multiple-cancers-at-once-promises-to-boost-early-detection-191728">many types of cancer at early stages</a>. </p>
<p>One day there might even be a RAT-type test for cancer, like there is for COVID.</p>
<h2>Will we be able to prevent metastasis in the future?</h2>
<p>Understanding how metastasis occurs allows us to figure out new ways to prevent it. One idea is to <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2019/breast-cancer-chemotherapy-sensitizing-dormant-cells">target dormant cancer cells</a> and prevent them from waking up. </p>
<p>Directly preventing metastasis with drugs is not yet possible. But there is hope that as research efforts continue to improve cancer therapies, they will also be more effective at treating metastatic cancers. </p>
<p>For now, early detection is the best way to ensure a patient can beat their cancer.</p><img src="https://counter.theconversation.com/content/219616/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sarah Diepstraten receives funding from the Victorian Cancer Agency. </span></em></p><p class="fine-print"><em><span>John (Eddie) La Marca is also affiliated with the Olivia Newton John Cancer Research Institute.</span></em></p>A cancer that spreads is much more dangerous. Here’s why – and how it happens.Sarah Diepstraten, Senior Research Officer, Blood Cells and Blood Cancer Division, Walter and Eliza Hall InstituteJohn (Eddie) La Marca, Senior Resarch Officer, Walter and Eliza Hall InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2157652024-01-11T17:23:58Z2024-01-11T17:23:58ZHow much life has ever existed on Earth?<figure><img src="https://images.theconversation.com/files/567152/original/file-20231221-25-fybvl8.jpg?ixlib=rb-1.1.0&rect=0%2C5%2C3619%2C2197&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">In primary production, inorganic carbon is used to build the organic molecules life needs. </span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/how-much-life-has-ever-existed-on-earth" width="100%" height="400"></iframe>
<p>All organisms are made of living cells. While it is difficult to pinpoint exactly when the first cells came to exist, geologists’ best estimates suggest at least as early as <a href="https://doi.org/10.1016/S0301-9268(00)00128-5">3.8 billion years ago</a>. But how much life has inhabited this planet since the first cell on Earth? And how much life will ever exist on Earth? </p>
<p>In our new study, published in <a href="https://doi.org/10.1016/j.cub.2023.09.040"><em>Current Biology</em></a>, my colleagues from the <a href="https://www.weizmann.ac.il/">Weizmann Institute of Science</a> and <a href="https://www.smith.edu/academics/geosciences">Smith College</a> and I took aim at these big questions.</p>
<h2>Carbon on Earth</h2>
<p>Every year, about 200 billion tons of carbon is taken up through what is known as primary production. During primary production, inorganic carbon — such as carbon dioxide in the atmosphere and bicarbonate in the ocean — is used for energy and to build the organic molecules life needs. </p>
<p>Today, the most notable contributor to this effort is <a href="https://doi.org/10.1038/nrm1525">oxygenic photosynthesis</a>, where sunlight and water are key ingredients. However, deciphering past rates of primary production has been a challenging task. In lieu of a time machine, scientists like myself rely on clues left in ancient sedimentary rocks to reconstruct past environments. </p>
<p>In the case of primary production, the isotopic composition of <a href="https://doi.org/10.1038/s41586-018-0349-y">oxygen</a> in the form of sulfate in ancient salt deposits allows for such estimates to be made. </p>
<p>In <a href="https://doi.org/10.1016/j.cub.2023.09.040">our study</a>, we compiled all previous estimates of ancient primary production derived through the method above, as well as many others. The outcome of this productivity census was that we were able to estimate that 100 quintillion (or 100 billion billion) tons of carbon has been through primary production since the origin of life. </p>
<p>Big numbers like this are difficult to picture; 100 quintillion tons of carbon is about 100 times the amount of carbon contained within the Earth, a pretty impressive feat for Earth’s primary producers. </p>
<h2>Primary production</h2>
<p>Today, primary production is mainly achieved by plants on land and marine micro-organisms such as algae and cyanobacteria. In the past, the proportion of these major contributors was very different; in the case of Earth’s earliest history, primary production was mainly conducted by an entirely different group of organisms that don’t rely on oxygenic photosynthesis to stay alive.</p>
<p>A combination of different techniques has been able to give a sense of when different primary producers were most active in Earth’s past. Examples of such techniques include identifying the <a href="https://doi.org/10.1016/j.cub.2021.07.038">oldest forests</a> or using molecular fossils called <a href="https://doi.org/10.1038/nature23457">biomarkers</a>. </p>
<p>In <a href="https://doi.org/10.1016/j.cub.2023.09.040">our study</a>, we used this information to explore what organisms have contributed the most to Earth’s historical primary production. We found that despite being late on the scene, land plants have likely contributed the most. However, it is also very plausible that cyanobacteria contributed the most.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="green hair-like strands of bacteria" src="https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=565&fit=crop&dpr=1 754w, https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=565&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/567163/original/file-20231221-21-1tcat1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=565&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Filamentous cyanobacteria from a tidal pond at Little Sippewissett salt marsh, Falmouth, Mass.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/argonne/26719316190">(Argonne National Laboratory)</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span>
</figcaption>
</figure>
<h2>Total life</h2>
<p>By determining how much primary production has ever occurred, and by identifying what organisms have been responsible for it, we were also able to estimate how much life has ever been on Earth. </p>
<p>Today, one may be able to approximate how many humans exist based on how much food is consumed. Similarly, we were able to calibrate a ratio of primary production to how many cells exist in the modern environment. </p>
<p>Despite the large variability in the number of cells per organism and the sizes of different cells, such complications become secondary since single-celled microbes dominate global cell populations. In the end, we were able to estimate that about 10<sup>30</sup> (10 noninillion) cells exist today, and that between 10<sup>39</sup> (a duodecillion) and 10<sup>40</sup> cells have ever existed on Earth. </p>
<h2>How much life will Earth ever have?</h2>
<p>Save for the ability to move Earth into the orbit of a younger star, the lifetime of Earth’s biosphere is limited. This morbid fact is a consequence of <a href="https://doi.org/10.1007/978-94-010-9633-1_4">our stars life cycle</a>. Since its birth, the sun has slowly been getting brighter over the past four and half billion years as hydrogen has been converted to helium in its core. </p>
<p>Far in the future, about two billion years from now, all of the biogeochemical fail-safes that keep Earth habitable will be pushed past their <a href="https://doi.org/10.1038/s41561-021-00693-5">limits</a>. First, land plants will die off, and then eventually the oceans will boil, and the Earth will return to a largely lifeless rocky planet as it was in its infancy. </p>
<p>But until then, how much life will Earth house over its entire habitable lifetime? Projecting our current levels of primary productivity forward, we estimated that about 10<sup>40</sup> cells will ever occupy the Earth. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="a blue planet in space" src="https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/567209/original/file-20231222-15-cdexst.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A planetary system 100 light-years away in the constellation Dorado is home to the first Earth-size habitable-zone planet, discovered by NASA’s Transiting Exoplanet Survey Satellite.</span>
<span class="attribution"><a class="source" href="https://images.nasa.gov/details/PIA23408">(NASA Goddard Space Flight Center)</a></span>
</figcaption>
</figure>
<h2>Earth as an exoplanet</h2>
<p>Only a few decades ago, exoplanets (planets orbiting other stars) were just a hypothesis. Now we are able to not only <a href="https://exoplanets.nasa.gov/">detect them</a>, but describe many aspects of thousands of far off worlds around distant stars. </p>
<p>But how does Earth compare to these bodies? In our new study, we have taken a birds eye view of life on Earth and have put forward Earth as a benchmark to compare other planets. </p>
<p>What I find truly interesting, however, is what could have happened in Earth’s past to produce a radically different trajectory and therefore a radically different amount of life that has been able to call Earth home. For example, what if oxygenic photosynthesis never took hold, or what if endosymbiosis never happened?</p>
<p>Answers to such questions are what will drive my laboratory at <a href="https://earthsci.carleton.ca/">Carleton University</a> over the coming years.</p><img src="https://counter.theconversation.com/content/215765/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Peter Crockford receives funding from the Canadian Natural Sciences and Engineering Research Council and Carleton University</span></em></p>Over two billion years from now, Earth will no longer be able to sustain life. A new study looks at how much life has ever existed and what this means for the discovery of new life-supporting planets.Peter Crockford, Assistant Professor, Earth Sciences, Carleton UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2033242023-07-20T12:30:22Z2023-07-20T12:30:22ZZooming across time and space simultaneously with superresolution to understand how cells divide<figure><img src="https://images.theconversation.com/files/531154/original/file-20230609-17-rkdph4.png?ixlib=rb-1.1.0&rect=8%2C0%2C1355%2C1245&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">This image of actin filaments in a cell was taken using a type of superresolution microscopy.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/SNa523">Xiaowei Zhuang, HHMI, Harvard University, and Nature Publishing Group/NIH via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p><a href="https://www.britannica.com/science/cell-biology/Cell-division-and-growth">Cell division</a>, or the process of how daughter cells emerge from a mother cell, is fundamental to biology. Every cell inherits the same protein and DNA building blocks that make up the cell it originally came from. Yet exactly how these molecular building blocks arrange themselves into new cells has remained a mystery. </p>
<p>Studying cell division requires simultaneously viewing nanometer-scale macromolecules like proteins and DNA all the way up to millimeter-scale populations of cells, and over a time frame that ranges from seconds to weeks. <a href="https://doi.org/10.1002%2F0471142301.ns0201s50">Previous microscopes</a> have been able to capture tiny objects only in short time frames, typically just tens of seconds. There hasn’t been a method that can examine a wide range of size and time scales all at once.</p>
<p>My team <a href="https://scholar.google.com/citations?user=kpr2nocAAAAJ&hl=en">and I</a> at the University of Michigan’s <a href="https://bioplasmonics.org/home.html">Bioplasmonics Group</a> developed a <a href="https://doi.org/10.1038/s41467-023-39624-w">new kind of superresolution imaging</a> that reveals previously unknown features of how cells divide.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration depiecting superresolution over time as an hourglass, where the bottom shows a protein and the top a dividing cell going from unresolved to resolved" src="https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This hourglass depicts the process of superresolution over time, where the bottom shows a protein and the top a dividing cell going from unresolved, at left, to resolved, at right.</span>
<span class="attribution"><span class="source">Somin Lee</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Advancing superresolution imaging</h2>
<p>It wasn’t possible to view cells at the molecular level until recently with the <a href="https://www.nobelprize.org/prizes/chemistry/2014/press-release/">2014 Nobel Prize-winning</a> development of superresolution. </p>
<p>Traditional light microscopes <a href="https://courses.lumenlearning.com/suny-physics/chapter/27-6-limits-of-resolution-the-rayleigh-criterion/">blur very small objects</a> that are close together in a sample, because light spreads out as it moves through space. With superresolution, fluorescent probes attached to the sample could be switched on and off like twinkling stars on a clear night. By collecting and combining many images of these probes, a superresolution image can bring very small objects into view. Superresolution opened a whole new world in biology, revealing structures as small as 10 nanometers, which is about the size of a protein molecule. </p>
<p>However, the fluorescent probes that this technique relies on can quickly wear out. This limits its use in studying processes that take place over extended periods, such as cell division. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Two blue blobs, one at the bottom left and one at the top right, are separated by pink and blue specks on a black background." src="https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=276&fit=crop&dpr=1 600w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=276&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=276&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=347&fit=crop&dpr=1 754w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=347&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=347&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This PINE microscopy image shows cells dividing, their nuclei stained blue.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41467-023-39624-w">Somin Lee/Nature Communications</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>My research team and I have a developed a solution we call <a href="https://doi.org/10.1038/s41467-023-39624-w">PINE nanoscopy</a>. Instead of absorbing light as traditional fluorescent probes do, the probes we use scatter the light so they do not break down with repeated light exposure.</p>
<p>To resolve very small objects that are close together, we built filters made of thin layers of polymers and liquid crystals that allow for detection of scattered light, which triggers the probes to switch on and off. This allowed us to see nanometer-scale details of cells that would otherwise be blurred by traditional microscopes.</p>
<p>Remarkably, we found that these nanometer-scale details could be viewed for very long periods – over 250 hours. These details would typically be lost over time with traditional superresolution methods.</p>
<h2>Shedding new light on cell division</h2>
<p>We then applied our method to study how molecular building blocks organize in cell division. </p>
<p>We focused on a <a href="https://www.britannica.com/science/actin">protein called actin</a> that helps maintain cell structure, among many other functions. Actin is shaped like branching filaments, each about 7 nanometers (millionths of a millimeter) in diameter, that link together to span thousands of nanometers. Using PINE nanoscopy, we attached scattering probes to actin to visually follow human cells as they divided.</p>
<p>We made three observations on how actin building blocks organize during cell division. First, these molecular building blocks expand to increase their connections to their neighbors. Second, they also draw closer to their neighbors to increase their points of contact. And third, the resulting networks tend to contract when the actin molecules are more connected to one another and expand when they are less connected to one another.</p>
<p>Based on these findings, we were able to <a href="https://doi.org/10.1038/s41467-023-39624-w">discover new information</a> about the process of cell division. We found that interactions between actin building blocks sync up with the contraction and expansion of the whole cell during division. In other words, the behavior of the actin molecules is connected to the behavior of the cell: The cell contracts when the actin expands, and it expands when the actin contracts.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/J2_wdNT4KyM?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Superresolution microscopy won the 2014 Nobel Prize in chemistry.</span></figcaption>
</figure>
<h2>Uncovering disease with superresolution</h2>
<p>We plan to use our method to study how other molecular building blocks organize into tissues and organs. Like cells, tissues and organs are <a href="https://courses.lumenlearning.com/wm-biology2/chapter/levels-of-organization-of-living-things/">organized in a hierarchy</a> that can be examined from a scale of small to large. Examining the dynamic and complex process of how protein building blocks interact with one another to form larger structures could advance the future creation of new replacement tissues and organs, such as skin grafts. </p>
<p>We also plan to use our imaging technique to study how protein building blocks become disorganized in disease. Proteins organize into cells, cells organize into tissues and tissues organize into organs. A very small change in building blocks can <a href="https://www.ncbi.nlm.nih.gov/books/NBK9963/">disturb this organization</a>, with effects that can lead to diseases like cancer. Our technique could potentially help researchers visualize and, in turn, better understand how molecular defects in tissues and organs may develop into disease.</p><img src="https://counter.theconversation.com/content/203324/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Somin Lee receives funding from the Air Force of Scientific Research (AFOSR) and National Science Foundation (NSF). </span></em></p>Superresolution microscopy allowed researchers to view cells at the molecular level. Improvements on the technique can help study the building blocks of complex cell processes over time.Somin Lee, Assistant Professor of Electrical & Computer Engineering, Biomedical Engineering, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2020962023-07-06T12:27:34Z2023-07-06T12:27:34ZAging is complicated – a biologist explains why no two people or cells age the same way, and what this means for anti-aging interventions<figure><img src="https://images.theconversation.com/files/535886/original/file-20230705-16248-djnyz1.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">While some people may be older in chronological age, their biological age might be much younger.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/close-up-of-older-chinese-womans-eye-royalty-free-image/1082691656">FangXiaNuo/E+ via Getty Images</a></span></figcaption></figure><p>You likely know someone who seems to <a href="https://theconversation.com/are-you-a-rapid-ager-biological-age-is-a-better-health-indicator-than-the-number-of-years-youve-lived-but-its-tricky-to-measure-198849">age slowly</a>, appearing years younger than their birth date suggests. And you likely have seen the opposite – someone whose body and mind seem much more ravaged by time than others. Why do some people seem to glide though their golden years and others physiologically struggle in midlife? </p>
<p>I have <a href="https://scholar.google.com/citations?user=DDc-okgAAAAJ&hl=en">worked in the field of aging</a> for all of my scientific career, and I teach the cellular and molecular biology of aging at the University of Michigan. Aging research doesn’t tend to be about finding the one cure that fixes all that may ail you in old age. Instead, the last decade or two of work points to aging as a multi-factoral process – and no single intervention can stop it all.</p>
<h2>What is aging?</h2>
<p>There are many different definitions of aging, but scientists generally agree upon <a href="https://doi.org/10.1007/978-3-319-69892-2_29-1">some common features</a>: Aging is a time-dependent process that results in increased vulnerability to disease, injury and death. This process is both intrinsic, when your own body causes new problems, and extrinsic, when environmental insults damage your tissues.</p>
<p>Your body is comprised of <a href="https://medlineplus.gov/genetics/understanding/basics/cell/">trillions of cells</a>, and each one is not only responsible for one or more functions specific to the tissue it resides in, but must also do all the work of keeping itself alive. This includes metabolizing nutrients, getting rid of waste, exchanging signals with other cells and adapting to stress.</p>
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<figcaption><span class="caption">Aging results from a number of physiological factors.</span></figcaption>
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<p>The trouble is that every single process and component in each of your cells <a href="https://doi.org/10.1016/j.cell.2022.11.001">can be interrupted or damaged</a>. So your cells spend a lot of energy each day preventing, recognizing and fixing those problems. </p>
<p>Aging can be thought of as a gradual loss of the ability to <a href="https://doi.org/10.1113/JP275072">maintain homeostasis</a> – a state of balance among body systems – either by not being able to prevent or recognize damage and poor function, or by not adequately or rapidly fixing problems as they occur. Aging results from a combination of these issues. Decades of research has shown that nearly every cellular process becomes more impaired with age.</p>
<h2>Repairing DNA and recycling proteins</h2>
<p>Most research on cellular aging focuses on studying how DNA and proteins change with age. Scientists are also beginning to address the potential roles many other important biomolecules in the cell play in aging as well.</p>
<p>One of the cell’s chief jobs is to maintain its DNA – the instruction manual a cell’s machinery reads to produce specific proteins. DNA maintenance involves protecting against, and accurately repairing, damage to genetic material and the molecules binding to it. </p>
<p>Proteins are the workers of the cell. They perform chemical reactions, provide structural support, send and receive messages, hold and release energy, and much more. If the protein is damaged, the cell uses <a href="https://doi.org/10.1093/jnci/92.19.1564">mechanisms involving</a> <a href="https://theconversation.com/research-that-shines-light-on-how-cells-recover-from-threats-may-lead-to-new-insights-into-alzheimers-and-als-163210">special proteins</a> that either attempt to fix the broken protein or send it off for recycling. Similar mechanisms tuck proteins out of the way or destroy them when they are no longer needed. That way, its components can be used later to build a new protein.</p>
<h2>Aging disrupts a delicate biological network</h2>
<p>The cross-talk between the components inside cells, cells as a whole, organs and the environment is a complex and ever-changing network of information. </p>
<p>When all processes involved in creating and maintaining DNA and protein function are working normally, the different compartments within a cell serving specialized roles – <a href="https://www.genome.gov/genetics-glossary/Organelle">called organelles</a> – can maintain the cell’s health and function. For an organ to work well, the majority of the cells that make it up need to function well. And for a whole organism to survive and thrive, all of the organs in its body need to work well. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of cross-section of an animal cell and its organelles" src="https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=471&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Each organelle within a cell carries out specific functions.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/internal-structure-of-an-animal-cell-3d-rendering-royalty-free-image/1306045773">Jian Fan/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>Aging can lead to dysfunction at any of these levels, from the sub-cellular to the organismal. Maybe a <a href="https://doi.org/10.1016/j.arr.2020.101154">gene encoding an important protein for DNA repair</a> has become damaged, and now all of the other genes in the cell are more likely to be repaired incorrectly. Or perhaps the cell’s <a href="https://theconversation.com/cells-routinely-self-cannibalize-to-take-out-their-trash-aiding-in-survival-and-disease-prevention-199148">recycling systems</a> are unable to degrade dysfunctional components anymore. Even the <a href="https://doi.org/10.1016%2FS2213-8587(18)30026-3">communication systems</a> between cells, tissues and organs can become compromised, leaving the organism less able to respond to changes within the body. </p>
<p>Random chance can lead to a growing burden of molecular and cellular damage that is progressively less well-repaired over time. As this damage accumulates, the systems that are meant to fix it are accruing damage as well. This leads to a <a href="https://doi.org/10.1038%2Fs43587-021-00150-3">cycle of increasing wear and tear</a> as cells age.</p>
<h2>Anti-aging interventions</h2>
<p>The interdependence of life’s cellular processes is a double-edged sword: Sufficiently damage one process, and all the other processes that interact with or depend on it become impaired. However, this interconnection also means that bolstering one highly interconnected process could improve related functions as well. In fact, this is how the most successful anti-aging interventions work. </p>
<p>There is no silver bullet to stop aging, but certain interventions do seem to slow aging in the laboratory. While there are ongoing clinical trials investigating different approaches in people, most existing data comes from animals like nematodes, flies, mice and nonhuman primates. </p>
<p>One of the best studied interventions is <a href="https://doi.org/10.1126/science.abe7365">caloric restriction</a>, which involves reducing the amount of calories an animal would normally eat without depriving them of necessary nutrients. An FDA-approved drug used in organ transplantation and some cancer treatments <a href="https://doi.org/10.1007/s11357-020-00274-1">called rapamycin</a> seems to work by using at least a <a href="https://doi.org/10.1016/j.arr.2020.101240">subset of the same pathways</a> that calorie restriction activates in the cell. Both affect signaling hubs that direct the cell to preserve the biomolecules it has rather than growing and building new biomolecules. Over time, this cellular version of “reduce, reuse, recycle” removes damaged components and leaves behind a higher proportion of functional components.</p>
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<figcaption><span class="caption">The effects of calorie restriction on aging are still under study.</span></figcaption>
</figure>
<p>Other interventions include changing the <a href="https://theconversation.com/can-this-new-anti-ageing-supplement-turn-back-the-clock-126795">levels of certain metabolites</a>, selectively <a href="https://doi.org/10.1111%2Fjoim.13141">destroying senescent cells</a> that have stopped dividing, changing the <a href="https://theconversation.com/hangry-bacteria-in-your-gut-microbiome-are-linked-to-chronic-disease-feeding-them-what-they-need-could-lead-to-happier-cells-and-a-healthier-body-199486">gut microbiome</a> and <a href="https://doi.org/10.1111%2Facel.12338">behavioral modifications</a>.</p>
<p>What all of these interventions have in common is that they affect core processes that are critical for cellular homeostasis, often become dysregulated or dysfunctional with age and are connected to other cellular maintenance systems. Often, these processes are the central drivers for mechanisms that protect DNA and proteins in the body. </p>
<p>There is no single cause of aging. No two people age the same way, and indeed, neither do any two cells. There are countless ways for your basic biology to go wrong over time, and these add up to create a unique network of aging-related factors for each person that make finding a <a href="https://theconversation.com/despite-research-breakthroughs-an-anti-aging-pill-is-still-a-long-way-off-44949">one-size-fits-all anti-aging treatment</a> extremely challenging.</p>
<p>However, researching interventions that target multiple important cellular processes simultaneously could help improve and maintain health for a greater portion of life. These advances could help people live longer lives in the process.</p><img src="https://counter.theconversation.com/content/202096/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ellen Quarles does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Aging is a culmination of factors spanning from your cells to your environment. A number of interconnected processes determine how quickly your body is able to repair and recover from damage.Ellen Quarles, Assistant Professor in Molecular, Cellular, and Developmental Biology, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2083432023-06-27T12:24:42Z2023-06-27T12:24:42ZLab-grown meat techniques aren’t new – cell cultures are common tools in science, but bringing them up to scale to meet society’s demand for meat will require further development<figure><img src="https://images.theconversation.com/files/533777/original/file-20230623-15-zpv5wg.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cell cultures are often grown in petri dishes.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/barcoded-petri-dishes-royalty-free-image/478184231">Wladimir Bulgar/Science Photo Library via Getty Images</a></span></figcaption></figure><p>You might be old enough to remember the famous “<a href="https://www.yahoo.com/news/the-inside-story-of-wendys-wheres-the-beef-ad-140051010.html">Where’s the Beef?</a>” Wendy’s commercials. This question may be asked in a different context since <a href="https://apnews.com/article/cultivated-meat-lab-grown-cell-based-a88ab8e0241712b501aa191cdbf6b39a">U.S. regulators approved</a> the sale of lab-grown chicken meat made from cultivated cells in June 2023.</p>
<p>Growing animal cells in the lab isn’t new. Scientists have been culturing animal cells in artificial environments <a href="https://doi.org/10.1007/978-3-319-07758-1_3">since the 1950s</a>, initially focusing on studying developmental biology and cancer. This technique remains one of the major tools in life science research, especially for <a href="https://doi.org/10.1016%2Fj.jsps.2014.04.002">drug development</a>. </p>
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<figcaption><span class="caption">The USDA approved cell-cultivated chicken on June 21, 2023.</span></figcaption>
</figure>
<h2>What are cell cultures?</h2>
<p>Cell cultures are typically grown using either <a href="https://dx.doi.org/10.13070/mm.en.3.175">natural or artificial growth media</a>. Natural media comprise naturally-derived biological fluids, whereas artificial media comprise both organic and inorganic nutrients and compounds. Both contain the necessary ingredients to foster the growth and development of cells. These ingredients typically contain nutrients such as vitamins, carbohydrates, amino acids and other molecules that provide the fuel for cells to grow and multiply.</p>
<p>Researchers use cells grown using tissue culture to answer a <a href="https://doi.org/10.1016%2Fj.jsps.2014.04.002">variety of experimental questions</a>. <a href="https://scholar.google.com/citations?user=zLwzHqcAAAAJ&hl=en">As a biochemist</a>, I use plant tissue culture techniques in my courses and research program. Researchers can add viruses, bacteria, fungi, hormones, vitamins and other pathogens or compounds to cells grown in culture to observe how different factors affect the cells’ behavior or function, especially as it relates to which genes are turned on or off in the cell and which proteins respond to those pathogens or compounds. </p>
<p>In <a href="https://theconversation.com/from-the-research-lab-to-your-doctors-office-heres-what-happens-in-phase-1-2-3-drug-trials-138197">drug development</a>, growing cells in culture is usually the first step before potential drug candidates can be tested in animals.</p>
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<figcaption><span class="caption">Cell cultures involve growing cells outside of their native environment.</span></figcaption>
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<h2>How is lab-grown meat made?</h2>
<p>Researchers use similar techniques to <a href="https://thehumaneleague.org/article/lab-grown-meat">grow meat in the lab</a>. The process can generally be broken down into <a href="https://www.youtube.com/watch?v=u468xY1T8fw">three major steps</a>. </p>
<p>The first step involves removing a small number of cells – typically muscle or stem cells – from an animal during a harmless and painless procedure. <a href="https://theconversation.com/triggering-cancer-cells-to-become-normal-cells-how-stem-cell-therapies-can-provide-new-ways-to-stop-tumors-from-spreading-or-growing-back-191559">Stem cells</a> are cells from an organism that are not specialized and can be manipulated in the lab to turn into the many different types of cells of that organism.</p>
<p>The next step is culturing the cells. The cells are placed in an artificial environment favorable to their growth. Because of the large amount of cells that have to be grown to produce meat, the cells are incubated <a href="https://www.engr.colostate.edu/CBE101/topics/bioreactors.html">in a bioreactor</a> – a steel tank that provides controlled temperature, humidity, pressure and sterile conditions – with the appropriate medium to facilitate growth. The growth media are changed a number of times to encourage the cells to differentiate and multiply into the three major components of meat: muscle, fat and connective tissue. </p>
<p>In last step of the process, known as scaffolding, the cells are organized and packed tightly together to create the desired size, shape and cut of meat for consumption. </p>
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<figcaption><span class="caption">Making cultured meat has seen lots of progress in the lab, but there is still a long way to go.</span></figcaption>
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<h2>Pros and cons of cultured meat</h2>
<p>There are pros and cons to growing meat through cell culture techniques. While cultured meat may produce relatively less greenhouse gas than conventional livestock production in <a href="https://doi.org/10.1038/s43016-020-0112-z">certain conditions</a>, researchers <a href="https://doi.org/10.3389/fsufs.2019.00005">need to refine the process</a> before it can be cost-efficient and brought to scale. </p>
<p>A 2021 analysis estimated that lab-grown meat will <a href="https://doi.org/10.1002/bit.27848">cost US$17 to $23 per pound</a> to produce, and that does not include grocery store markups. In comparison, conventionally grown ground beef typically costs <a href="https://www.bls.gov/regions/mid-atlantic/data/averageretailfoodandenergyprices_usandmidwest_table.htm">a little under $5 per pound</a>. </p>
<p>A 2021 <a href="https://www.mckinsey.com/industries/agriculture/our-insights/cultivated-meat-out-of-the-lab-into-the-frying-pan">McKinsey report</a> estimates that it will take approximately <a href="https://www.greenbiz.com/article/lab-meat-has-3-big-problems-it-time-pivot">220 million to 440 million liters of bioreactor capacity</a> to meet 1% of current protein market share, but current bioreactor capacity tops out at 200 million liters. There are also concerns about the biological limitations of growing large numbers of various cell types in the same bioreactor.</p>
<p>Lab-grown meat may <a href="https://theconversation.com/no-animal-required-but-would-people-eat-artificial-meat-72372">improve animal welfare</a> and be less likely to carry disease or cause food-borne illnesses. However, consumers may also perceive lab-grown meat to be unnatural or have concerns about its taste.</p>
<p>Companies are likely paying attention and adapting to the public’s response. To put things in perspective, the <a href="https://www.forbes.com/sites/lanabandoim/2022/03/08/making-meat-affordable-progress-since-the-330000-lab-grown-burger/?sh=523ac7c24667">first lab-grown burger</a> cost $330,000 to create in 2013. The price has fallen to just under $10 per burger today, which is remarkable progress in just a decade.</p><img src="https://counter.theconversation.com/content/208343/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>André O. Hudson receives funding from the National Institutes of Health </span></em></p>Cell cultures are common tools in biology and drug development. Bringing them up to scale to meet the meat needs of societies will require further development.André O. Hudson, Dean of the College of Science, Professor of Biochemistry, Rochester Institute of TechnologyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2034952023-05-03T12:10:09Z2023-05-03T12:10:09ZHow do ‘Candida auris’ and other fungi develop drug resistance? A microbiologist explains<figure><img src="https://images.theconversation.com/files/523473/original/file-20230428-18-9slhum.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2073%2C1368&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Candidiasis is a severe fungal infection that can spread easily in medical facilities.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/8ysD2e">Atlas of Pulmonary Pathology/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>One of the scariest things you can be told when at a doctor’s office is “You have an antimicrobial-resistant infection.” That means the bacteria or fungus making you sick can’t be easily killed with common antibiotics or antifungals, making treatment more challenging. You might have to take a combination of drugs for weeks to overcome the infection, which could result in more severe side effects.</p>
<p>Unfortunately, this diagnosis is <a href="https://www.who.int/publications/i/item/9789240062702">becoming more common around the world</a>.</p>
<p>The yeast <em><a href="https://doi.org/10.1128/jcm.01588-17">Candida auris</a></em> has recently emerged as a potentially dangerous fungal infection for hospital patients and nursing home residents. First <a href="https://doi.org/10.3947%2Fic.2022.0008">discovered in the late 2000s</a>, <em>Candida auris</em> has very quickly become a <a href="https://doi.org/10.3390/microorganisms9040807">major health challenge</a> due to its ease of spread and ability to resist common antifungal drugs.</p>
<p>How did this fungus become so strong, and what can researchers and physicians do to combat it? </p>
<p><a href="https://scholar.google.com/citations?user=U69z9VsAAAAJ&hl=en&oi=ao">I am a microbiologist</a> researching new ways to kill fungi. <em>Candida auris</em> and other fungi use three common cellular tricks to overcome treatments. Luckily, exciting new research hints at ways we can still fight this fungus.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/VOn5Udfx7eQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Drug-resistant <em>Candida auris</em> infections are on the rise in the U.S. and around the world.</span></figcaption>
</figure>
<h2>Targeting the sensitive parts of fungal cells</h2>
<p>Fungal cells contain a structure called a <a href="https://doi.org/10.1128/microbiolspec.funk-0035-2016">cell wall</a> that helps maintain their shape and protects them from the environment. Fungal cell walls are constructed in part from several different types of polysaccharides, which are long strings of sugar molecules linked together. </p>
<p>Two polysaccharides found in almost all fungal cell walls are <a href="https://doi.org/10.1016/j.mib.2010.05.002">chitin</a> and <a href="https://doi.org/10.1016/j.tcsw.2019.100022">beta-glucan</a>. The fungal cell wall is an attractive target for drugs because human cells do not have a cell wall, so drugs that block chitin and beta-glucan production will have fewer side effects. </p>
<p>Some of the most common drugs used to treat fungal infections are called <a href="https://doi.org/10.4103%2F0253-7613.62396">echinocandins</a>. These drugs stop fungal cells from making beta-glucan, which significantly weakens their cell wall. This means the fungal cell can’t maintain its shape well. While the fungus is struggling to grow or is breaking apart, your immune system has a much better chance of fighting off the infection. </p>
<h2>How fungi become drug resistant</h2>
<p>Unfortunately, some strains of <em>Candida auris</em> are resistant to echinocandin treatment. But how does the fungus actually do it? For decades, scientists have been studying how fungi overcome drugs designed to weaken or kill them. In the case of echinocandins, <em>Candida auris</em> commonly uses three tricks to beat these treatments: <a href="https://doi.org/10.1128/AAC.00238-18">hide</a>, <a href="https://doi.org/10.1101%2Fcshperspect.a019752">build</a> and <a href="https://doi.org/10.3389/fmicb.2019.02573">change</a>. </p>
<p>The first trick is to hide in a complex mixture of sugars, proteins, DNA and cells <a href="https://doi.org/10.1128/msphere.00458-19">called a biofilm</a>. Made with irregular 3D structures, biofilms have lots of places for cells to hide. Drugs aren’t good at penetrating biofilms, so they can’t access and kill cells deep inside. Biofilms are especially problematic when they <a href="https://doi.org/10.3390/antibiotics4010001">grow on</a> <a href="https://doi.org/10.2147/ijn.s353071">medical equipment</a> like ventilators or catheters. Once free of a biofilm, cells that have gained the ability to resist the drugs a patient was taking become more dangerous.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of two types of Candida attaching to each other" src="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=300&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=300&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=300&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=377&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=377&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=377&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This image shows <em>Candida albicans</em> (red) producing branching filaments that allow it to attach to <em>Candida glabrata</em> (green), forming biofilms. Both of these species can cause infections in people.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/HE7JbY">Edgerton Lab, State University of New York at Buffalo/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>The second trick fungi use to evade treatment is to build cell walls differently. Fungal cells treated with echinocandins can’t make beta-glucan. So instead, they start to <a href="https://doi.org/10.3109/13693786.2011.577104">make more chitin</a>, another important polysaccharide in the fungal cell wall. Echinocandins are unable to stop chitin production, so the fungus is still able to build a strong cell wall and avoid being killed. While there are some drugs that can <a href="https://doi.org/10.3390/jof6040261">stop chitin production</a>, none are currently approved for use in people. </p>
<p>The third trick fungi rely on is to <a href="https://doi.org/10.3389/fmicb.2019.02788">change the shape of the</a> <a href="https://doi.org/10.1093/cid/civ791">beta-glucan production enzyme</a> so echinocandins cannot block it. These mutations allow beta-glucan production to continue even in the presence of the drug. It is not surprising that <em>Candida</em> uses this trick to resist antifungal drugs since it is <a href="https://doi.org/10.1111%2Fnyas.12831">very effective</a> at keeping the cells alive. </p>
<h2>New tactics to fight fungi</h2>
<p>What can be done to treat echinocandin-resistant fungal infections? Thankfully, scientists and physicians are researching new ways to kill <em>Candida auris</em> and similar fungi. </p>
<p>The first approach is to find new drugs. For example, there are two drugs in development, <a href="https://doi.org/10.3390/antibiotics9050227">rezafungin</a> and <a href="https://doi.org/10.4155%2Ffmc-2018-0465">ibrexafungerp</a>, that appear to be able to stop beta-glucan production even in fungi resistant to echinocandins. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of budding yeast cells" src="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This microscopy image shows budding yeast cells.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/budding-yeast-cell-in-gram-stain-royalty-free-image/1464904014">toeytoey2530/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>A complementary approach my research group is exploring is whether a class of enzymes called <a href="https://doi.org/10.1007/s11274-016-2068-6">glycoside hydrolases</a> might also be able to combat drug-resistant fungi. Some of these enzymes actively destroy the fungal cell wall, breaking apart both beta-glucan and chitin at the same time, which could potentially help prevent fungi from surviving on medical equipment or on hospital surfaces.</p>
<p>My lab’s work on discovering enzymes that strongly degrade fungal cell walls is part of a new strategy to combat antifungal resistance that uses a combination of approaches to kill fungi. But the end goal of this research is the same: having a physician tell you, “You’ve got a fungal infection, but we have a good treatment for it now.”</p><img src="https://counter.theconversation.com/content/203495/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeffrey Gardner receives funding from the National Science Foundation (NSF) and the National Institutes of Health (NIH).</span></em></p>Multidrug-resistant fungal infections are an emerging global health threat. Figuring out how fungi evade treatments offers new avenues to counter resistance.Jeffrey Gardner, Associate Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1911552023-03-06T13:34:47Z2023-03-06T13:34:47ZHow does RNA know where to go in the city of the cell? Using cellular ZIP codes and postal carrier routes<figure><img src="https://images.theconversation.com/files/510384/original/file-20230215-22-fap759.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2309%2C1299&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cells move their genetic material from one place to another in the form of RNA.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/ribonucleic-acid-strand-illustration-royalty-free-illustration/1395711573">Christoph Burgstedt/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Before 2020, when my friends and acquaintances asked me what I study <a href="https://scholar.google.com/citations?user=P6al_I8AAAAJ&hl=en">as a molecular biologist</a>, their eyes would inevitably glaze over as soon as I said “RNA.” Now, as the COVID-19 pandemic has shown the power and promise of this molecule to the world at large, their eyes widen. </p>
<p>Despite growing recognition of the importance of RNA, how these molecules get to where they need to be within cells remains largely a mystery.</p>
<p><a href="https://www.genome.gov/genetics-glossary/RNA-Ribonucleic-Acid">RNA</a> is a chemical cousin of DNA. It plays many roles in the cell, but perhaps it’s most well-known as the relay messenger of genetic information. RNA takes a copy of the information in DNA from its storehouse in the nucleus to sites in the cell where this information is decoded to create the building blocks – <a href="https://www.genome.gov/genetics-glossary/Protein">proteins</a> – that make cells what they are. This transport process is <a href="https://doi.org/10.1016/0092-8674(91)90137-N">critical for animal development</a>, and its dysfunction is linked to a variety of <a href="https://doi.org/10.1523/JNEUROSCI.2352-16.2016">genetic diseases in people</a>. </p>
<p>In some ways, cells are like cities, with proteins carrying out specific functions in the “districts” they occupy. Having the right components at the right time and place is essential.</p>
<p>For example, it makes little sense to put a high-security vault in the fashion district. Instead, it needs to be in the financial district, where there are tellers to fill it with currency. Similarly, proteins devoted to energy production for the cell are most functional not when they are confined to the nucleus but when they are in the cell’s power plant, the mitochondria, surrounded by the raw materials and accessories needed for their job.</p>
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<figcaption><span class="caption">The inside of a cell is much like a city.</span></figcaption>
</figure>
<p>So how do cells ensure the millions of proteins they contain are where they are supposed to be? One way is as simple as it sounds: transport them directly. However, every transport step costs energy. Dragging a heavy vault across town isn’t easy. An alternative strategy is to instead take the instructions for making the vault directly to the bank so it’s already in the correct location immediately after construction. </p>
<p>The instructions for making a given protein are contained within RNA. One way to ensure proteins are where they are supposed to be is to transport their RNA blueprint to where their specific functions are needed. But how does RNA get where it needs to be?</p>
<p>My research team focuses on this very question: What are the molecular mechanisms that control RNA transport? Our recently published research hints that some of the <a href="https://doi.org/10.1093/nar/gkac763">molecular language</a> governing this process may be universal <a href="https://doi.org/10.7554/eLife.80040">across all cell types</a>.</p>
<h2>The molecular language of RNA transport</h2>
<p>For a handful of mRNAs – or RNA sequences coding for specific proteins – researchers have an idea about how they’re transported. They often contain a particular string of <a href="https://www.genome.gov/genetics-glossary/Nucleotide">nucleotides</a>, the chemical building blocks that make up RNA, that tell cells about their desired destination. These sequences of nucleotides, or what scientists refer to as RNA “<a href="https://doi.org/10.1111/tra.12730">ZIP codes</a>,” are recognized by proteins that act like mail carriers and deliver the RNAs to where they are supposed to go.</p>
<p>My team and I set out to discover new ZIP codes that <a href="https://doi.org/10.1093/nar/gkac763">send RNAs to neurites</a>, the precursors to the axons and dendrites on neurons that transmit and receive electrical signals. We reasoned that these ZIP codes must lie somewhere within the thousands of nucleotides that make up the RNAs in neurites. But how could we find our ZIP code needle in the RNA haystack?</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/hr8-ZWmVG0Y?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Neurites are long, thin branches extending from the body of a neuron.</span></figcaption>
</figure>
<p>We started by breaking eight mouse neurite-localized RNAs into about 10,000 smaller chunks, each about 250 nucleotides long. We then appended each of these chunks to an unrelated firefly RNA that mouse cells are unlikely to recognize, and watched for chunks that caused the firefly RNA to be transported to neurites. To extend the mail analogy, we took 10,000 blank envelopes (firefly RNAs) and wrote a different ZIP code (pieces of neurite-localized RNA) on each one. By observing which envelopes were delivered to neurites, we were able to discover many new neurite ZIP codes.</p>
<p>We still didn’t know the identity of the protein that acted as the “mail carrier,” however. To figure this out, we purified RNAs containing the newly identified ZIP codes and observed what proteins were purified along with them. The idea was to catch the mail carrier in the act of transport while bound to its target RNA.</p>
<p>We found that one protein that regulates neurite production, named <a href="https://doi.org/10.1101%2Fgad.258483.115">Unkempt</a>, repeatedly appeared with ZIP code-containing RNAs. When we depleted cells of Unkempt, the ZIP codes were no longer able to direct RNA transport to neurites, implicating Unkempt as the “mail carrier” that delivered these RNAs.</p>
<h2>Toward a universal language</h2>
<p>With this work, we identified ZIP codes that sent RNAs to neurites (in our analogy, the bank). But where would an RNA containing one of these ZIP codes end up if it were in a cell that didn’t have neurites (a city that didn’t have a bank)? </p>
<p>To answer this, we looked at where RNAs were in a <a href="https://doi.org/10.7554/eLife.80040">completely different cell type, epithelial cells</a> that line the body’s organs. Interestingly, the same ZIP codes that sent RNAs to neurites sent them to the bottom of epithelial cells. This time we identified another mail carrier, a protein called LARP1, responsible for the transport of RNAs containing a particular ZIP code to both neurites and the bottom end of epithelial cells.</p>
<p>How could one ZIP code and mail carrier transport an RNA to two different locations in two very different cells? It turns out that both of these cell types contain structures called microtubules that are oriented in a very particular way. Microtubules can be thought of as cellular streets that serve as tracks to transport a variety of cargo in the cell. Importantly, these microtubules are polarized, meaning they have ingrained “plus” and “minus” ends. Cargo can therefore be transported in specific directions by targeting to one of these ends.</p>
<figure>
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<figcaption><span class="caption">Microtubules are the roads proteins called kinesin use to transport materials from one cellular location to another.</span></figcaption>
</figure>
<p>In neurons, microtubules stretch through to and have their plus ends at the neurite tip. In epithelial cells, microtubules run from top to bottom, with their plus ends toward the bottom. Given that both of these locations are associated with the plus ends of microtubules, is that why we saw one ZIP code direct RNAs to both of these areas?</p>
<p>To test this, we inhibited the cell’s ability to transport cargo to the plus end of microtubules and monitored whether our ZIP code-containing RNAs were delivered. We found that these RNAs made it to neither the neurites in neurons nor to the bottom end of epithelial cells. This confirmed the role of microtubules in the transport of RNAs containing these particular ZIP codes. Rather than directing RNA to go to specific locations in the cell, these ZIP codes direct RNA to go to the plus ends of microtubules, wherever that might be in a given cell type.</p>
<p>We could compare this process to a mailing address. While the top line (“The Bank”) tells us the name of the building, it’s really the address and street name (“150 Maple Street”) that contains actionable information for the mail carrier. These RNA ZIP codes send RNAs to specific places along microtubule streets, not to specific structures in the cell. This allows for a more flexible yet uniform code, as not all cells share the same structures.</p>
<h2>Moving mRNA into the clinic</h2>
<p>Our research uncovers a new piece of how ZIP code sequences and proteins work together to get RNAs where they need to be. Our findings and methods can also be generalized to discover other new facets of the genetic ZIP code that direct RNAs to other locations in the cell.</p>
<p>Understanding how ZIP code sequences work can help researchers design RNAs that deliver their payload instructions to precise locations in the cell. Given the <a href="https://doi.org/10.1016/j.biotechadv.2020.107534">growing promise of RNA-based therapeutics</a>, ranging from vaccines to cancer therapies, knowing how to make an RNA go from point A to point B is more important than ever.</p><img src="https://counter.theconversation.com/content/191155/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Matthew Taliaferro receives funding from the National Institutes of Health and the W.M. Keck Foundation. </span></em></p>Making sure RNA molecules are in the right place at the right time in a cell is critical to development and normal function. Researchers are figuring out exactly how they get to where they need to go.Matthew Taliaferro, Assistant Professor of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1978802023-02-20T13:19:21Z2023-02-20T13:19:21ZWere viruses around on Earth before living cells emerged? A microbiologist explains<figure><img src="https://images.theconversation.com/files/507461/original/file-20230131-26-ml6jvg.jpg?ixlib=rb-1.1.0&rect=0%2C3%2C2305%2C1292&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Maybe the first life on Earth was part of an 'RNA world.'</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/molecule-illustration-royalty-free-illustration/1359392488">Artur Plawgo/Science Photo Library via Getty Images</a></span></figcaption></figure><figure class="align-left ">
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<p><em><a href="https://theconversation.com/us/topics/curious-kids-us-74795">Curious Kids</a> is a series for children of all ages. If you have a question you’d like an expert to answer, send it to <a href="mailto:curiouskidsus@theconversation.com">curiouskidsus@theconversation.com</a>.</em></p>
<hr>
<blockquote>
<p><strong>Were there already viruses on Earth when the first living cells appeared billions of years ago? – Aayush A., age 16, India</strong></p>
</blockquote>
<p>How life on Earth started has puzzled scientists for a long time. And it still does.</p>
<p>Fossils provide very important evidence about the evolution of plants and animals. Unfortunately, there are <a href="https://ucmp.berkeley.edu/bacteria/bacteriafr.html">very few fossils of ancient microbes available</a>, so scientists rely on modern microbes to devise theories about how life started. I studied bacteria and another type of microbe called archaea from hot environments <a href="https://scholar.google.com/citations?user=pN5i54IAAAAJ&hl=en">for many years</a> to learn how they might have evolved on early Earth, but I still have so many unanswered questions.</p>
<p>Based on the fossil evidence we have, single-celled microbes appeared on Earth before larger cellular life like plants and animals. But which kinds of microbes were the very first kind of life?</p>
<figure>
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<figcaption><span class="caption">Some scientists think hydrothermal vents are the cradle of early life on Earth.</span></figcaption>
</figure>
<h2>Which microbes are considered alive?</h2>
<p>Microbes are living, single-celled creatures surrounded by a membrane. They consume and convert nutrients into biological molecules or energy and are too small to be seen without a microscope.</p>
<p>By this definition, bacteria, archaea and single-celled eukaryotes are microbes. <a href="https://bio.libretexts.org/Courses/University_of_California_Davis/BIS_2A%3A_Introductory_Biology_(Easlon)/Readings/02.2%3A_Bacterial_and_Archaeal_Diversity">Bacteria and archaea</a> are single-celled creatures that lack internal membrane-enclosed structures, like a nucleus to hold their genetic material. Single-celled eukaryotes have a nucleus and may have other membrane-enclosed structures.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram comparing a eukaryotic and prokaryotic cell" src="https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1131&fit=crop&dpr=1 754w, https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1131&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/507680/original/file-20230201-8834-kxai71.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1131&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Unlike prokaryotic cells, eukaryotic cells have membrane-enclosed structures like a nucleus and mitochondria.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/eukaryotic-vs-prokaryotic-cells-educational-royalty-free-illustration/1201105509">VectorMine/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>Some scientists <a href="https://www.genome.gov/genetics-glossary/Virus">consider viruses</a> to be microbes made of genetic material enclosed in a protein coat. They are unable to replicate on their own and hijack the machinery of other cells to make copies of themselves. Because they don’t have many <a href="https://www.khanacademy.org/test-prep/mcat/cells/viruses/a/are-viruses-dead-or-alive">features of living cells</a>, they are <a href="https://microbiologysociety.org/publication/past-issues/what-is-life/article/are-viruses-alive-what-is-life.html">not technically alive</a>.</p>
<h2>Evidence for early life on Earth</h2>
<p>Fossils can provide scientists with clues as to when life started, but they best record hard things like bones and teeth. Microbes are made of soft materials that do not fossilize well. However, some live together in very large groups of cells that can accumulate minerals and leave behind quite large fossils. </p>
<p>For example, cyanobacteria formed large structures called <a href="https://theconversation.com/ancient-microbial-life-used-arsenic-to-thrive-in-a-world-without-oxygen-146533">stromatolites</a> in the oceans of early Earth. Scientists have found fossil stromatolites that date back to <a href="https://www.sciencedaily.com/releases/2022/11/221107135817.htm">3.48 billion years ago</a>.</p>
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<a href="https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Stromatolites near a river" src="https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/510650/original/file-20230216-759-docyl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Stromatolites can provide information about life on early Earth.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/stromatolites-found-by-the-ottawa-river-rock-royalty-free-image/1176691303">Jana Kriz/Moment via Getty Images</a></span>
</figcaption>
</figure>
<p>Other scientists found what they believe are <a href="https://www.the-scientist.com/news-opinion/microbial-fossils-found-in-3-4-billion-year-old-subseafloor-rock-68975">fossilized archaea</a> in rocks from a 3.4 billion-year-old hot seafloor. The Earth became habitable about 4 billion years ago, so bacteria and archaea must have appeared between 3.5 billion and 4 billion years ago.</p>
<p>Looking at the chemical reactions that cells carry out can also provide clues. The reactions that make biological molecules and generate energy make up what’s called the cell’s metabolism. Scientists have found evidence that some metabolic reactions were occurring at least <a href="https://newsroom.ucla.edu/releases/life-on-earth-likely-started-at-least-4-1-billion-years-ago-much-earlier-than-scientists-had-thought">4.1 billion years ago</a>. These reactions may have been occurring on their own <a href="https://news.ncbs.res.in/research/unravelling-origin-life">before cells had evolved</a>, perhaps on the surfaces of <a href="https://doi.org/10.3390/life11080795">clays or minerals</a>.</p>
<h2>Theories about how life started on Earth</h2>
<p>Cells copy their genetic material, made of DNA and RNA, to pass it on to new generations. Although DNA is the form of genetic material most living organisms use today, some scientists believe that RNA was the <a href="https://news.ncbs.res.in/research/unravelling-origin-life">first information storage molecule</a> on early Earth because it can make copies of itself. </p>
<p>Because some modern viruses use RNA to store genetic information, some scientists believe that viruses could have <a href="https://doi.org/10.1016/j.biochi.2005.03.015">evolved from self-replicating RNAs</a>. This possibility would mean that viruses may have appeared before bacteria. But because viruses don’t leave fossils behind, there isn’t available evidence to support this idea.</p>
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<figcaption><span class="caption">The RNA-world hypothesis proposes that self-replicating RNA evolved before DNA or proteins.</span></figcaption>
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<p>At some point, metabolic reactions and replication processes had to come together inside a membrane to make an early form of a cell: a pre-cell. Perhaps this happened when a viruslike structure infected a collection of metabolic reactions enclosed within a membrane. The pre-cell could then duplicate itself, leading to the <a href="https://doi.org/10.1098/rstb.2002.1183">evolution of the first living cell</a>. This cell would have been like today’s bacteria and archaea.</p>
<p>Maybe viruslike structures did form before cells. However, those simple viruslike structures might have been just pieces of DNA or RNA, so could they really be considered “viruses”? </p>
<p>Another popular theory states that viruses evolved from degenerated bacteria or archaea that lost most of the genetic instructions for carrying out metabolism and forming cells. There are <a href="http://www.biologyaspoetry.com/textbooks/microbes_and_evolution/symbioses_serial_endosymbiosis.html">many examples</a> of similar smaller degenerations that have occurred in the bacterial world today.</p>
<h2>Uncovering early life</h2>
<p>The surface of the Earth today is very different from <a href="https://eos.org/science-updates/rethinking-the-search-for-the-origins-of-life">what it was 4 billion years ago</a>. Some have speculated that deep under the Earth’s surface, where it is too hot for modern life, these early conditions <a href="https://www.chemistryworld.com/features/hydrothermal-vents-and-the-origins-of-life/3007088.article">might still be present</a>, allowing some protolife forms to continue to exist where they are protected from being consumed by other microbes. </p>
<p>When people can explore other planets or moons, perhaps we will find processes similar to those that were at work on early Earth. This kind of discovery could help us solve the puzzle of life’s origin here.</p>
<hr>
<p><em>Hello, curious kids! Do you have a question you’d like an expert to answer? Ask an adult to send your question to <a href="mailto:curiouskidsus@theconversation.com">CuriousKidsUS@theconversation.com</a>. Please tell us your name, age and the city where you live.</em></p>
<p><em>And since curiosity has no age limit – adults, let us know what you’re wondering, too. We won’t be able to answer every question, but we will do our best.</em></p><img src="https://counter.theconversation.com/content/197880/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kenneth Noll previously received funding from NSF, NASA, DOE and the Office of Naval Research. </span></em></p>Fossil evidence of how the earliest life on Earth came to be is hard to come by. But scientists have come up with a few theories based on the microbes, viruses and prions existing today.Kenneth Noll, Professor Emeritus of Microbiology, University of ConnecticutLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1985372023-02-08T14:28:15Z2023-02-08T14:28:15ZHow do I improve my immunity? Expert shares tips on what to do - and what to avoid<figure><img src="https://images.theconversation.com/files/507107/original/file-20230130-7241-9z07f6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Exercising regularly, and spending time outdoors can improve your health. </span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>The human immune system is arguably the most complex system in the human body. But scientists have made a lot of progress in understanding how it functions.</p>
<p>That’s important for understanding illnesses and how to manage them. For instance, it’s important to understand that an immune response takes several days to fully develop. This knowledge would hopefully prevent people from getting impatient and seeking inappropriate care. </p>
<p>The immune system is made up of an intricate network of cells, tissues and molecules. These control the delicate balance between eliminating cancerous or infected cells, and not harming the body in the process. </p>
<p>A poorly functioning immune system can cause a variety of health problems. </p>
<p>It could lead to a person getting recurrent infections. Depending on the nature of the immune deficiency, the infections can range from viral (such as colds, flu, shingles and fever blisters) to bacterial (such as tuberculosis) or fungal (such as thrush). </p>
<p>Immune system dysfunction can also present as excessive inflammation or even auto-immunity. In this case the body starts seeing its own tissues as foreign and attacks them. Some examples of these conditions are rheumatoid arthritis, lupus and psoriasis.</p>
<p>The factors that affect our immune system range from things we can’t change, such as our genetic make-up and exposure to past pathogens, to things we may be able to control or modify.</p>
<p>I am an immunologist, and in this article I unpack the changes you can make today to help your immune system function better. They include diet, managing stress levels, and limiting exposure to environmental factors, such as germs, pollution and toxins. </p>
<p>Optimal immune function plays an important role in maintaining health. Given the immense complexity of the immune system, simplistic solutions are not effective. It’s important to understand some of the things you should – and shouldn’t – do. </p>
<h2>What not to do</h2>
<p>Many products claim to “boost” the immune system. But given the complex interplay between the cells in our bodies, it’s not really possible to “boost” just one part of the immune system. </p>
<p>And even if it was possible, “boosting” one aspect of your immune system can set off bad reactions by upsetting the delicate balance that makes up our bodies. For instance, “boosting” the immune system’s ability to fight infection could also “boost” other aspects, such as inflammation, that could harm normal tissue. </p>
<p>It is true that the immune system relies on vitamins and minerals to perform its tasks. But there is no solid evidence that taking vitamins and mineral supplements will improve its functioning. </p>
<p>The exception is when a person has a known deficiency, such as vitamin D deficiency. Most people with vitamin D deficiency do not have any symptoms or only have vague, non-specific symptoms, such as tiredness or lower back ache. People living with osteoporosis, diabetes, kidney disease, obesity, or depression, or those with limited sun exposure, especially the elderly, are at increased risk of having a deficiency. It’s important to address the problem because it can increase the risk of fractures, as well as infection from various pathogens, especially those affecting the lungs, such as flu and SARS-CoV-2. </p>
<p>If you think you’ve got a nutrient deficiency you should consult a healthcare practitioner for an accurate diagnosis. They can set out an evidence-based management strategy for you. </p>
<p>The reason for seeking professional help is that dosing up on supplements can be bad for you. </p>
<p>Firstly, some vitamins, such as vitamin A, D, E and K, are fat-soluble and are stored in the body. It is therefore possible to have levels that are too high, which can cause its own problems. For instance, too-high levels of vitamin D can cause kidney stones, constipation and high blood pressure. Too much vitamin A or iron can cause damage to the liver and other organs. </p>
<p>Secondly, nutrients should not be seen as independent components. Rather they should be seen as parts of a whole. Many supplements can interact negatively with other supplements and even with medication. For instance, vitamin K can reduce the ability of the blood thinner warfarin to prevent blood clots.</p>
<p>Combining different supplements can also lead to excessive or inadequate amounts of certain nutrients, with potentially detrimental effects. For example, prolonged zinc supplementation can cause copper deficiency, which has been linked to anaemia and impaired brain function. </p>
<h2>What to do</h2>
<p>The best way to ensure that your immune system gets what it needs is through a healthy and balanced lifestyle. </p>
<p>Diet is critical. Eat food that is unprocessed, preservative-free, and rich in a variety of vitamins, minerals and antioxidants. Your diet should include green and yellow vegetables, fruit and berries, whole grains, seeds and nuts. </p>
<p>And it’s not just the individual components of food that are important. The interplay between them matters too. This is something that cannot be reproduced in a tablet. </p>
<p>Lifestyle factors are also key. Stress is a normal and essential part of life, but it must be switched off to protect the body. Finding effective ways to control stress, such as breathing exercises, yoga and meditation, is important. </p>
<p>Activities that have been shown to improve health include getting enough rest, exercising regularly, spending time outdoors, and staying connected socially. Smoking and excessive alcohol use are clearly harmful. </p>
<p>Finally, we often forget to be kind to ourselves. When you are ill, take time to recover. When you are going through an especially stressful time, make an extra effort to de-stress. </p>
<p>Most importantly, don’t regard these as emergency measures. Make them part of your lifestyle. As tempting as it may be, it is not possible to “supplement” yourself out of a bad lifestyle.</p><img src="https://counter.theconversation.com/content/198537/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Theresa Rossouw does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>As tempting as it is, it is not possible to “supplement” oneself out of a bad lifestyle.Theresa Rossouw, Professor, University of PretoriaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1958102023-01-31T13:16:07Z2023-01-31T13:16:07ZMicrobes in your food can help or hinder your body’s defenses against cancer – how diet influences the conflict between cell ‘cooperators’ and ‘cheaters’<figure><img src="https://images.theconversation.com/files/506674/original/file-20230126-31491-80kf4u.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1731%2C1731&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">You can change your gut microbiome composition by eating different foods.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/bacteria-and-germs-on-food-royalty-free-image/596371624">wildpixel/iStock via Getty Images</a></span></figcaption></figure><p>The microbes living in your food can affect your risk of cancer. While some help your body fight cancer, others help tumors evolve and grow. </p>
<p>Gut microbes can influence your cancer risk by changing how your cells behave. Many cancer-protective microbes support normal, cooperative behavior of cells. Meanwhile, cancer-inducing microbes undermine cellular cooperation and increase your risk of cancer in the process. </p>
<p>We are <a href="https://scholar.google.com/citations?user=8abR970AAAAJ&hl=en">evolutionary</a> <a href="https://search.asu.edu/profile/2854856">biologists</a> who study how cooperation and conflict occur inside the human body, including the ways cancer can evolve to exploit the body. Our <a href="https://doi.org/10.1007/s13668-022-00420-5">systematic review</a> examines how diet and the microbiome affect the ways the cells in your body interact with each other and either increase or decrease your risk of cancer.</p>
<h2>Cancer is a breakdown of cell cooperation</h2>
<p>Every human body is a symphony of multicellular cooperation. <a href="https://www.scientificamerican.com/article/our-bodies-replace-billions-of-cells-every-day/">Thirty trillion cells</a> cooperate and coordinate with each other to make us viable multicellular organisms. </p>
<p>For multicellular cooperation to work, cells must engage in behaviors that <a href="https://doi.org/10.1111/eva.12303">serve the collective</a>. These include controlled cell division, proper cell death, resource sharing, division of labor and protection of the extracellular environment. Multicellular cooperation is what allows the body to function effectively. If genetic mutations interfere with these proper behaviors, they can lead to the breakdown of cellular cooperation and the emergence of cancer.</p>
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<figcaption><span class="caption">The food in your diet affects the composition of your gut microbiome.</span></figcaption>
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<p>Cancer cells can be thought of as <a href="https://press.princeton.edu/books/hardcover/9780691163840/the-cheating-cell">cellular cheaters</a> because they do not follow the rules of cooperative behavior. They mutate uncontrollably, evade cell death and take up excessive resources at the expense of the other cells. As these cheater cells replicate, cancer in the body begins to grow.</p>
<p>Cancer is fundamentally a problem of having multiple cells living together in one organism. As such, it has been around <a href="http://dx.doi.org/10.1098/rstb.2014.0219">since the origins of multicellular life</a>. This means that cancer suppression mechanisms have been evolving for hundreds of millions of years to help keep would-be cancer cells in check. Cells monitor themselves for mutations and induce cell death, also known as apoptosis, when necessary. Cells also monitor their neighbors for evidence of abnormal behavior, sending signals to aberrant cells to induce apoptosis. In addition, the body’s immune system monitors tissues for cancer cells to destroy them.</p>
<p>Cells that are able to evade detection, avoid apoptosis and replicate quickly have an evolutionary advantage within the body over cells that behave normally. This process within the body, called <a href="https://doi.org/10.1371/journal.pcbi.0020108">somatic evolution</a>, is what leads cancer cells to grow and make people sick.</p>
<h2>Microbes can help or hinder cell cooperation</h2>
<p>Microbes can affect cancer risk through changing the ways that the cells of the body interact with one another. </p>
<p>Some microbes can <a href="https://doi.org/10.1007/s13668-019-0257-2">protect against cancer</a> by helping maintain a healthy environment in the gut, reducing inflammation and DNA damage, and even by directly limiting tumor growth. Cancer-protective microbes like <em>Lactobacillus pentosus</em>, <em>Lactobacillus gasseri</em> and <em>Bifidobacterium bifidum</em> are found in the environment and different foods, and can live in the gut. These microbes <a href="https://doi.org/10.1007/s13668-022-00420-5">promote cooperation among cells</a> and limit the function of cheating cells by strengthening the body’s cancer defenses. <em>Lactobacillus acidophilus</em>, for example, increases the <a href="https://doi.org/10.1017/s0007114510000516">production of a protein called IL-12</a> that stimulates immune cells to act against tumors and suppress their growth.</p>
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<figcaption><span class="caption">Gut bacteria can influence the effectiveness of certain cancer treatments.</span></figcaption>
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<p>Other microbes can promote cancer by inducing mutations in healthy cells that make it more likely for cellular cheaters to emerge and outcompete cooperative cells. <a href="https://doi.org/10.1002/path.5047">Cancer-inducing microbes</a> such as <em>Enterococcus faecalis</em>, <em>Helicobacter pylori</em> and <em>Papillomavirus</em> are associated with increased tumor burden and cancer progression. They can release toxins that damage DNA, change gene expression and <a href="https://doi.org/10.1007/s13668-019-0257-2">increase the proliferation</a> of tumor cells. <a href="https://doi.org/10.1002/ijc.23484"><em>Helicobacter pylori</em></a>, for example, can induce cancer by secreting a protein called Tipα that can penetrate cells, alter their gene expression and drive gastric cancer.</p>
<h2>Healthy diet with cancer-protective microbes</h2>
<p>Because what you eat determines the amount of cancer-inducing and cancer-preventing microbes inside your body, we believe that the microbes we consume and cultivate are an important component of <a href="https://doi.org/10.1007/s13668-022-00420-5">a healthy diet</a>.</p>
<p>Beneficial microbes are typically found in <a href="https://doi.org/10.1002/ijc.31959">fermented</a> and plant-based diets, which include foods like vegetables, fruits, yogurt and whole grains. These foods have high nutritional value and contain microbes that increase the immune system’s ability to fight cancer and lower overall inflammation. <a href="https://doi.org/10.1093%2Fcdn%2Fnzy005">High-fiber foods are prebiotic</a> in the sense that they provide resources that help beneficial microbes thrive and subsequently provide benefits for their hosts. Many cancer-fighting microbes are abundantly present in fermented and high-fiber foods. </p>
<p>In contrast, harmful microbes can be found in highly-processed and meat-based diets. The Western diet, for example, contains an abundance of red and processed meats, fried food and high-sugar foods. It has been long known that meat-based diets are linked to higher cancer prevalence, and that red meat is a <a href="https://doi.org/10.2533/chimia.2018.718">carcinogen</a>. Studies have shown that meat-based diets are associated with cancer-inducing microbes including <a href="https://doi.org/10.1007/s13668-022-00420-5"><em>Fusobacteria</em> and <em>Peptostreptococcus</em></a> in both humans and other species.</p>
<p>Microbes can enhance or interfere with how the body’s cells cooperate to prevent cancer. We believe that purposefully cultivating a microbiome that promotes cooperation among our cells can help reduce cancer risk.</p><img src="https://counter.theconversation.com/content/195810/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gissel Viridiana Marquez Alcaraz receives funding from the National Cancer Institute. </span></em></p><p class="fine-print"><em><span>Athena Aktipis receives funding from the National Cancer Institute and the John Templeton Foundation.</span></em></p>Cancer cells are ‘cheaters’ that do not cooperate with the rest of the body. Certain microbes in your diet can either protect against or promote tumor formation by influencing cell cooperation.Gissel Marquez Alcaraz, Ph.D. Student in Evolutionary Biology, Arizona State UniversityAthena Aktipis, Associate Professor of Psychology, Center for Evolution and Medicine, Arizona State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1961002023-01-10T13:30:06Z2023-01-10T13:30:06ZOrgan-on-a-chip models allow researchers to conduct studies closer to real-life conditions – and possibly grease the drug development pipeline<figure><img src="https://images.theconversation.com/files/501906/original/file-20221219-18-6xab1c.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2044%2C1581&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The lung-on-a-chip can mimic both the physical and mechanical qualities of a human lung.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/HQBa1g">Wyss Institute for Biologically Inspired Engineering, Harvard University/Flickr</a></span></figcaption></figure><p><a href="https://doi.org/10.1007/s40273-021-01065-y">Bringing a new drug to market</a> costs billions of dollars and can take over a decade. These high monetary and time investments are both strong contributors to today’s skyrocketing health care costs and significant obstacles to delivering new therapies to patients. One big reason behind these barriers is the lab models researchers use to develop drugs in the first place.</p>
<p><a href="https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research">Preclinical trials</a>, or studies that test a drug’s efficacy and toxicity before it enters clinical trials in people, are mainly conducted on cell cultures and animals. Both are limited by their poor ability to mimic the conditions of the human body. <a href="https://doi.org/10.1016%2FB978-0-12-803077-6.00009-6">Cell cultures</a> in a petri dish are unable to replicate every aspect of tissue function, such as how cells interact in the body or the dynamics of living organs. And <a href="https://doi.org/10.1093/bioinformatics/btu611">animals</a> are not humans – even small genetic differences between species can be amplified to major physiological differences. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902221/">Fewer than 8%</a> of successful animal studies for cancer therapies make it to human clinical trials. Because animal models often fail to predict drug effects in human clinical trials, these late-stage failures can significantly drive up both costs and patient health risks. </p>
<p>To address this translation problem, researchers have been developing a promising model that can more closely mimic the human body – organ-on-a-chip. </p>
<p>As an <a href="https://scholar.google.com/citations?user=FppSA-0AAAAJ&hl=en">analytical chemist</a>, I have been working to develop organ and tissue models that avoid the simplicity of common cell cultures and the discrepancies of animal models. I believe that, with further development, organs-on-chips can help researchers study diseases and test drugs in conditions that are closer to real life.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/CpkXmtJOH84?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Organs-on-chips offer an alternative model for early-phase biomedical research.</span></figcaption>
</figure>
<h2>What are organs-on-chips?</h2>
<p>In the late 1990s, researchers figured out a way to <a href="https://gmwgroup.harvard.edu/files/gmwgroup/files/1073.pdf">layer elastic polymers</a> to control and examine fluids at a microscopic level. This launched the field of <a href="https://doi.org/10.1016/j.mne.2019.01.003">microfluidics</a>, which for the biomedical sciences involves the use of devices that can mimic the dynamic flow of fluids in the body, such as blood.</p>
<p>Advances in microfluidics have provided researchers a platform to culture cells that function more closely to how they would in the human body, specifically with <a href="https://doi.org/10.1038/s41578-018-0034-7">organs-on-chips</a>. The “chip” refers to the microfluidic device that encases the cells. They’re commonly made using the same technology as computer chips. </p>
<p>Not only do organs-on-chips mimic blood flow in the body, these platforms have microchambers that allow researchers to integrate multiple types of cells to mimic the diverse range of cell types normally present in an organ. The fluid flow connects these multiple cell types, allowing researchers to study how they interact with each other.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/M37ZU0Ptkww?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Microfluidics can be used for many applications in biological research.</span></figcaption>
</figure>
<p>This technology can overcome the limitations of both static cell cultures and animal studies in several ways. First, the presence of fluid flowing in the model allows it to mimic both what a cell experiences in the body, such as how it receives nutrients and removes wastes, and how a drug will move in the blood and interact with multiple types of cells. The ability to control fluid flow also enables researchers to fine-tune the optimal dosing for a particular drug.</p>
<p>The <a href="https://doi.org/10.1126/science.1188302">lung-on-a-chip</a> model, for instance, is able to integrate both the mechanical and physical qualities of a living human lung. It’s able to mimic the dilation and contraction, or inhalation and exhalation, of the lung and simulate the interface between the lung and air. The ability to replicate these qualities allows researchers to better study lung impairment across different factors.</p>
<h2>Bringing organs-on-chips to scale</h2>
<p>While organ-on-a-chip pushes the boundaries of early-stage pharmaceutical research, the technology has <a href="https://doi.org/10.1016/j.drudis.2019.03.011">not been widely integrated</a> into drug development pipelines. I believe that a core obstacle for wide adoption of such chips is its high complexity and low practicality.</p>
<p>Current organ-on-a-chip models are difficult for the average scientist to use. Also, because most models are single-use and allow only one input, which limits what researchers can study at a given time, they are both expensive and time- and labor-intensive to implement. The <a href="https://doi.org/10.1039/c6lc01554a">high investments required</a> to use these models might dampen enthusiasm to adopt them. After all, researchers often use the least complex models available for preclinical studies to reduce time and cost.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Close-up of blood-brain barrier on a chip" src="https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=433&fit=crop&dpr=1 600w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=433&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=433&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=544&fit=crop&dpr=1 754w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=544&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=544&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This chip mimics the blood-brain barrier. The blue dye marks where brain cells would go, and the red dye marks the route of blood flow.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/HRUHqg">Vanderbilt University/Flickr</a></span>
</figcaption>
</figure>
<p>Lowering the technical bar to make and use organs-on-chips is critical to allowing the entire research community to take full advantage of their benefits. But this does not necessarily require simplifying the models. <a href="https://chenresearchlab.umbc.edu">My lab</a>, for example, has designed various <a href="https://doi.org/10.26434/chemrxiv.12964604.v1">“plug-and-play” tissue chips</a> that are standardized and modular, allowing researchers to readily assemble premade parts to run their experiments.</p>
<p>The advent of <a href="https://pubs.acs.org/doi/full/10.1021/ac403397r">3D printing</a> has also significantly facilitated the development of organ-on-a-chip, allowing researchers to directly manufacture entire tissue and organ models on chips. 3D printing is ideal for fast prototyping and design-sharing between users and also makes it easy for mass production of standardized materials.</p>
<p>I believe that organs-on-chips hold the potential to enable breakthroughs in drug discovery and allow researchers to better understand how organs function in health and disease. Increasing this technology’s accessibility could help take the model out of development in the lab and let it make its mark on the biomedical industry.</p><img src="https://counter.theconversation.com/content/196100/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Chengpeng Chen receives funding from the NIH.</span></em></p>Successes in the lab mostly don’t translate to people. Research models that better mimic the human body could close the gap.Chengpeng Chen, Assistant Professor of Chemistry and Biochemistry, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1957922023-01-09T13:18:31Z2023-01-09T13:18:31ZHow cancer cells move and metastasize is influenced by the fluids surrounding them – understanding how tumors migrate can help stop their spread<figure><img src="https://images.theconversation.com/files/502978/original/file-20230103-70338-2503wk.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2476%2C1209&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Tumor cells traverse many different types of fluids as they travel through the body.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/spreading-cancer-cell-illustration-royalty-free-illustration/1407269122">Christoph Burgstedt/Science Photo Library via Getty Images</a></span></figcaption></figure><p><a href="https://doi.org/10.1016/C2020-0-03305-0">Cell migration</a>, or how cells move in the body, is essential to both normal body function and disease progression. Cell movement is what allows body parts to grow in the right place during early development, wounds to heal and tumors to become metastatic.</p>
<p>Over the last century, how researchers understood cell migration was limited to the effects of biochemical signals, or <a href="https://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Boundless)/7%3A_Microbial_Genetics/7.21%3A_Sensing_and_Signal_Transduction/7.21A%3A__Chemotaxis">chemotaxis</a>, that direct a cell to move from one place to another. For example, a type of immune cell called a neutrophil migrates toward areas in the body that have a <a href="https://doi.org/10.4049/jimmunol.155.3.1428">higher concentration of a protein called IL-8</a>, which increases during infection.</p>
<p>In the past two or three decades, however, scientists have started to recognize the importance of the <a href="https://www.mechanobio.info/">mechanical, or physical, factors</a> that play a role in cell migration. For example, human mammary epithelial cells – the cells lining the milk ducts in the breast – <a href="https://doi.org/10.1126/science.aaf7119">migrate toward areas of increasing stiffness</a> when placed on a surface with a stiffness gradient.</p>
<p>And now, instead of focusing on just the effect of the “solid” environment of cells, researchers are turning toward their “fluid” environment. As a <a href="https://scholar.google.com/citations?user=nKmJNpQAAAAJ&hl=en">theoretician</a> trained in applied mathematics, I use mathematical models to understand the physics behind cell biology. My colleagues <a href="https://scholar.google.com/citations?user=otbcd-EAAAAJ&hl=en">Sean X. Sun</a> and <a href="https://scholar.google.com/citations?user=sMrPz8sAAAAJ&hl=en">Konstantinos Konstantopoulos</a> and I were among the pioneering scientists who discovered how <a href="https://doi.org/10.1242/jcs.240341">water and hydraulic pressure</a> influence cell migration through theoretical models and lab experiments. In our recently published research, we found that human breast cancer cell migration is enhanced by the <a href="https://doi.org/10.1038/s41467-022-33683-1">flow</a> and <a href="https://doi.org/10.1038/s41586-022-05394-6">viscosity</a> of the fluids surrounding them, clarifying one of the factors influencing how tumors metastasize.</p>
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<figcaption><span class="caption">Cells can move in different ways.</span></figcaption>
</figure>
<h2>How fluids affect cell migration</h2>
<p>Cells in the human body are constantly exposed to fluids of <a href="https://doi.org/10.1038/s41586-022-05394-6">different physical properties</a>. Water is one such fluid that can direct cell migration. For example, we found that <a href="https://doi.org/10.1038/s41467-022-33683-1">how water flows across the membranes</a> of breast cancer cells influences how they move and metastasize. This is because the amount of water traveling in and out of a cell causes it to shrink or swell, inducing movement by translocating different parts of the cell.</p>
<p>The viscosity, or thickness, of body fluids varies from organ to organ, and from health to disease, and this can also affect cell migration. For example, the fluid between cancer cells in tumors is more viscous than the fluid between normal cells in healthy tissues. When we compared how quickly breast cancer cells move in confined channels filled with fluid of normal viscosity versus fluid of high viscosity, we found that cells in high viscosity channels <a href="https://doi.org/10.1038/s41586-022-05394-6">counterintuitively sped up</a> by a significant 40%. This discovery was unexpected because the fundamental laws of physics tell us that inert particles should slow down in high viscosity fluids due to increased resistance.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Animation comparing two fluids with lower and higher viscosity." src="https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=463&fit=crop&dpr=1 600w, https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=463&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=463&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=582&fit=crop&dpr=1 754w, https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=582&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/502975/original/file-20230103-105030-c8xq8d.gif?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=582&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The blue fluid on the left has a lower viscosity relative to the orange fluid on the right.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/File:Viscosities.gif">Synapticrelay/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>We wanted to figure out the mechanism behind this surprising result. So we identified what molecules were involved in this process, discovering a cascade of events that allow high viscosity environments to enhance cell motility. </p>
<p>We found that high viscosity fluids first promote the growth of protein filaments called actin, which open channels in the cell’s membrane and increase water intake. The cell expands from the water, activating another channel that takes in calcium ions. These calcium ions activate another type of protein filament called myosin that induces the cell to move. This cascade of events induces cells to change their structure and generate more force to overcome the resistance imposed by high viscosity fluid, meaning the cells aren’t inert at all.</p>
<p>We also discovered that cells retained “memory” after exposure to a high viscosity medium. This meant that if we put cells in a high viscosity medium for several days and then returned them to a normal viscosity medium, they would still move at a faster speed. How cells retain this memory is still an open question.</p>
<p>We then wondered whether our findings on viscous memory would remain true in animals, not just in Petri dishes. So we exposed human breast cancer cells to a high viscosity medium for six days, then placed them in a normal viscosity medium. We then injected the cells into chicken embryos and mice.</p>
<p>Our results were consistent: Cells pre-exposed to a high viscosity medium had an increased ability to leak into surrounding tissues and metastasize compared to cells that were not pre-exposed. This result demonstrates that the viscosity of the fluids in a cell’s surrounding environment is a mechanobiological cue that promotes cancer cells to metastasize.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/OcigJn8UJNQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Understanding how cells move could help elucidate how tumors metastasize.</span></figcaption>
</figure>
<h2>Implications for cancer treatment</h2>
<p>Cancer patients usually don’t die from the original source of the tumor, but from its <a href="https://doi.org/10.1002%2Fcam4.2474">spread to other parts of the body</a>.</p>
<p>When cancer cells travel through the body, they move into spaces that will have varying fluid viscosity. Understanding how fluid viscosity affects the movement of tumor cells could help researchers figure out ways to better treat and detect cancer before it metastasizes. </p>
<p>The next step is to build imaging and analysis techniques to precisely examine how cells from various types of lab animals respond to changes in fluid viscosity. Identifying the molecules that regulate how cells respond to changes in viscosity could help researchers identify potential drug targets to reduce the spread of cancer.</p><img src="https://counter.theconversation.com/content/195792/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Yizeng Li receives funding from National Science Foundation.</span></em></p>Counterintuitively, cells move faster in thicker fluids. New research on breast cancer cells explains why, and reveals the role that fluid viscosity plays in metastasis.Yizeng Li, Assistant Professor of Biomedical Engineering, Binghamton University, State University of New YorkLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1958732023-01-06T13:30:53Z2023-01-06T13:30:53ZVisualizing the inside of cells at previously impossible resolutions provides vivid insights into how they work<figure><img src="https://images.theconversation.com/files/501408/original/file-20221215-16-mtk39u.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1078%2C913&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cryo-electron tomography shows what molecules look like in high-resolution – in this case, the virus that causes COVID-19.</span> <span class="attribution"><a class="source" href="https://nanographics.at/projects/coronavirus-3d/">Nanographics</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>All life is <a href="https://www.khanacademy.org/science/biology/intro-to-biology/what-is-biology/a/what-is-life">made up of cells</a> several magnitudes <a href="https://learn.genetics.utah.edu/content/cells/scale/">smaller than a grain of salt</a>. Their seemingly simple-looking structures mask the intricate and complex molecular activity that enables them to carry out the functions that sustain life. Researchers are beginning to be able to visualize this activity to a level of detail they haven’t been able to before.</p>
<p>Biological structures can be visualized by either starting at the level of the whole organism and working down, or starting at the level of single atoms and working up. However, there has been a resolution gap between a cell’s smallest structures, such as the cytoskeleton that supports the cell’s shape, and its largest structures, such as the ribosomes that make proteins in cells.</p>
<p>By analogy of Google Maps, while scientists have been able to see entire cities and individual houses, they did not have the tools to see how the houses came together to make up neighborhoods. Seeing these neighborhood-level details is essential to being able to understand how individual components work together in the environment of a cell.</p>
<p>New tools are steadily bridging this gap. And ongoing development of one particular technique, <a href="https://doi.org/10.1002/1873-3468.13948">cryo-electron tomography, or cryo-ET</a>, has the potential to deepen how researchers study and understand how cells function in health and disease. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/026rzTXb1zw?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cryo-EM won the 2017 Nobel Prize in chemistry.</span></figcaption>
</figure>
<p>As the former <a href="https://www.science.org/content/article/jeremy-berg-named-science-editor-chief">editor-in-chief of Science magazine</a> and as a <a href="https://scholar.google.com/citations?user=MZ6qrPUAAAAJ&hl=en">researcher</a> who has studied hard-to-visualize large protein structures for decades, I have witnessed astounding progress in the development of tools that can determine biological structures in detail. Just as it becomes easier to understand how complicated systems work when you know what they look like, understanding how biological structures fit together in a cell is key to understanding how organisms function.</p>
<h2>A brief history of microscopy</h2>
<p>In the 17th century, <a href="https://doi.org/10.1098/rsob.150019">light microscopy</a> first revealed the existence of cells. In the 20th century, electron microscopy offered even greater detail, revealing the <a href="https://www.nobelprize.org/prizes/medicine/1974/summary/">elaborate structures within cells</a>, including organelles like the endoplasmic reticulum, a complex network of membranes that play key roles in protein synthesis and transport.</p>
<p>From the 1940s to 1960s, biochemists worked to separate cells into their molecular components and learn how to determine the 3D structures of proteins and other macromolecules at or near atomic resolution. This was first done using X-ray crystallography to visualize the structure of <a href="https://www.historyofinformation.com/detail.php?entryid=3015">myoglobin</a>, a protein that supplies oxygen to muscles. </p>
<p>Over the past decade, techniques based on <a href="https://www.nobelprize.org/prizes/chemistry/2002/press-release/">nuclear magnetic resonance</a>, which produces images based on how atoms interact in a magnetic field, and <a href="https://doi.org/10.1016/j.molcel.2015.02.019">cryo-electron microscopy</a> have rapidly increased the number and complexity of the structures scientists can visualize.</p>
<h2>What is cryo-EM and cryo-ET?</h2>
<p><a href="https://theconversation.com/scientists-uncovered-the-structure-of-the-key-protein-for-a-future-hepatitis-c-vaccine-heres-how-they-did-it-193705">Cryo-electron microscopy, or cryo-EM</a>, uses a camera to detect how a beam of electrons is deflected as the electrons pass through a sample to visualize structures at the molecular level. Samples are rapidly frozen to protect them from radiation damage. Detailed models of the structure of interest are made by taking multiple images of individual molecules and averaging them into a 3D structure.</p>
<p><a href="https://doi.org/10.1038/nmeth.4115">Cryo-ET</a> shares similar components with cryo-EM but uses different methods. Because most cells are too thick to be imaged clearly, a region of interest in a cell is first thinned by using an ion beam. The sample is then tilted to take multiple pictures of it at different angles, analogous to a CT scan of a body part – although in this case the imaging system itself is tilted, rather than the patient. These images are then combined by a computer to produce a 3D image of a portion of the cell. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Cryo-ET image of algal chloroplast" src="https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=932&fit=crop&dpr=1 600w, https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=932&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=932&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1172&fit=crop&dpr=1 754w, https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1172&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/501410/original/file-20221215-27-mqhygu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1172&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This is a cryo-ET image of the chloroplast of an algal cell.</span>
<span class="attribution"><a class="source" href="https://dx.doi.org/10.7554/eLife.04889">Engel et al. (2015)</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>The resolution of this image is high enough that researchers – or computer programs – can identify the individual components of different structures in a cell. Researchers have used this approach, for example, to show how proteins move and are degraded inside an <a href="https://doi.org/10.1073/pnas.1905641117">algal cell</a>.</p>
<p>Many of the steps researchers once had to do manually to determine the structures of cells are becoming automated, allowing scientists to identify new structures at vastly higher speeds. For example, combining cryo-EM with artificial intelligence programs like <a href="https://doi.org/10.1038/s41586-021-03819-2">AlphaFold</a> can facilitate image interpretation by predicting protein structures that have not yet been characterized. </p>
<h2>Understanding cell structure and function</h2>
<p>As imaging methods and workflows improve, researchers will be able to tackle some key questions in cell biology with different strategies.</p>
<p>The first step is to decide what cells and which regions within those cells to study. Another visualization technique called <a href="https://doi.org/10.1002/1873-3468.14421">correlated light and electron microscopy, or CLEM</a>, uses fluorescent tags to help locate regions where interesting processes are taking place in living cells.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Cryo-EM image of human T-cell leukemia virus type-1 (HTLV-1)" src="https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=406&fit=crop&dpr=1 600w, https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=406&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=406&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=510&fit=crop&dpr=1 754w, https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=510&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/501414/original/file-20221215-13-dadsmp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=510&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This is a cryo-EM image of a human T-cell leukemia virus type-1 (HTLV-1).</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/cryo-em-structure-of-human-t-cell-leukemia-virus-royalty-free-image/1300707029">vdvornyk/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>Comparing the <a href="https://doi.org/10.1016/j.isci.2018.07.014">genetic difference between cells</a> can provide additional insight. Scientists can look at cells that are unable to carry out particular functions and see how this is reflected in their structure. This approach can also help researchers study how cells interact with each other.</p>
<p>Cryo-ET is likely to remain a specialized tool for some time. But further technological developments and increasing accessibility will allow the scientific community to examine the link between cellular structure and function at previously inaccessible levels of detail. I anticipate seeing new theories on how we understand cells, moving from disorganized bags of molecules to intricately organized and dynamic systems.</p><img src="https://counter.theconversation.com/content/195873/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeremy Berg does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Many microscopy techniques have won Nobel Prizes over the years. Advancements like cryo-ET that allow scientists to see the individual atoms of cells can reveal their biological functions.Jeremy Berg, Professor of Computational and Systems Biology, Associate Senior Vice Chancellor for Science Strategy and Planning, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1925972022-10-30T12:21:24Z2022-10-30T12:21:24ZHow COVID-19 damages lungs: The virus attacks mitochondria, continuing an ancient battle that began in the primordial soup<figure><img src="https://images.theconversation.com/files/492284/original/file-20221028-37683-z5drng.jpeg?ixlib=rb-1.1.0&rect=18%2C9%2C2011%2C1578&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Red mitochondria in airway cells become coated with green SARS-COV-2 proteins after viral infection: Researchers discovered that the virus that causes COVID-19 damages lungs by attacking mitochondria.</span> <span class="attribution"><span class="source">(Stephen Archer)</span>, <span class="license">Author provided</span></span></figcaption></figure><iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/how-covid-19-damages-lungs--the-virus-attacks-mitochondria--continuing-an-ancient-battle-that-began-in-the-primordial-soup" width="100%" height="400"></iframe>
<p>Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those <a href="https://doi.org/10.1016/0022-5193(67)90079-3">bacteria eventually became mitochondria</a>, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes). </p>
<p>Ultimately, mitochondria became the powerhouses within all human cells. </p>
<p>Fast-forward to the rise of novel coronaviruses like SARS-CoV-2, and the <a href="https://coronavirus.jhu.edu/map.html">global spread of COVID-19</a>. <a href="http://doi.org/10.1056/NEJMoa2002032">Approximately five per cent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen)</a> requiring hospitalization. <a href="https://resources-covid19canada.hub.arcgis.com">In Canada about 1.1 per cent of infected patients (almost 46,000 people) have died</a>. </p>
<p>This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria — more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.</p>
<p>SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following <a href="https://www.who.int/health-topics/severe-acute-respiratory-syndrome#tab=tab_1">SARS-CoV in 2003</a> and <a href="https://www.who.int/health-topics/middle-east-respiratory-syndrome-coronavirus-mers#tab=tab_1">MERS-CoV in 2012</a>. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.</p>
<h2>How COVID-19 affects lungs</h2>
<p>People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:</p>
<ul>
<li>First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up). </li>
<li>Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.</li>
</ul>
<p>Together, these abnormalities lower blood oxygen. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers at three Canadian universities set about to unravel this mystery. <a href="https://doi.org/10.1161/circulationaha.120.047915">We proposed that SARS-CoV-2 worsened COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (the cells that line the airways) and pulmonary artery smooth muscle cells</a>. </p>
<p>We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and <a href="https://doi.org/10.1056/nejmra050002">sensors of oxygen</a>. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction. </p>
<p>This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels. </p>
<p>It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage — an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction — were making lung injury and hypoxemia (low blood oxygen) worse. </p>
<p>Our discovery, <a href="https://doi.org/10.1016/j.redox.2022.102508">published in <em>Redox Biology</em></a>, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels. </p>
<p>We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels. </p>
<h2>Attacking mitochondria</h2>
<p>Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these <a href="http://doi.org/10.1038/s41586-020-2286-9">viral proteins also target host proteins, causing them to malfunction</a>. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Cartoon with three panels: a coronavirus shooting arrows at mitochondria and spitting them in two; lungs and contrasting healthy and damaged lung cells; an oxygen meter with the needle in the red zone; and a human silhouette showing airways" src="https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=384&fit=crop&dpr=1 600w, https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=384&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=384&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=483&fit=crop&dpr=1 754w, https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=483&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/490891/original/file-20221020-25-rozyzy.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=483&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">How SARS-CoV-2 targets mitochondria to kill lung cells and prevent oxygen sensing.</span>
<span class="attribution"><span class="source">(drawn by Brooke Ring)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization). </p>
<p>In our experiments, we didn’t need to use a replicating virus to damage the mitochondria — simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied. </p>
<p>We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify <a href="https://doi.org/10.1096/fj.201901467r">a promising mitochondrial fission inhibitor, called Drpitor1a</a>. </p>
<p>Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition — fatigue and neurologic dysfunction — could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.</p>
<h2>The ongoing evolutionary battle</h2>
<p>This research also has an interesting evolutionary angle. Considering that <a href="https://doi.org/10.1016/0022-5193(67)90079-3">mitochondria were once bacteria, before being adopted by cells back in the primordial soup</a>, our findings reveal an Alien versus Predator scenario in which viruses are attacking “bacteria.”</p>
<p>Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for <a href="https://www.synthego.com/blog/gene-editing-nobel-prize">a Nobel Prize-winning gene editing discovery</a>. </p>
<p>The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.</p>
<h2>Pandemic pivot</h2>
<p>The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field — virology — in an effort to make a small contribution to the COVID-19 puzzle. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A grid of photographs of 25 scientists, and the three collaborating institutions (Queen's University, the Vaccine and Infectious Disease Organization (VIDO) and University of Toronto)" src="https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=342&fit=crop&dpr=1 600w, https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=342&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=342&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=429&fit=crop&dpr=1 754w, https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=429&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/492257/original/file-20221028-27-7vme8l.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=429&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The COVID team: The face of research. The diverse team includes members who came to Canada from India, Iran, England, Brazil, Iraq, China and Taiwan to pursue research here.</span>
<span class="attribution"><span class="source">(Stephen Archer)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p><a href="https://youtu.be/cJlAsFoTWLg">The diverse team we put together also brought expertise</a> in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, <a href="https://www.phgfoundation.org/blog/what-is-transcriptomics">transcriptomics</a>, synthetic chemistry, molecular imaging and infectious diseases. </p>
<p>Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43. </p>
<p>Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at <a href="https://www.vido.org">Vaccine and Infectious Disease Organization (VIDO)</a> in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus. </p>
<p>Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.</p>
<p>“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.</p>
<p>Our discovery will hopefully be translated into new medicines to counter future pandemics.</p><img src="https://counter.theconversation.com/content/192597/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Stephen L Archer receives funding from the Canadian Institutes of Health Research for research on COVID-19. Dr Archer is convector on a patent for small molecule inhibitors of mitochondrial fission.</span></em></p>COVID-19 causes lung injury and lowers oxygen levels in patients because the SARS-CoV-2 virus attacks cells’ mitochondria. This attack is a throwback to a primitive war between viruses and bacteria.Stephen L Archer, Professor, Head of Department of Medicine, Queen's University, OntarioLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1785772022-10-27T09:14:59Z2022-10-27T09:14:59ZThe unusual ways viruses and parasites use their cell membranes to spread – and how scientists are fighting back<figure><img src="https://images.theconversation.com/files/491703/original/file-20221025-3834-llifm3.jpg?ixlib=rb-1.1.0&rect=4%2C0%2C994%2C693&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Red onion skin cells seen through a microscope.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/high-resolution-light-photomicrograph-onion-epidermus-233534170">Claudio Divizia/Shutterstock</a></span></figcaption></figure><p>Cell membranes make up the exterior of all cells and are a basic structure found in most living organisms. But they can also help parasites survive in the human body, play an important part in cancer growth and enclose and protect deadly viruses, including the one that causes COVID. Scientists are looking to understand how bilayers (cell membranes with two layers) work and whether they can be used to develop new drugs to combat infections.</p>
<p>It has been known for a long time that living cells are enclosed <a href="https://academic.oup.com/aob/article-abstract/32/3/457/444888?redirectedFrom=fulltext">by a fatty layer</a> that separates different cells. This can be clearly seen in red onion skin cells in which the dye that gives the onion its distinctive colour is confined in these layers. Building on previous work, Seymour Singer and Garth Nicolson suggested a structure for this layer in 1972 which they called <a href="https://www.sciencedirect.com/science/article/pii/S0005273613003933?ia=ihub">the fluid mosaic model</a>. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Red onion cut in half revealing red layers." src="https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/491706/original/file-20221025-21-4dgpm7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Visible bilayers.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/red-onion-isolated-on-white-background-304270775">Jiang Hongyan/Shutterstock</a></span>
</figcaption>
</figure>
<p>Their model has since been found to explain many features in living organisms. The bilayer is even part of the structure and function of many viruses such as influenza and SARS-Covid-2. Viral particles can use it as a protective layer which helps them to spread. For example, we can trace how a viral particle of SARS-Covid-2 enters a lung cell and what happens next.</p>
<p>When one of these viral particles enters a lung cell, it releases its ribonucleic acid (RNA) – single-stranded genetic code. This translates into viral proteins on ball-like structures called ribosomes that are attached to membranes inside the host cell. These viral proteins are then transported to another part of the cell called <a href="https://www.hopkinsmedicine.org/news/articles/the-weird-way-coronaviruses-assemble-their-offspring">the Golgi apparatus</a> which encloses them in lipid (fatty) bilayers. They then make a further journey, fusing with the surface membrane of the cell, before leaving it altogether – a process known as exocytosis. </p>
<figure class="align-right ">
<img alt="Man coughing into clenched fist." src="https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/491709/original/file-20221025-15-hham00.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Virus particles go through a number of changes before spreading.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/spread-pathogens-when-coughing-shown-man-1720857718">Ralf Geithe/Shutterstock</a></span>
</figcaption>
</figure>
<p>When the virus leaves the cell it carries <a href="https://doi.org/10.1038/s41579-020-00468-6">some of the membranes</a> from the host cell with it. And the virus – now carrying a protective coat – will attempt to infect another lung cell or be released into the air as we breathe or cough. </p>
<h2>Disrupting the virus</h2>
<p>Biochemists in a team led by Valerie O’Donnell at Cardiff University are trying <a href="https://doi.org/10.1093/function/zqaa002">to find out more about this bilayer</a> with the hope that drugs could be designed to combat the virus itself. By growing the COVID virus in the laboratory and extracting the lipid from it, they have found that its surface membrane is very different from that of the host surface membrane – it has much less cholesterol and sphingomyelin (a fatty lipid component) and many more lipids which can increase blood clotting.</p>
<p>When we look at the way the virus acquires its membrane, a number of drugs might be used to disrupt its pathway. This has been done before. Scientists working with <em>tubercle bacilli</em> in the 1950s showed that certain harmless detergents disrupted the tuberculosis infection they cause. With COVID, <a href="https://theconversation.com/yes-washing-our-hands-really-can-help-curb-the-spread-of-coronavirus-132915">widespread handwashing</a>, using hand sanitiser and mouth washing attacked the virus’ bilayer and destroyed it.</p>
<p>Perhaps the virus will produce, by mutation, a new strain that has a tougher bilayer. The Cardiff laboratory is looking into the lipid composition of different strains and the results may indicate novel pathways for evolution of viruses and their treatment.</p>
<h2>Other roles for bilayers</h2>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=553&fit=crop&dpr=1 600w, https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=553&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=553&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=694&fit=crop&dpr=1 754w, https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=694&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/491707/original/file-20221025-23-poplij.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=694&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Schistosoma larvae change to survive in human blood.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/microscopic-photo-schistosoma-worm-causative-agent-2082244726">Mohammed_Al_Ali/Shutterstock</a></span>
</figcaption>
</figure>
<p>Bilayers are also involved in the infection of humans by diseases <a href="https://doi.org/10.1017/S003118200999093X">such as schistosomiasis</a> (also known as bilharzia). Infective larvae swimming in water penetrate human skin and the bilayer on the larval surface immediately changes to a unique double layer to allow it to survive in human blood. The larvae then covers itself with lipids from this blood and scientists <a href="https://doi.org/10.3389/fimmu.2020.624178">have suggested</a> that this disguises the membrane from the immune response of hosts – in other words, us. </p>
<p>Another hypothesis put forward by scientists in Egypt about the toughness of this double bilayer comes <a href="https://doi.org/10.29245/2689-9981/2018/3.1127">from the amount of sphingomyelin</a>, which they found protects the membrane by forming hydrogen bonds at the surface. This is thought to prevent access to immune antibodies and cells. Reducing the amount of sphingomyelin with <a href="https://www.kcbd.com/story/1467213/arachidonic-acid-the-good-and-bad/">arachidonic acid</a> – a fatty acid found in the body and also used in some supplements – can act as a drug against the disease. It is usually used in combination with <a href="https://doi.org/10.1186/s12879-020-05053-z">another drug called praziquantel</a> which attacks the parasite’s membrane.</p>
<p>One exception to the generalisation that bilayers are in all living cells are the parasitic and soil nematodes. Enormous numbers of these are found in soil: ones that do not affect other plants or animals such as <a href="https://www.yourgenome.org/facts/why-use-the-worm-in-research"><em>Caenorhabditis</em></a>, but also <a href="https://doi.org/10.3389/fpls.2019.01165">numerous</a> other animal and plant parasitic <a href="https://doi.org/10.3389/fpls.2019.01165">species</a> in the tropics and temperate zones. These organisms have a surface in which lipids are thought to be <a href="https://doi.org/10.3389/fpls.2013.00494">arranged in unusual hexagonal</a> structures to form <a href="https://doi.org/10.3389/fmicb.2021.631274">large rafts</a> which give an alternative structure to the bilayer found in most cells.</p>
<p>Study of lipids can surprise us and lead to new ideas about life and its structure, but also, excitingly, towards drugs that can be developed to disturb the structure of the lipid membranes of pathogens, cancers and other human infections.</p><img src="https://counter.theconversation.com/content/178577/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Kusel does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Cell membranes are a basic structure common to most living organisms – but they can be hijacked.John Kusel, Emeritus professor of cellular biochemistry, University of GlasgowLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1852572022-07-07T15:18:34Z2022-07-07T15:18:34ZHow the cell’s waste management systems might be targeted to treat cancer<figure><img src="https://images.theconversation.com/files/472399/original/file-20220704-17-lg7mjs.jpg?ixlib=rb-1.1.0&rect=0%2C97%2C7167%2C3944&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The proteasome is a cellular machine that chews up misfolded and unwanted proteins, and can promote cell death, making it an interesting target for cancer treatment. </span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Human organs and tissues are made up of millions of microscopic living units called cells. Over their lifespans, these cells accumulate waste products that include unwanted, misfolded and surplus proteins. </p>
<p>Waste management within these cells is a complex and critically important process that is essential for the proper functioning of organs within any given system. </p>
<p>The faulty functioning of cellular waste management machinery can lead to <a href="https://www.nature.com/articles/nrm1552">cancer and neurodegenerative diseases</a>. As researchers in immunology and oncology at the Université de Montréal, we want to explain how this process allows cells to adapt to adverse situations. </p>
<h2>Proteins are essential</h2>
<p>Every cell, tissue or organ contains thousands of different genes. Like a barcode, the genetic information in our DNA is read and translated, enabling the production of thousands of different proteins. Each protein has a precise 3D structure, a specific location and role within a cell type.</p>
<p>Proteins are functional units, similar to tiny machines, that carry out many processes within cells. These processes include the uptake of nutrients to ensure cell survival, cell respiration using oxygen to promote energy production, cell proliferation to replace dead cells and promote organ growth, and cell migration within tissue to place them in the right place at the right time. In short, proteins are responsible for the proper functioning of all cellular processes and allow cells to coexist in harmony within an organism.</p>
<p>Each of our cells has exactly the same set of genes, but each cell type has a unique protein profile. For example, one type of protein may be present and active in brain cells but absent in kidney or muscle cells. A protein might be essential for one organ but not for another, and their presence or absence within the cell is governed by a dynamic balance, orchestrated by mechanisms that regulate <a href="https://tbiomed.biomedcentral.com/articles/10.1186/1742-4682-7-25">protein production and elimination</a>.</p>
<h2>How cells decide which proteins to discard</h2>
<p>Over the past few decades, researchers have learned a great deal about how proteins are produced from genes via messenger RNA translation. This process involves a structure called the ribosome, the <a href="https://www.nature.com/collections/qmwjqzqcrb/">factory for protein production</a>. </p>
<p>Once produced, some proteins must be eliminated, either because of they are misfolded or because they have become redundant. Protein degradation is a highly co-ordinated and complex cellular process.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="figure" src="https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Balance between protein synthesis by the ribosome and degradation by the proteasome.</span>
<span class="attribution"><span class="source">(El Bachir Affar, created on BioRender.com)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Our lab, among others, is interested in understanding how cells make the initial decision to eliminate proteins and then proceed to destroy them. To ensure their removal, cells set up a complex process of quality control and decision-making that <a href="https://www.nature.com/articles/nrm.2017.83">results in protein ubiquitination</a>. Ubiquitination is an essential process that consists of binding a small protein, called ubiquitin, to various unwanted protein targets. It occurs in all cells in the body.</p>
<p>The ubiquitination stamp allows the proteasome to recognize unwanted proteins and sort them for removal. The proteasome is a tiny cylindrical chamber made up of many specialized proteins, which act like molecular scissors to shred proteins. As an essential protein complex, there are multiple copies of the proteasome in all living cells. </p>
<p>The proteasome is responsible for the rapid and highly specific breakdown of unwanted, misfolded or surplus proteins. This process is extremely important for the proliferation and proper functioning of cells.</p>
<p>The aberrant or reduced degradation of cellular proteins can lead to a variety of diseases, including cancer and brain diseases. However, the exact mechanisms underlying the normal functions and pathological alterations associated with the proteasome are still poorly understood. </p>
<h2>Cells react to lack of nutrients</h2>
<p>We recently discovered that when the body is nutrient deprived, proteasomes assemble in the nucleus of cells to form <a href="https://www.nature.com/articles/s41467-021-27306-4">large structures called “bodies” or “foci.”</a> This aggregation of proteasomes can be observed in various cell types and is a general cellular response to nutrient deprivation. </p>
<p>Specifically, this phenomenon only occurs when cells are deprived of amino acids, the necessary building blocks of proteins. Consequently, there’s a tightly controlled balance between the supply of amino acids for protein synthesis and their break down by the proteasome.</p>
<p>The formation of proteasome foci amplifies this degradation process during periods of nutrient deprivation. Interestingly, our study also found that these foci promote cell death during severe nutrient stress, where the cell triggers molecular mechanisms that lead to its destruction, a form of cellular suicide. Although this cell death is detrimental to individual cells, the outcome could be beneficial for overall cell population that forms the tissues and organs.</p>
<p>In fact, the death of some cells in an organ, in response to nutrient deficiency, could initially decrease the competition between cells for limited resources. The release of cellular components, in particular nutrients, during cell death could help nearby cells survive. In addition, dying cells could send signals to summon specialized rescue cells to repair tissues.</p>
<p>We also found that some cells present in tumours have a reduced ability to form proteasome foci following nutrient deprivation, suggesting that these cells have acquired resistance to stress. The formation of these foci, in normal cells, could be a defence mechanism that promotes the death of cells that have undergone drastic changes caused by the absence of nutrients. </p>
<p>In this respect, inducing cellular suicide by forming proteasome foci in cells that have undergone changes that promote cancer development could be an interesting new approach to prevent cancer.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="figure" src="https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=704&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=704&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=704&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=884&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=884&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=884&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Proteasome foci and their involvement in cell death.</span>
<span class="attribution"><span class="source">(El Bachir Affar, created on BioRender.com)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Now that researchers have a better understanding of what affects proteasome function, they could target it for personalized cancer treatment, which requires the knowledge of all the molecular disruptors of cancer cells.</p>
<p>It is possible that cells that escaped death as a result of nutrient stress have nevertheless accumulated changes in their functioning that could make them vulnerable. We are currently working on this hypothesis. </p>
<p><em>Malik Affar co-authored this article and helped produce the graphics.</em></p><img src="https://counter.theconversation.com/content/185257/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>El Bachir Affar received funding from the Canadian Institutes of Health Research (CIHR).</span></em></p><p class="fine-print"><em><span>Clémence Messmer received funding from the Canadian Institutes of Health Research (CIHR).</span></em></p>Faulty cellular waste management machinery can lead to cancer and neurodegenerative diseases, but researchers are also targeting this machinery to treat these diseases.El Bachir Affar, Professeur en biochimie et oncologie moléculaire, Université de MontréalClémence Messmer, Etudiante au doctorat en biochimie, Université de MontréalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1856542022-07-07T09:45:03Z2022-07-07T09:45:03ZThe human body has 37 trillion cells. If we can work out what they all do, the results could revolutionise healthcare<figure><img src="https://images.theconversation.com/files/472254/original/file-20220704-22-1y09ee.jpg?ixlib=rb-1.1.0&rect=95%2C15%2C1922%2C1201&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Priscilla Chan and Mark Zuckerberg with Moshe Biton (right) and Aviv Regev (left). The Chan Zuckerberg Initiative is one of the major funders of the Human Cell Atlas.</span> <span class="attribution"><span class="source">Chan Zuckerberg Initiative</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>The average body contains about 37 trillion cells – and we are in the midst of a revolutionary quest to understand what they all do. Unravelling this requires the expertise of scientists from all different backgrounds – computer scientists, biologists, clinicians and mathematicians – as well as new technology and some pretty sophisticated algorithms. </p>
<p>Where once a primitive microscope, essentially little more than a magnifying glass, would reveal a new cell directly and viscerally – in the same way that <a href="https://377.medium.com/first-person-in-the-world-who-discovered-the-sperm-cells-6c91b17a8df5#:%7E:text=Sperm%20were%20unknown%20to%20science,filled%20with%20tiny%2C%20wiggling%20cells.">Antonie van Leeuwenhoek discovered sperm</a> in 1677 – today it is analysis on a computer screen which brings us such revelations. But it’s just as wonderful.</p>
<p>This type of research is hard in all sorts of ways – from the science itself to the sociology of large teams working on it – but the pay-off can be huge. It certainly was for a consortium of 29 scientists who set out to determine which types of cells make up the lining of the trachea, or windpipe – and stumbled upon a new type of cell that could transform our understanding and treatment of cystic fibrosis.</p>
<p>The first time the team – co-led by <a href="https://biology.mit.edu/profile/aviv-regev/">Aviv Regev</a> at the <a href="https://www.broadinstitute.org/about-us">Broad Institute</a> of MIT and Harvard – came across these cells, they were looking at an analysis of 300 cells in the trachea of mice. Three cells didn’t seem to correspond to anything that had been seen before. Had it been just two, they might have dismissed it as an outcome of noise in the data – but three strange cells warranted a closer look.</p>
<p>In lab banter, they became known as the “hot cells”. The scientists repeated the experiment several times, and it soon became clear they really had stumbled upon a new type of cell in the trachea.</p>
<hr>
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<img alt="" src="https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/288776/original/file-20190820-170910-8bv1s7.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<p><strong><em>This story is part of Conversation Insights</em></strong>
<br><em>The Insights team generates <a href="https://theconversation.com/uk/topics/insights-series-71218">long-form journalism</a> and is working with academics from different backgrounds who have been engaged in projects to tackle societal and scientific challenges.</em></p>
<hr>
<p>As it turned out, another team from the US and Switzerland had independently found the same thing. The two teams learnt of each other’s work by chance at a seminar in 2017. “It was one of those beautiful moments in science,” recalled <a href="http://www.weizmann.ac.il/dept/irb/Biton/">Moshe Biton</a> from the Broad Institute team, “when two groups found the same results separately.”</p>
<p>Both groups confirmed that these new cells exist in the human airways as well as in mice and, after meeting up, agreed to publish their <a href="https://www.nature.com/articles/s41586-018-0394-6">two papers</a> <a href="https://www.nature.com/articles/s41586-018-0393-7">side-by-side</a>. These new cells had not been noticed before, simply because they are so rare – they make up around 1% of cells in the airway. But that doesn’t mean they’re unimportant. When the two teams looked in detail at what made these cells stand out, they came across something astonishing.</p>
<p>One of the genes active in these new-found trachea cells turned out to be CFTR – the “cystic fibrosis transmembrane conductance regulator” gene. This gave their work a whole other level of meaning because <a href="https://www.cff.org/research-clinical-trials/basics-cftr-protein">mutations in this gene cause cystic fibrosis</a>.</p>
<p>Exactly how this disease is caused by the inheritance of a dysfunctional version of the CFTR gene has been a mystery ever since the link was <a href="https://www.science.org/doi/10.1126/science.2772644">discovered in 1989</a>. Cystic fibrosis is a complex disease, usually beginning in childhood, with symptoms often including lung infections and difficulty breathing. There are treatments but no cure.</p>
<p>Now it seems possible that the key to understanding the cause could lie in working out what these newly discovered cells do, and what happens to these cells if the CFTR gene is defective. The research continues.</p>
<p>But already from this discovery, and other research using similar methods, there is the sense that our understanding of the body’s cells is being transformed by a piercing new combination of biology and computer science. And this is where even more game-changing discoveries are about to be made.</p>
<h2>The diversity of human cells</h2>
<p>Every one of the 37 trillion-or-so cells in your body is unique to some extent. Types of cell are determined by the particular proteins they contain – so only a red blood cell has haemoglobin, for example, and a <a href="https://www.ninds.nih.gov/health-information/patient-caregiver-education/brain-basics-life-and-death-neuron#:%7E:text=Neurons%20are%20information%20messengers.,rest%20of%20the%20nervous%20system.">neuron</a> contains different proteins from an <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-cell">immune cell</a>. No two cells in the body contain exactly the same amounts of each protein.</p>
<p><a href="https://www.penguin.co.uk/books/431895/the-beautiful-cure-by-daniel-m-davis/9781784702212">The immune system is especially complex</a>. It comprises many types of cells categorised by their core function – T cells, B cells and so on. But there are also countless subtle variations of these T cells and B cells. We don’t even really know how many variants there are – but if we could understand what they all do, we would better understand the immune system. This in turn would enable us to design new medicines to help the immune system to, for example, better fight cancer. </p>
<figure class="align-center ">
<img alt="Image of a human cell using super-resolution microscope" src="https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=521&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=521&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=521&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=655&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=655&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472258/original/file-20220704-19-xwkp0u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=655&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A human natural killer cell pictured using Stimulated Emission Depletion (STED) microscopy.</span>
<span class="attribution"><span class="source">Ashley Ambrose and Daniel M Davis</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>One kind of immune cell that my research team at Manchester University studies is called the <a href="https://www.immunology.org/public-information/bitesized-immunology/cells/natural-killer-cells">natural killer cell</a>. There are about a thousand of these immune cells in each drop of your blood, and they are especially good at detecting and killing other cells that have turned cancerous or have become infected with a virus. Again, not all natural killer cells are alike. <a href="https://pubmed.ncbi.nlm.nih.gov/24154599/">One analysis</a> has estimated that there are many thousands of variants of this immune cell in any one person.</p>
<p>In 2020, my research lab carried out <a href="https://ashpublications.org/bloodadvances/article/4/7/1388/454300/Diversity-of-peripheral-blood-human-NK-cells">an analysis</a> which suggested that variants of natural killer cells in blood could be organised into eight categories. While their different roles in the body aren’t yet fully understood, it’s likely that some are especially adept at attacking particular kinds of virus, others are better at detecting cancer, and so on.</p>
<p>Other types of immune cell can be even more varied. Evidently, our component cells are as diverse as the human beings they make up, and understanding how such complex populations of cells work together (in this case, to defend against disease) is a vital frontier.</p>
<h2>Using the language of algorithms</h2>
<p>To penetrate this complexity, the diversity of human cells must be translated into the language of algorithms.</p>
<p>Imagine a cell contains just two kinds of protein, X and Y. Every individual cell will have a specific amount of each of these two proteins. This can be represented as a point on a graph where the level of protein X becomes a position along the x-axis, and the level of protein Y its location along the y-axis.</p>
<p>One cell may contain a high amount of protein X and a little of protein Y (which can be revealed by a <a href="https://www.beckman.com/resources/videos/scientific/introduction-to-flow-cytometry">flow cytometer</a> showing that the cell stains with a high amount of one antibody and a low amount of another antibody). This cell can then be represented as a point placed far along the x-axis and a little way up the y-axis.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=570&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=570&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=570&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=716&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=716&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472263/original/file-20220704-21-dtlrr8.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=716&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Illustration of cell identification process.</span>
<span class="attribution"><span class="source">Manon Chauvin via Wikimedia, modified</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>As each cell takes up a position on the graph, those with similar levels of the X and also the Y protein – likely to be the same type of cell – appear as a cluster of points. If thousands or millions of cells are plotted in this way, the number of discrete clusters that emerge tells us how many types of cells there are. Also, the number of points within a cluster tells us how many cells there are of that type.</p>
<p>The wonderful thing is that this form of analysis can reveal how many kinds of cells are present in, say, a sample of blood or a tumour biopsy, without being guided in any way about which cells we are expecting to find. This means that unexpected results can turn up. A cluster of data points might appear with unexpected properties – implicating the discovery a new kind of cell.</p>
<p>Of course, cells need more than two coordinates to describe them. In fact, over the last decade, a type of analysis – known as <a href="https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0467-4">single-cell sequencing</a>– has been developed to measure the extent to which individual cells use each of the 20,000 human genes it contains.</p>
<p>Which ones out of all the 20,000 human genes a particular cell is using – called the cell’s <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transcriptome">transcriptome</a> – can then be analysed to create a “map” of different cells. We can’t imagine cells represented on a graph with 20,000 axes, but a computer algorithm can handle this analysis in just the same way it would one with only two variables. Similar cells are positioned close together, while cells using very different sets of genes are far apart.</p>
<p><a href="https://www.nature.com/articles/s41598-020-74567-y">Algorithms</a> to do this are borrowed from other fields of science, such as those used in analysing social networks. Then we get to spend days, if not years, mining the output, deciphering what the map means: how many types of cells there are, what defines their differences, and what they do in the body? </p>
<p>Right now, this endeavour is happening on an unprecedented scale thanks to the <a href="https://www.humancellatlas.org/learn-more/">Human Cell Atlas consortium</a> – leading to all kinds of <a href="https://www.penguin.co.uk/books/439335/the-secret-body-by-davis-daniel-m/9781529110975">discoveries about the human body</a>.</p>
<h2>The Human Cell Atlas</h2>
<p>In October 2016, Regev and <a href="https://www.sanger.ac.uk/person/teichmann-sarah/">Sarah Teichmann</a> from the <a href="https://www.sanger.ac.uk/about/">Wellcome Sanger Institute</a> organised an event in London for around 100 world-leading scientists to discuss how to chart every cell in the human body. The elevator pitch was to assemble something like Google Maps for the body: “We know the countries and main cities, now we need to map the streets and buildings.”</p>
<p>A year later, they had drafted a specific plan – to first try to profile 100 million cells from different systems and organs, using different people around the globe. Thousands of scientists in over 70 countries from every inhabited content have joined the consortiu since – it is an especially diverse community, as it should be for such a huge global scientific endeavour.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Large gathering of scientists" src="https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=388&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=388&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=388&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=488&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=488&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472261/original/file-20220704-19-wlwce0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=488&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">First meeting of the Human Cell Atlas team in London, 2016.</span>
<span class="attribution"><span class="source">Thomas Farnetti/Wellcome</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>In many ways, this bold new ambition is a direct descendant of the <a href="https://www.genome.gov/human-genome-project/What">Human Genome Project</a>. By sequencing all the human genes contained in each human cell, officially completed in April 2003, all sorts of genetic variations have been linked to increased susceptibility to a specific illness.</p>
<p>However, genetic diseases manifest in the specific cells where that gene is normally used. So, crucially, an analysis of genes alone isn’t enough – we also need to know where in the human body these disease-causing genes are being switched on.</p>
<p>The Human Cell Atlas is bridging this gap between abstract genetic codes and the physicality of the human body. We’ve already seen one example of how important this is – the discovery of the cystic fibrosis gene being used by a new, rare cell. Another example comes from what happens during pregnancy.</p>
<h2>Unlocking the secrets of pregnancy</h2>
<p>For many years, we have known that <a href="https://www.penguin.co.uk/books/182952/the-compatibility-gene-by-davis-daniel-m/9780141972527">the immune system is intimately linked with pregnancy</a>. For example, some combinations of immune system genes are slightly more frequent than would be expected by chance in couples who have had three or more miscarriages. While we don’t yet understand why this is, working it out might be medically important in resolving problems in pregnancy.</p>
<p>To tackle the issue, a consortium of scientists (co-led by Teichmann as part of the Human Cell Atlas project) analysed around 70,000 cells from the placenta and lining of the womb from women who had terminated their pregnancy at between six and 14 weeks.</p>
<p>The placenta is the organ where nutrients and gases pass back and forth between the mother and developing baby. It was once thought the mother’s immune system must be switched off in the lining of the womb where the placenta embeds, so that the placenta and foetus aren’t attacked for being “alien” (like an unmatched transplant) on account of half the foetus’s genes coming from the father. But this view turned out to be wrong – or too simple at the very least.</p>
<p>We now know, from a variety of experiments including this analysis, that in the womb, the activity of the mother’s immune cells is somewhat lessened, presumably to prevent an adverse reaction against cells from the foetus, but the immune system is not switched off. Instead, the immune cells we met earlier, natural killer cells, well known for killing infected cells or cancer cells, take on a completely different, more constructive job in the womb; helping build the placenta.</p>
<p>The scientists’ analysis of 70,000 cells <a href="https://www.nature.com/articles/s41586-018-0698-6">has also highlighted</a> that all sorts of other immune cells are also important in the construction of a placenta. What they all do, though, isn’t yet clear – this is at the edge of our knowledge.</p>
<figure class="align-center ">
<img alt="Scientist talking at meeting" src="https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=417&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=417&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=417&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=523&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=523&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472281/original/file-20220704-21-v511u5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=523&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Muzlifah Haniffa at the Human Cell Atlas launch meeting in 2016.</span>
<span class="attribution"><span class="source">Thomas Farnetti/Wellcome</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p><a href="https://www.ncl.ac.uk/medical-sciences/people/profile/mahaniffa.html">Muzlifah “Muzz” Haniffa</a> is one of the three women who led this analysis. As a physician and scientist, she sees the body from two perspectives on an almost daily basis: as a computational analysis of cells on a screen, and as patients who walk through the door. Both as stones and the arch they make.</p>
<p>Right now, these two views don’t easily mesh. But in time, they will. In the future, Haniffa thinks the tools doctors use on a daily basis – such as a stethoscope to listen to a person’s lungs, or a simple blood count – will be replaced by instruments that profile our body’s cells. Algorithms will analyse the results, clarify the underlying problem, and predict the best treatment. Many other physicians agree with her – this is the coming future of healthcare.</p>
<h2>What this could mean for you</h2>
<p>Babies are now routinely born by IVF, organ transplants have become common, and overall cancer survival rates in the UK have roughly doubled in recent years – but all these achievements are nothing to what’s coming.</p>
<p>As I’ve written about in <a href="https://www.amazon.co.uk/Secret-Body-Science-Human-Changing/dp/1529110971/">The Secret Body</a>, progress in human biology is accelerating at an unprecedented rate – not only through the Human Cell Atlas but in many other areas too. Analysis of our genes presents a <a href="https://www.theguardian.com/books/2013/aug/08/compatibility-gene-daniel-davis-review">new understanding of how we differ</a>; the actions of brain cells give clues to how our minds work; new structures found inside our cells lead to new ideas for medicine; proteins and other molecules found to be circulating in our blood change our view of mental health.</p>
<p>Of course, all science has an ever-increasing impact on our lives, but nothing affects us as deeply or directly as new revelations about the human body. On the horizon now, from all this research, are entirely new ways of defining, screening and manipulating health.</p>
<p>We are already accustomed to the idea that our personal genetic information can be used to guide our health. But a quieter – almost secret – revolution is also under way and it may have an even bigger impact on the future of healthcare: deep analytics of the human body’s cells.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=329&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=329&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=329&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=414&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=414&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472745/original/file-20220706-23-vv620k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=414&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">In the future a whole cloud of health information will be available to you, if you want to delve into it.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/genetic-research-biotech-science-concept-human-1084540790">Shutterstock</a></span>
</figcaption>
</figure>
<p>One day, a watch that can measure a few simple things about your body will be seen as a laughably primitive tool. In the future, maybe within ten years or so, a whole cloud of information will be available – including an analysis of your body’s cells – and you will have to decide how much you want to delve into it. This revolution in human biology will equip us individually with new powers – and we will each need to decide for ourselves if and when to deploy them.</p>
<p>You may, for example, one day visit your doctor with something abnormal on your skin – a rash, itch, or something else. The doctor may then take a small sample of your skin, or perhaps a blood sample, and from a complete cell-by-cell analysis of what’s there, be able to precisely diagnose the problem and know the best treatment. Indeed, some of this might even be automated. Further into the future, if the equipment needed to do this gets small and cheap enough, perhaps the analysis could be done by yourself at home.</p>
<p>Diseases will also be more frequently predicted before any symptoms are present at all. Of course, this is one of the most vital missions of science: to stop human disease before it even begins. For some illnesses, this has been achieved already – with vaccines, clean water and improved sanitation. Now, with the human body opening up to us through computational analysis of cells, genes and more, new ways of pre-empting disease are emerging. We are compelled to seize this new opportunity – yet in practice, there are challenges and unintended consequences to contend with.</p>
<p>Take a familiar example: the idea of the body-mass index, a value derived from a person’s weight and height. This is used to label us as underweight, normal weight, overweight or obese. It’s useful as it indicates an increased risk of health problems arising, such as type 2 diabetes, and steps can be taken to reduce the likelihood of this occurring. But the label itself can also trigger other sorts of problems relating to a person’s self-worth, and how society views obesity and human diversity.</p>
<h2>Difficult decisions about how you live</h2>
<p>Every one of us is susceptible to some disease or other, to some extent. So as science progresses and we learn more and more about ourselves, we will surely all find ourselves drowning in data about ourselves, awash with estimates and probabilities that play games with our mind and our identity, and require us to make difficult decisions about our health and how we live.</p>
<p>It seems feasible, for example, that the state of a person’s immune system, analysed in depth, could help predict the symptoms they are likely to have if infected with the Sars-CoV-2 virus, for example. Markers of immune activity might even correlate with a person’s mental health. One analysis concluded that particular pro-inflammatory secretions from immune cells (called cytokines) are found at higher levels in <a href="https://www.sciencedirect.com/science/article/pii/S088915911830789X?via%3Dihub">people who are depressed</a>.</p>
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Read more:
<a href="https://theconversation.com/coronavirus-we-must-step-up-research-to-harness-immense-power-of-the-immune-system-138071">Coronavirus: we must step up research to harness immense power of the immune system</a>
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<p>As we learn about the composition and status of the human body, this will inevitably establish new ways of assessing health. And it may very well help resolve problems in pregnancy too, as we’ve seen. But there are problems here too – if an analysis suggests a chance of a problem, say 50%, how would you act on this information if the medical intervention that could help has its own risks too?</p>
<p>There is seemingly no end to how the metric analysis of the human body will lead to important but complex new health decisions. <a href="https://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html">Angelina Jolie</a> famously acted on genetic information when she had both of her breasts surgically removed in 2013, and later her ovaries and fallopian tubes, following a genetic test which established that she had inherited a particular variation in a gene known as BRCA1. Crucially, she had been given a very high – 87% – chance of developing breast cancer. In general, risks and probabilities about our health are much less clear than this.</p>
<p>So the question arises, how are we to act on all this new information? What if something has been identified that means your risk of developing an autoimmune disease or cancer is one in six in the next ten years? Would it be different if it was one in four? At what point would you decide to take medicine as a precaution, or undergo surgery, knowing that they also carry their own risks? And would this knowledge in itself make you feel ill? Would your identity be affected?</p>
<p>I don’t have the answers – but that’s the point. As this new science progresses, each of us will have to decide how much we really want to know about ourselves.</p>
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<img alt="" src="https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=112&fit=crop&dpr=1 600w, https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=112&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=112&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=140&fit=crop&dpr=1 754w, https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=140&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/313478/original/file-20200204-41481-1n8vco4.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=140&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<p class="fine-print"><em><span>This article is an edited extract from Daniel M. Davis' new book The Secret Body (Vintage paperback, 2022). Davis is also the author of two previous books The Beautiful Cure and The Compatibility Gene. He receives research funding from The Medical Research Council, Cancer Research UK, Wellcome, GSK and Bristol Myers Squibb. He tweets at @dandavis101
</span></em></p>Pioneered by the Human Cell Atlas consortium, our understanding of the human body is about to be transformed – and with it, the way we treat and prevent diseaseDaniel M Davis, Professor of Immunology, University of ManchesterLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1825582022-05-12T15:51:53Z2022-05-12T15:51:53ZLab-grown mini-brains could help find treatments for Alzheimer’s and other diseases<figure><img src="https://images.theconversation.com/files/462026/original/file-20220509-11-qljz0l.png?ixlib=rb-1.1.0&rect=9%2C6%2C1002%2C1016&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It is possible to grow cells from a skin sample in a Petri dish and transform them into neurons in about a month.</span> <span class="attribution"><span class="source">(Camille Pernegre)</span>, <span class="license">Author provided</span></span></figcaption></figure><p>To assess whether a compound holds promise for treating a disease, researchers usually begin by studying its use in animals. This allows us to see if the compound has a chance of curing the disease. </p>
<p>Animal models, however, rarely reproduce all aspects of a disease. The alternative is to represent the disease in cell cultures. While at first glance, Petri dishes look quite different from a person with a disease, the reality could be quite different when you look at them more closely.</p>
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<p>Alzheimer’s has been cured more than <a href="https://doi.org/10.1002/trc2.12179">400 times in laboratories</a>. How then can we still consider Alzheimer’s to be incurable? The reason is that it has only been cured <a href="https://dx.doi.org/10.1111%2Fjoim.12191">in animals</a>. </p>
<p>A mouse does not naturally develop Alzheimer’s, it must be induced. To do this, scientists use our limited knowledge of what triggers Alzheimer’s and reproduce it in mice. In short, these mice don’t have Alzheimer’s: they have our flawed conception of Alzheimer’s.</p>
<p>As a doctoral student in psychology, I completed a research internship at the University of Montréal Health Centre (CHUM) in the laboratory of Professor Nicole Leclerc, with the goal of developing new models to study Alzheimer’s while discarding our limited theories about the disease.</p>
<p>In modern science, a new, untested compound <a href="https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research">cannot be used to treat a human disease</a> because it poses an unacceptable risk. Therefore, a disease model, which replicates our observations of the disease in humans, is used to test whether the new compound shows promise. Disease models, which often involve animals, allow researchers to develop treatments and diagnostic tools. They also give us the opportunity to better understand the <a href="https://dx.doi.org/10.1016%2FB978-0-12-811710-1.00008-2">processes behind the disease being studied</a>. Models are an essential tool in biomedical science.</p>
<h2>Disease models of the future</h2>
<p>Studying a disease would be easier if we could directly observe and act on the cells that stop functioning properly. In the case of Alzheimer’s, it is impossible to take a slice of brain from a living person to experiment on the neurons inside. </p>
<p>However, I am working on developing a technique that will come very close to replicating that process. By taking a small piece of skin from the patient, I can grow the cells in a Petri dish and turn them into neurons in about a month.</p>
<figure class="align-center ">
<img alt="Hand of a man wearing blue rubber gloves and holding a blue liquid sample in a Petri dish in a chemistry lab" src="https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">While at first glance the Petri dish looks quite different from a person with a disease, the reality could be quite different when you look at them more closely.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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<p>The method takes advantage of the fact that all of the cells in a person’s body have the same genetic code. What differentiates a skin cell from a neuron is simply the genes the cell expresses. This means I can force a skin cell to express typical neuronal genes so that it is gradually transformed into a neuron. </p>
<p>These neurons retain the signatures of aging, which are crucial for studying age-related diseases. The advantages are clear: one can produce a colony of human neurons from a person with Alzheimer’s. The neurons from Alzheimer’s patients will then develop <a href="https://www.sciencedirect.com/science/article/pii/S1934590921001612">Alzheimer’s characteristics</a>, making it easier to study the disease.</p>
<p>However, the neuron does not function in a vacuum; other cell types interact with it. To improve a neuronal culture, researchers can push the concept even further by producing <a href="https://www.frontiersin.org/articles/10.3389/fcell.2020.579659/full">organoids</a>. These are cell cultures comprising several types of cells. A brain organoid could more accurately re-create brain function, and be a better model of nervous system diseases.</p>
<h2>Versatile disease models</h2>
<p>If a cell functions abnormally in a person with a particular disease, we will try to understand its behaviour. By observing a model of the disease, we can find out if this abnormal functioning is similar to that observed in the brains of actual patients. If it is, we can try to modify the cell function in our model to see if there is a beneficial effect.</p>
<p>The primary function of models is to make it easier to study a disease. A good model must represent the disease as reliably as possible. When a model is considered sufficiently representative of the disease, it can be used in preclinical studies to verify whether a compound has the potential to cure it without being harmful. </p>
<p>When the disease is well reproduced by the model, researchers can assume that a treatment that works on it will be likely to work in people with the disease. Cell cultures and organoids from patients are particularly promising because of this. Even if we don’t know all the features of a disease, there is a chance that these will also be replicated in the models.</p>
<p>Because these models come from real patients, they could be used for a third unique purpose in the future: <a href="https://doi.org/10.1186/s13619-020-00059-z">personalized medicine</a>. Patients with the same disease are heterogeneous and may not respond in the same way to a treatment. When several types of therapies exist, we rely on trial and error to identify the best one for each patient.</p>
<p>In 2021, Kimberly K. Leslie’s team at the University of Iowa demonstrated that organoids might remedy this problem. They used endometrial and ovarian cancer tissues from patients to create organoids, <a href="https://www.mdpi.com/2072-6694/13/12/2901">showing their potential to evaluate different treatments</a>. In the same year, a team from Singapore and Hong Kong demonstrated that organoids could be used to <a href="https://doi.org/10.3389/fonc.2021.622244">predict the response of nasopharyngeal tumours to radiation therapy and adjust the dose</a>. </p>
<p>This method may make it possible to select the most promising treatment for an individual in a much shorter time. But it has only been tested in animal models and cell extracts, and its feasibility in humans has yet to be proven.</p>
<h2>Promising, but imperfect models</h2>
<p>A treatment that works in a disease model will not necessarily work in humans. This is precisely why Alzheimer’s, or at least its reconstruction in a laboratory animal model, has been “cured” more than 400 times but not in humans. </p>
<p>Similarly, it is possible that compounds that slow the progression of Alzheimer’s have failed to cure these animals, and have been discarded. For neurodegenerative diseases like Alzheimer’s, creating a representative model is particularly complex since the disease does not have a single cause. We know of <a href="https://pubs.rsc.org/en/content/chapterhtml/2022/bk9781839162305-00001?isbn=978-1-83916-230-5&sercode=bk">hundreds of processes that are thought to be deregulated by Alzheimer’s</a>, involving the nervous, cardiovascular and immune systems.</p>
<p>It is not yet possible to reproduce these interactions in cell cultures. Even if future models allow researchers to better represent the disease, and perhaps discover treatments, they will always be imperfect. So, finding a cure in a model will never be the same as identifying a cure for a disease.</p><img src="https://counter.theconversation.com/content/182558/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Étienne Aumont has received a scholarship from the Canadian Institutes of Health Research</span></em></p>Cell cultures have shown promise in representing diseases. The Petri dish is not as different from a sick person as one might think.Étienne Aumont, Étudiant au doctorat en psychologie, Université du Québec à Montréal (UQAM)Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1732102022-01-28T13:27:13Z2022-01-28T13:27:13ZNew insights from biology can help overcome siloed thinking in cancer clinical trials and treatment<figure><img src="https://images.theconversation.com/files/441611/original/file-20220119-25-164wpa0.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C537%2C420&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Metabolic conditions like obesity and diabetes can influence how cancer develops and responds to treatment.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/chemo-therapy-royalty-free-image/1134307405?adppopup=true">Eric Kitayama/iStock via Getty Images Plus</a></span></figcaption></figure><p>Rarely does an oncologist closely question a breast cancer patient about their blood glucose, body weight, lipid profile, or medications for diabetes and cardiovascular disease. Instead, these issues are usually the concern of the patient’s primary care provider. </p>
<p>Medical experts have <a href="https://doi.org/10.1152/physrev.00030.2014">recognized that obesity</a>, defined as a body mass index of 30 or greater, increases the <a href="https://doi.org/10.1016/j.canep.2016.01.003">risk of several cancers</a>. They include cancers of the breast, esophagus, kidney, gallbladder, liver, colon and several other organs. We have been aware of this relationship for <a href="https://doi.org/10.1038/sj.onc.1207751">about 20 years</a>. Despite this awareness, medicine is still missing a holistic view of people with cancer.</p>
<p>When testing new cancer drugs, clinical trials traditionally exclude patients with a history of heart disease, kidney disease, diabetes or similar chronic conditions related to obesity. The purpose is to make <a href="https://doi.org/10.1001/jamaoncol.2019.1187">study results easier to interpret</a>. But this practice leaves cancer researchers with a weak understanding of how patients could be monitored and treated for <a href="https://doi.org/10.1038/nrc1550">obesity-driven cancers</a>. One way it limits their knowledge is by leaving out significant numbers of patients. Among them are patients of color, who are already underrepresented in <a href="https://doi.org/10.3233/SHTI190369">scientific studies</a> generally and <a href="https://doi.org/10.1002/cncr.23157">cancer treatment treatment trials</a> in particular.</p>
<p>As a <a href="https://profiles.bu.edu/Gerald.Denis">molecular oncologist</a> at Boston Medical Center, I explore how metabolic conditions like <a href="https://scholar.google.com/citations?user=2f8xa-oAAAAJ&hl=en">obesity and diabetes</a> can influence whether someone develops cancer. I look closely at how these conditions can affect how the cancer grows, spreads or responds to treatment.</p>
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<img alt="Blue-gloved hand holding clear vial of blood." src="https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441767/original/file-20220120-8584-1uztb33.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Less invasive cancer detection and treatment is one potential benefit of better communication between endocrinologists and cancer specialists.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/blood-sample-for-lipid-profile-testing-medical-royalty-free-image/1354714222?adppopup=true">Juan Ruiz Parmo/iStock via Getty Images Plus</a></span>
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<p>Our teams at Boston Medical Center’s Cancer Center have have identified how obesity and diabetes may provoke cancer to spread in potentially deadly ways. In particular, <a href="https://doi.org/10.1016/S0026-0495(78)80007-9">insulin-resistant fat cells</a> are likely to play a critical role in provoking breast cancer cells to move from the original tumor to distant organs like the lungs, liver, bones or brain. These distant metastases commonly define the end stage before someone with breast cancer dies.</p>
<p>Our results show that in the <a href="https://doi.org/10.1126/scisignal.abj2807">microscopic neighborhood inside or near a tumor</a>, cancer cells and noncancerous fat cells sit right next to each other, like neighbors on a park bench. Our research has shown that these two cell types engage in active “cross-talk.” This communication may inhibit or promote a tumor’s ability to grow and spread. How that happens is not well understood, partly because oncologists – whether studying cancer or treating it – generally don’t take nearby fat cells into consideration. </p>
<h2>Strategic diagnosis and treatment</h2>
<p>Acknowledging the relationship between fat cells and cancer cells offers opportunities to find and treat cancer less invasively. With molecules isolated from just a teaspoon or less of a patient’s blood, specialists can learn the risk that the cancer might be growing and spreading. These molecules, <a href="https://doi.org/10.1016/j.molonc.2012.01.010">called biomarkers</a>, can also show which patients are in the greatest danger of treatment failure. Taking occasional blood samples is less invasive than repeated biopsies, which involves getting samples of breast or other tissue. </p>
<p>When endocrinologists and oncologists consult with one another, they can consider obesity and metabolism alongside the current standard of care for patients with cancer. This combination would likely benefit populations, like <a href="https://doi.org/10.1200/JCO.2003.08.010">older adults</a>, in which both obesity and metabolic disease are more prevalent. </p>
<p>Furthermore, the cancer patient population may soon include more <a href="https://doi.org/10.1038/s41571-020-00445-1">young people</a>. A 2019 study found that people age 50 or younger have a <a href="https://doi.org/10.1016/S2468-2667(18)30267-6">disproportionately elevated risk</a> for certain obesity-driven cancers, including obesity-associated colorectal cancer. The relationship between fat cells and cancer cells could explain some of these trends.</p>
<h2>Closing gaps in care</h2>
<p>And already, more young African American adults are developing <a href="https://doi.org/10.1097/MEG.0000000000001205">aggressive colorectal cancers</a> than young adults of <a href="https://doi.org/10.3322/caac.21555">other races</a>. This fact came to the nation’s attention in 2020, when actor <a href="https://doi.org/10.2196/29387">Chadwick Boseman died</a> from an <a href="https://doi.org/10.1002/cncr.33919">aggressive colon cancer</a> at age 43. </p>
<p>Although Boseman was not overweight, his death brought attention to the community of African American adults who experience higher risks not only <a href="https://doi.org/10.1007/s10549-015-3353-z">for obesity</a> and <a href="https://doi.org/10.2105/ajph.92.4.543">diabetes</a> but also for several cancers including <a href="https://doi.org/10.1007/s11934-017-0724-5">prostate</a>, <a href="https://doi.org/10.1158/1055-9965.EPI-07-0336">breast</a> and <a href="https://doi.org/10.1053/j.gastro.2019.10.029">colorectal</a>. And despite their higher risks, Black patients are often not effectively counseled <a href="https://doi.org/10.1093/jnci/djab073">by physicians</a> regarding cancer risk and treatment.</p>
<p>[<em>Get fascinating science, health and technology news.</em> <a href="https://memberservices.theconversation.com/newsletters/?nl=science&source=inline-science-fascinating">Sign up for The Conversation’s weekly science newsletter</a>.]</p>
<p>At Boston Medical Center, 50% of our patients have diagnoses of obesity and 30% have Type 2 diabetes. We see similar numbers and patterns in our cancer patient population. One potential reason is that Boston Medical Center is a <a href="https://doi.org/10.1177/1077558708315440">safety-net hospital</a>, providing essential and excellent care to a very diverse range of patients regardless of insurance, immigration status or medical literacy. Such hospitals are often located in neighborhoods with high rates of <a href="https://doi.org/10.1001/archinternmed.2011.287">obesity and diabetes</a>.</p>
<p>Black and Latino adults with cancer tend to be overrepresented in <a href="https://doi.org/10.1007/BF02345673">safety-net hospital systems</a>. They receive cancer screenings <a href="https://doi.org/10.1016/j.athoracsur.2019.11.052">less often</a>. They also experience
<a href="https://doi.org/10.1080/03630242.2010.530928">longer wait times</a>, first for diagnosis and then for treatment. These factors contribute to <a href="https://doi.org/10.1016/j.canep.2017.05.003">worse survival rates</a> among Black and Latino cancer patients. Some of these worse outcomes may be a result of cancer and diabetes <a href="https://doi.org/10.1530/ERC-16-0222">interacting in these patients</a>.</p>
<p>Addressing disparities like these would be a natural benefit of bringing together previously disconnected clinical specialties. Research on the linkage among obesity, diabetes and cancer is revealing new pathways and molecules that tie these different diseases together. These new insights could improve outcomes for patients who are at greatest risk, and prompt more holistic assessments and treatments for all patients.</p><img src="https://counter.theconversation.com/content/173210/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gerald Denis receives funding from the National Cancer Institute.</span></em></p>Fat cells and cancer cells talk to each other. Specialists in both systems can do the same.Gerald Denis, Professor of Medicine and Pharmacology, Boston UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1658042021-12-02T13:42:06Z2021-12-02T13:42:06ZSea otters demonstrate that there is more to muscle than just movement – it can also bring the heat<figure><img src="https://images.theconversation.com/files/432004/original/file-20211115-21-1852gim.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C5472%2C3637&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Sea otters are born with a supercharged metabolism.
</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/cute-sea-otter-making-a-splash-royalty-free-image/1304610196">Adria Photography/Moment via Getty Images</a></span></figcaption></figure><p>Life in the cold can be difficult for animals. As the body chills, organs including the brain and muscles slow down. </p>
<p>The body temperature of animals such as reptiles and amphibians mostly depends on the temperature of their environment – but mammals can increase their metabolism, using more energy to warm their body. This allows them to <a href="https://doi.org/10.1146/annurev.ph.57.030195.000441">live in colder areas and stay active when temperatures drop</a> at night or during winter months. </p>
<p>Although scientists know mammals can increase their metabolism in the cold, it has not been clear which organs or tissues are using this extra energy to generate more heat. Staying warm is especially challenging for small, aquatic mammals like sea otters, so we wanted to know how they have adapted to survive the cold. </p>
<p>We assembled <a href="https://scholar.google.com/citations?hl=en&user=j27jLwUAAAAJ">a</a> <a href="https://scholar.google.com/citations?hl=en&user=oWs13ikAAAAJ">research</a> <a href="https://scholar.google.com/citations?hl=en&user=-BQkMmoAAAAJ">team</a> with expertise in both human and marine mammal metabolism, including <a href="https://scholar.google.com/citations?hl=en&user=hsiWIEEAAAAJ">Heidi Pearson</a> of the University of Alaska Southeast and <a href="https://scholar.google.com/citations?hl=en&user=G3AiPisAAAAJ">Mike Murray</a> of the Monterey Bay Aquarium. Understanding energy use in animals adapted to life in the cold may also provide clues for manipulating human metabolism.</p>
<h2>Sea otter metabolism</h2>
<p>It is especially difficult for water-living mammals to stay warm because <a href="https://doi.org/10.1080/23328940.2021.1988817">water conducts heat away from the body much faster than air</a>. Most marine mammals have large bodies and a thick layer of fat or <a href="https://doi.org/10.1080/23328940.2021.1988817">blubber for insulation</a>. </p>
<p>Sea otters are the smallest of the marine mammals, and do not have this thick layer of blubber. Instead, they are insulated by the densest fur of any mammal, with as many as <a href="https://doi.org/10.1111/j.1748-7692.1992.tb00120.x">a million hairs per square inch</a>. This fur, however, is high maintenance, requiring <a href="https://www.youtube.com/watch?v=sgFMVRtkpVY&list=PLq_DVMr7CmlIb0n3DhtcU8lESsxX-wqP7&index=2">regular grooming</a>. About 10% of a sea otter’s <a href="https://doi.org/10.1242/jeb.02767">daily activity</a> involves maintaining the insulating layer of air trapped in their fur.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Z4OKk2lErwc?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Grooming is a never-ending job.</span></figcaption>
</figure>
<p>Dense fur is not enough, by itself, to keep sea otters warm. To generate enough body heat, their metabolic rate at rest is <a href="https://link.springer.com/book/10.1007%2F978-3-319-98280-9">about three times higher</a> than that of most mammals of similar size. This high metabolic rate has a cost, though.</p>
<p>To obtain enough energy to fuel the high demand, sea otters must eat <a href="https://doi.org/10.1086/physzool.55.1.30158441">more than 20% of their body mass</a> in food each day. In comparison, humans eat around 2% of their body mass – about <a href="https://doi.org/10.1079/BJN19810074">3 pounds (1.3 kilograms) of food per day</a> for a 155-pound (70 kg) person.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A sea otter floating on its back eating a crab." src="https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/432007/original/file-20211115-17-rlq9ul.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Feeding on Dungeness crab in Monterey Bay, California.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/sea-otter-and-crab-royalty-free-image/1209955271">Chase Dekker Wild-Life Images/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>Where does the heat come from?</h2>
<p>When animals eat, the energy in their food cannot be used directly by cells to do work. Instead, the food is broken down into simple nutrients, such as fats and sugars. These nutrients are then transported in the blood and absorbed by cells. </p>
<p>Within the cell are compartments called mitochondria where nutrients are converted into <a href="https://www.nature.com/scitable/definition/atp-318/">ATP</a> – a high-energy molecule that acts as the energy currency of the cell. </p>
<p>The process of converting nutrients into ATP is similar to <a href="https://www.usgs.gov/special-topic/water-science-school/science/hydroelectric-power-how-it-works?qt-science_center_objects=0#qt-science_center_objects">how a dam turns stored water into electricity</a>. As water flows out from the dam, it makes electricity by spinning blades connected to a generator – similar to wind turning the blades on a windmill. If the dam is leaky, some water – or stored energy – is lost and cannot be used to make electricity.</p>
<p>Similarly, leaky mitochondria are less efficient at making ATP from nutrients. Although the leaked energy in the mitochondria cannot be used to do work, it generates heat to warm the sea otter’s body.</p>
<p><a href="https://doi.org/10.1152/physrev.1997.77.3.731">All tissues in the body use energy and make heat</a>, but some tissues are larger and more active than others. Muscle makes up 30% of the body mass of most mammals. When active, muscles consume a lot of energy and produce a lot of heat. You have undoubtedly experienced this, whether getting hot during exercise or <a href="https://theconversation.com/its-cold-a-physiologist-explains-how-to-keep-your-body-feeling-warm-108816">shivering when cold</a>. </p>
<p>To find out if muscle metabolism helps keep sea otters warm, we studied small muscle samples from sea otters ranging in size and age from newborn pups to adults. We placed the muscle samples in small chambers designed to monitor oxygen consumption – a measure of how much energy is used. By adding different solutions that stimulated or inhibited various metabolic processes, we determined how much energy the mitochondria could use to make ATP – and how much energy could go into heat-producing leak. </p>
<p>We discovered the mitochondria in <a href="https://doi.org/10.1126/science.abf4557">sea otter muscles could be very leaky</a>, allowing otters to turn up the heat in their muscles without physical activity or shivering. It turns out that sea otter muscle is good at being inefficient. The energy “lost” as heat while turning nutrients into movement allows them to survive the cold.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A sea otter floats on her back, feeding her pup small bits of food." src="https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=410&fit=crop&dpr=1 600w, https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=410&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=410&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=516&fit=crop&dpr=1 754w, https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=516&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/431999/original/file-20211115-17-1g2znp7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=516&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A mother sea otter ‘hand-feeds’ her baby bits of crab. Moro Bay, California.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/feeding-baby-dinner-royalty-free-image/582228357">PhotoviewPlus/Moment Open via Getty Images</a></span>
</figcaption>
</figure>
<p>Remarkably, we found newborn pups have the same metabolic ability as adults, even though their muscles have not yet matured for swimming and diving. </p>
<h2>Broader implications</h2>
<p>Our research clearly demonstrates that muscle is important for more than just movement. Because muscle makes up such a large portion of body mass, even a small increase in muscle metabolism can dramatically increase how much energy an animal uses. </p>
<p>[<em>More than 140,000 readers get one of The Conversation’s informative newsletters.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140K">Join the list today</a>.]</p>
<p>This has important implications for human health. If scientists discover ways to safely and reversibly increase skeletal muscle metabolism at rest, doctors could possibly use this as a tool to reduce climbing rates of obesity by increasing the amount of calories a patient can burn. Conversely, reducing skeletal muscle metabolism could conserve energy in patients suffering from cancer or other wasting diseases and could reduce food and resources needed to support astronauts on long-duration spaceflight.</p><img src="https://counter.theconversation.com/content/165804/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Randall Davis has received research funding from the National Science Foundation and NOAA.</span></em></p><p class="fine-print"><em><span>Melinda Sheffield-Moore and Traver Wright do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>New research finds that ‘leaky mitochondria’ help keep sea otters warm.Traver Wright, Research Assistant Professor of Health and Kinesiology, Texas A&M UniversityMelinda Sheffield-Moore, Professor of Health and Kinesiology, Texas A&M UniversityRandall Davis, Regents Professor, Department of Marine Biology, Texas A&M UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1698812021-10-21T12:10:20Z2021-10-21T12:10:20ZLife extension: the five most promising methods – so far<figure><img src="https://images.theconversation.com/files/427578/original/file-20211020-19-1loljgc.jpg?ixlib=rb-1.1.0&rect=121%2C55%2C7227%2C4847&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Exercise is still one of the best ways to boost longevity.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/senior-group-friends-exercise-relax-concept-494089063">Rawpixel.com/Shutterstock</a></span></figcaption></figure><p>Most people want to live a long and happy life – or at least avoid a short and miserable one. If you’re in that majority, then you’re in luck. Over the last decade, <a href="https://theconversation.com/is-150-years-really-the-limit-of-human-life-span-162209">a quiet research revolution</a> has occurred in our understanding of the biology of ageing. </p>
<p>The challenge is to turn this knowledge into advice and treatments we can benefit from. Here we bust the myth that lengthening healthy life expectancy is science fiction, and show that it is instead scientific fact.</p>
<h2>1. Nutrition and lifestyle</h2>
<p>There’s plenty of evidence for the benefits of doing the boring stuff, such as eating right. A <a href="https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0050012">study of large groups of ordinary people</a> show that keeping the weight off, not smoking, restricting alcohol to moderate amounts and eating at least five servings of fruit and vegetable a day can increase your life expectancy by seven to 14 years compared with someone who smokes, drinks too much and is overweight.</p>
<figure class="align-center ">
<img alt="Image of fruit and vegetables." src="https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=267&fit=crop&dpr=1 600w, https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=267&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=267&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=335&fit=crop&dpr=1 754w, https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=335&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/427579/original/file-20211020-18022-1wnwsz7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=335&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Your five a day is essential.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/healthy-food-clean-eating-selection-fruit-722718097">Natalia Lisovskaya/Shutterstock</a></span>
</figcaption>
</figure>
<p>Cutting down calories even more - by about a third, so-called dietary restriction - improves health and extends life in mice and monkeys, as long as they eat the right stuff, though that’s a tough ask for people constantly exposed to food temptation. The less extreme versions of <a href="https://www.nature.com/articles/s43587-020-00013-3.pdf?proof=t">time-restricted or intermittent fasting</a> – only eating during an eight-hour window each day, or fasting for two days every week – is thought to reduce the risk of middle-aged people getting age-related diseases. </p>
<h2>2. Physical activity</h2>
<p>You can’t outrun a bad diet, but that doesn’t mean that exercise does not do good things. Globally, inactivity directly causes roughly 10% of all premature <a href="https://www.sciencedirect.com/science/article/pii/S0140673612610319?via%3Dihub">deaths from chronic diseases</a>, such as coronary heart disease, type 2 diabetes and various cancers. If everyone on Earth got enough exercise tomorrow, the effect would probably be to increase healthy human life expectancy by almost a year. </p>
<p>But how much exercise is optimal? Very high levels are actually bad for you, not simply in terms of torn muscles or sprained ligaments. It can suppress the immune system and <a href="https://pubmed.ncbi.nlm.nih.gov/2266764/">increase the risk</a> of upper respiratory illness. Just over <a href="https://www.bmj.com/content/368/bmj.l6669.long">30 minutes</a> a day of moderate to vigorous physical activity is enough for most people. Not only does that make you stronger and fitter, it has been shown to <a href="https://onlinelibrary.wiley.com/doi/10.1111/acel.12750">reduce harmful inflammation</a> and even improve mood.</p>
<h2>3. Boosting the immune system</h2>
<p>However fit you are and well you eat, your immune system will, unfortunately, get less effective as you get older. Poor responses to vaccination and an inability to fight infection are consequences of this “immunosenescence”. It all starts to go downhill in early adulthood when the thymus – a bowtie-shaped organ in your throat – starts to wither. </p>
<p>That sounds bad, but it’s even more alarming when you realise that the thymus is where immune agents called T cells learn to fight infections. Closing such a major education centre for T cells means that they <a href="https://immunityageing.biomedcentral.com/articles/10.1186/s12979-020-0173-8;%20https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203483/">can’t learn to recognise</a> new infections or fight off cancer effectively in older people. </p>
<p>You can help – a bit – by making sure you have enough key vitamins, especially A and D. A promising area of research is looking at signals that the body sends to help make more immune cells, particularly a molecule called <a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL7">IL-7</a>. We may soon be able to produce <a href="https://www.nature.com/articles/nri2970">drugs that contain this molecule</a>, potentially boosting the immune system in older people. Another approach is to use the food supplement spermidine to trigger immune cells to clear out their internal garbage, such as damaged proteins, which improves the elderly immune system so much <a href="https://elifesciences.org/articles/57950">that it’s now being tested</a> as a way of getting better responses to COVID vaccines in older people. </p>
<h2>4. Rejuvenating cells</h2>
<p>Senescence is a toxic state that cells enter into as we get older, wreaking havoc across the body and generating chronic low-grade inflammation and disease – essentially causing biological ageing. In 2009, scientists showed that middle-aged mice <a href="https://www.nature.com/articles/nature08221">lived longer and stayed healthier</a> if they were given small amounts of a drug called rapamycin, which inhibits a key protein called mTOR that helps regulate cells’ response to nutrients, stress, hormones and damage. </p>
<p>In the lab, drugs like rapamycin (called mTOR inhibitors) make senescent (aged) human cells <a href="https://www.aging-us.com/article/100872/text">look and behave like their younger selves</a>. Though it’s too early to prescribe these drugs for general use, a new clinical trial has just been set up to test whether low-dose rapamycin <a href="https://clinicaltrials.gov/ct2/show/NCT04488601">can really slow down ageing in people</a>. </p>
<figure class="align-center ">
<img alt="Image of the structural chemical formula of sirolimus (rapamycin) molecule with white tablets and pills." src="https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=438&fit=crop&dpr=1 600w, https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=438&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=438&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=551&fit=crop&dpr=1 754w, https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=551&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/427576/original/file-20211020-19039-r1jref.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=551&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The sirolimus (rapamycin) molecules may help us live longer.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/structural-chemical-formula-sirolimus-molecule-white-1645943026">Danijela Maksimovic/Shutterstock</a></span>
</figcaption>
</figure>
<p>Discovered in the soil of Easter Island, Chile, rapamycin carries with it significant mystique and [has been hailed] in the popular press as a possible “elixir of youth”. It can even <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009979">improve the memory of mice</a> with dementia-like disease. </p>
<p>But all drugs come with pros and cons – and as too much rapamycin suppresses the immune system, many doctors are averse to even consider it to stave off age-related diseases. However, the dose is critical and newer drugs such as <a href="https://clinicaltrials.gov/ct2/show/NCT04668352">RTB101</a> that work in a similar way to rapamycin support the immune system in older people, and can even <a href="https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00062-3/fulltext">reduce COVID infection rates</a> and severity. </p>
<h2>5. Clearing out old cells</h2>
<p>Completely getting rid of senescent cells is another promising way forward. A growing number of lab studies in mice using drugs to kill senescent cells - so-called “senolytics” - show overall improvements in health, and as the mice aren’t dying of disease, <a href="https://www.science.org/doi/10.1126/science.aaw1299">they end up living longer too</a>. </p>
<p>Removing senescent cells also helps people. In a small clinical trial, people with severe lung fibrosis reported better overall function, including how far and fast they could walk, <a href="https://www.sciencedirect.com/sdfe/reader/pii/S2352396418306297/pdf">after they had been treated</a> with senolytic drugs. But this is only the tip of the iceberg. Diabetes and obesity, as well as infection with some bacteria and viruses, can lead to more senescent cells forming. Senescent cells also make the lungs more susceptible to COVID infection, and COVID <a href="https://www.science.org/doi/10.1126/science.abe4832">makes more cells become senescent</a>. Importantly, getting rid of senescent cells in old mice <a href="https://www.science.org/doi/10.1126/science.abi4474">helps them to survive COVID infection</a>.</p>
<p>Ageing and infection are a two-way street. Older people get more infectious diseases as their immune systems start to run out of steam, while infection drives faster ageing through senescence. Since ageing and senescence are inextricably linked with both chronic and infectious diseases in older people, treating senescence is likely to improve health across the board. </p>
<p>It is exciting that some of these new treatments are already looking good in clinical trials and may be available to us all soon.</p><img src="https://counter.theconversation.com/content/169881/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Faragher has received funding from the BBSRC. He serves on the Scientific Advisory Board of the Longevity Vision Fund and is a Director of the American Federation for Aging Research </span></em></p><p class="fine-print"><em><span>Lynne Cox runs a lab studying ageing at the University of Oxford. She receives research funding from Diabetes UK, BIRAX, Research England (UK SPINE), Public Health England, Elysium Health and the Mellon Longevity Science Programme at Oriel College, Oxford. She is affiliated with The British Society for Research on Ageing, The European Geriatric Medicine Society and serves on the Strategic Advisory Board of the All Party Parliamentary Group for Longevity. The views expressed are her own.</span></em></p>Life-extension therapies may be coming sooner than you think.Richard Faragher, Professor of Biogerontology, University of BrightonLynne Cox, Associate Professor of Biochemistry, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1598312021-04-30T15:09:34Z2021-04-30T15:09:34ZHow our immune system helps us fight antibiotic resistance<figure><img src="https://images.theconversation.com/files/398100/original/file-20210430-23-f1kt7e.jpg?ixlib=rb-1.1.0&rect=62%2C0%2C7000%2C4338&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/red-colored-multiple-antibiotic-resistant-pseudomonas-1535690891">Christoph Burgstedt/ Shutterstock</a></span></figcaption></figure><p>While our immune system and antibiotics both do a great job of helping us fight life-threatening infections, the emergence of <a href="https://theconversation.com/bacteria-shuffle-their-genetics-around-to-develop-antibiotic-resistance-on-demand-156439">antibiotic resistance</a> is quickly making it more difficult to cure common infections that were once easily treated. Antibiotic resistance happens when bacteria evolve and survive the treatments designed to eliminate them – and then reproduce or pass this resistance on to other bacteria.</p>
<p>Plenty of research is currently taking place to find ways of preventing the spread of antibiotic resistance. But there are still many questions that researchers don’t have answers to. One such question is knowing how resistance evolves inside a person in real-time. Knowing what happens in the body during an infection could help us develop better treatments for antibiotic resistance.</p>
<p>In our <a href="https://www.nature.com/articles/s41467-021-22814-9">recently published study</a>, we investigated the bacterial population in the lungs of an intensive care patient who had a lung infection caused by a common type of bacteria, <em>Pseudomonas aeruginosa</em>. We were able to observe in real-time how both the rapid evolution of antibiotic resistant bacteria, alongside the immune system’s action, were important in determining the outcome of the patient’s infection.</p>
<p>We used a number of techniques and experiments that measured bacterial growth and any changes in antibiotic resistance that happened during the infection. We paired these experiments with genome sequencing techniques to identify changes to the bacterial genetic code. This told us how the bacteria evolves, and whether it evolved antibiotic resistance.</p>
<p>We also measured the number of immune system molecules present in the lungs which were known to fight against <em>Pseudomonas aeruginosa</em>. Samples from the lungs were analysed every few days – allowing us to capture in high resolution the changes that were taking place. This revealed in unprecedented detail how the immune system played a role in suppressing the antibiotic resistant bacteria that evolved.</p>
<p>We found that the bacteria in the lungs became highly resistant to one of the antibiotics used to eliminate them. These bacteria evolved resistance by mutating and modifying components of their cell wall (the outer layer surrounding the cell). Some bacteria were even found to have modified an entry point in the cell wall used by antibiotics to destroy them. Others were found to have modified a structural element of this layer.</p>
<figure>
<iframe src="https://player.vimeo.com/video/542172264" width="500" height="281" frameborder="0" webkitallowfullscreen="" mozallowfullscreen="" allowfullscreen=""></iframe>
<figcaption><span class="caption">How our immune system and antibiotics can work together against an infection.</span></figcaption>
</figure>
<p>While modifying the entry point massively increased antibiotic resistance, it also made the bacteria less fit. This caused them to grow slower as a result. These highly resistant bacteria rapidly disappeared from the population following the end of antibiotic treatment, replaced by more fit and faster growing relatives.</p>
<p>But the bacteria which only modified a structural element of their cell wall had increased antibiotic resistance – without cost to their survival. In fact, they were able to grow faster. If these bacteria were passed to another person, they would be able to cause infections that are more difficult to treat with antibiotics. These bacteria remained in the lungs – even after their less fit relatives were replaced. </p>
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Read more:
<a href="https://theconversation.com/bacteria-shuffle-their-genetics-around-to-develop-antibiotic-resistance-on-demand-156439">Bacteria 'shuffle' their genetics around to develop antibiotic resistance on demand</a>
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<h2>The immune system</h2>
<p>Here is where the immune system was really important.</p>
<p>Before the person was treated with antibiotics, we found that the population of bacteria causing the infection had already begun to decline. This showed us that the immune system was doing its job. This also made the antibiotics more successful, as they work better when targeting small bacterial populations. </p>
<p>However, the bacterial infection reappeared around 11 days after it was last detected – and with antibiotic resistant mutants. The first time, the immune system worked together with the antibiotics. This time no new antibiotics were administered, and our research revealed that the immune system was able to fight the infection on its own. </p>
<p>Crucially, this revealed that natural immunity was able to wipe out the population of antibiotic resistance bacteria that emerged following the first course of antibiotic treatment. </p>
<p>We can’t be 100% sure whether the mutant bacteria were or weren’t passed on to other people, but the less time the bacteria are at high levels in the lungs, the less likely it is to be passed on. Such infections can be passed on via a patient coughing and expelling the bacteria from the lungs, and so on.</p>
<p>Our findings suggest that natural immunity can suppress resistance during infection and limit the transmission of resistant strains between patients. In the future, exploiting this link could help us develop new therapeutics to use against harmful bacteria – and may help us better prevent the spread of antibiotic resistant bacteria.</p><img src="https://counter.theconversation.com/content/159831/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rachel Wheatley receives funding from the Innovative Medicines Initiative Joint Undertaking under COMBACTE-MAGNET (Combatting Bacterial Resistance in Europe-Molecules against Gram-negative Infections) and COMBACTE-NET (Combatting Bacterial Resistance in Europe-Networks), resources of which are composed of financial contribution from the European Union’s Seventh Framework Program and EFPIA companies’ in kind contribution. </span></em></p><p class="fine-print"><em><span>Julio Diaz Caballero receives funding from The Wellcome Trust. </span></em></p>Observing the progression of an infection in real-time allows us to better understand how antibiotic resistance develops.Rachel Wheatley, Postdoctoral Researcher in Bacterial Evolution, University of OxfordJulio Diaz Caballero, Postdoctoral Researcher in Microbial Genomics, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1567192021-03-23T16:36:17Z2021-03-23T16:36:17ZCancer: tiny diamonds in cells could help to understand development process<figure><img src="https://images.theconversation.com/files/390933/original/file-20210322-13-1l38eav.jpg?ixlib=rb-1.1.0&rect=0%2C13%2C4500%2C4479&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-rendered-medically-accurate-illustration-human-1061676194">SciePro/Shutterstock</a></span></figcaption></figure><p>Over the years, scientists have put together an amazing array of microscopic markers that they can place within cells whenever they need to label and observe distinct parts of a cell’s interior. Such labelling is used for a wide array of research, including cancer research.</p>
<p>But sneaking these markers into cells, through the membrane that protects them from unwanted substances, is far from easy. Creating too wide a breach in the cell membrane when injecting the markers can be fatal for the cell. Plus, once they’re smuggled inside, many markers are actually toxic – and are either attacked by the cell, or lead to its demise.</p>
<p>In the search for non-toxic markers, scientists have landed upon nanodiamonds: identical to those bejewelling engagement rings, but a million times smaller. Nanodiamonds make excellent reporters within cells, but they’re yet to feature in scientists’ toolkits because getting them inside the cell without damaging the membrane has proven too difficult.</p>
<p>Led by my supervisor Christelle Prinz from NanoLund, Lund University, our team has created a new way to sneak nanodiamonds into cells without causing damage or provoking the cell to attack them. <a href="https://onlinelibrary.wiley.com/doi/full/10.1002/smll.202006421">Our new technique</a> will help scientists study the properties of living cells at the molecular level, but it could also become a versatile new tool to help us understand more about cellular diseases like cancer and Alzheimer’s.</p>
<h2>Monitoring cells</h2>
<p>Our bodies are built out of approximately <a href="https://www.tandfonline.com/doi/abs/10.3109/03014460.2013.807878?journalCode=iahb20">40 trillion cells</a>, ranging between 1 and 100 micrometers in size. Some of these cells sometimes get sick – causing cancer in various tissues, or neurological diseases such as Alzheimer’s in brain cells. By monitoring sick cells, researchers can learn more about the origins and development of these diseases.</p>
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<strong>
Read more:
<a href="https://theconversation.com/cancer-growth-in-the-body-could-originate-from-a-single-cell-target-it-to-revolutionise-treatment-110921">Cancer growth in the body could originate from a single cell – target it to revolutionise treatment</a>
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<p>Microscopes can peek within a cell, but they’re poor at discerning a diseased cell from its healthy counterpart. For more detailed monitoring, researchers label cells with biological markers which expose more about what’s happening inside cells.</p>
<p>Existing biological markers, like organic dyes and fluorescent proteins, can expose some of the conditions within a cell for researchers to study. But these markers often kill the cell, limiting their utility for long-term cellular studies. Nanodiamonds, on the other hand, don’t kill cells – which is why they’re now being used by researchers in <a href="https://aip.scitation.org/doi/abs/10.1063/1.4922557">cellular science</a>.</p>
<h2>Why nanodiamonds?</h2>
<p><a href="https://envirodiamond.net/what-are-nano-diamonds/">Nanodiamonds</a> are either produced by detonating synthetic diamonds, or from the powder left over after milling natural diamonds. Despite their luxury connotations, they’re actually relatively cheap for researchers like us to purchase – costing about the same as existing biomarkers.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A group of white shards pictured against a black background" src="https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/390931/original/file-20210322-19-11tv5ml.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Nanodiamonds viewed by a scanning electron microscope.</span>
<span class="attribution"><span class="source">Diogo Volpati, Lund University</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Crucially, nanodiamonds are biocompatible: they’re completely harmless and non-toxic when placed inside living tissue. That means they can lurk incognito within our cells. Once inside, nanodiamonds shine within cells – sending information back to researchers in the form of fluorescent light, the wavelength of which changes depending on the pH or the temperature within the cell.</p>
<h2>Infiltrating a cell</h2>
<p>It’s not easy getting nanodiamonds into a cell. Cell membranes have evolved an impressive protective apparatus to keep unwanted intruders outside. To sneak nanodiamonds in, we either have to hope that cells will invite them in voluntarily – a very slow and inefficient process – or else we have to force their entry through the cellular membrane.</p>
<p><a href="https://pubs.rsc.org/en/content/articlehtml/2010/jm/c0jm01570a?casa_token=kmFPx5frS5gAAAAA:ENqV4Axcy5s0AFKf-x_nLX42E2ebyV-lzu4XyMs2QwlUX4t3RtXdxg_JRutiYfGYSimpVhae9zPHBH4">Microinjection</a>, using microscopic needles, has been used to deliver markers like nanodiamonds across the cell membrane without fatally damaging the cell, but it’s a painstaking method that’s often unsuccessful.</p>
<p>Even after a successful infiltration, nanodiamonds risk being gobbled up by a cell’s lysosomes, which are a bit like a cell’s bodyguards. Biomarkers captured and confined within lysosomes are of little use for researchers trying to observe the whole cell. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A 3D diagram mapping out the anatomy of a call" src="https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=452&fit=crop&dpr=1 600w, https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=452&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=452&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=568&fit=crop&dpr=1 754w, https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=568&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/390940/original/file-20210322-17-ryhygq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=568&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A cell’s lysosomes, coloured orange in this diagram, tend to capture foreign agents they detect in the cell.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/human-animal-cell-cross-section-structure-213232894">Designua/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Nanodiamond smugglers</h2>
<p>We’ve developed a new method to sneak large numbers of nanodiamonds into cells, largely undetected by the lysosomes, and without damaging the cell itself. Our approach combines a very gentle electric field, which eases the cell membrane open, with so-called “<a href="https://www.pnas.org/content/117/35/21267?elqTrackId=dce04abc63ab48bc9df1eea8d7f6b71d">nanostraws</a>” – like drinking straws, but nanoscopically small.</p>
<p>In <a href="https://onlinelibrary.wiley.com/doi/full/10.1002/smll.202006421">our study</a>, we used cells derived from a patient with lung cancer. We lay these cells on thousands of nanostraws, comparable to a minuscule bed of nails. Underneath these nanostraws lay our nanodiamonds, in a slightly conductive solution.</p>
<p>When we applied low-voltage electrical pulses to the nanostraws, small openings appeared across the cellular membrane, at the tip of each nanostraw, creating an access pathway for the nanodiamonds to reach the cell’s interior. </p>
<p>The electric pulses encouraged the conductive solution to travel up through the straws, dragging the nanodiamonds with it through the tiny breaches in the cell membrane. When we stopped the pulses, the small openings in the cell membrane closed behind the smuggled cargo of nanodiamonds.</p>
<h2>A cell’s best friend</h2>
<p>Our new technique is roughly 300 times quicker than simply incubating cells in a solution of nanodiamonds and waiting for some of them to naturally pass into the cell. It also halved the entrapment of nanodiamonds inside lysosomes, thus allowing a big portion of the delivered nanodiamonds to stay free and mobile inside the cell’s interior: a successful infiltration. </p>
<p>Because nanodiamonds can report on the temperature or acidity of different parts of a cell over time, we hope our nanodiamond infiltration technique could help <a href="https://doi.org/10.1186/s12951%E2%80%91018%E2%80%910385%E2%80%917">identify and track</a> cancer cells, or brain cells that are implicated with Alzheimer’s disease. And, if we can find a way to pair nanodiamonds with certain chemicals, we could also find even more refined ways to spy on conditions within the fundamental building blocks of our bodies.</p><img src="https://counter.theconversation.com/content/156719/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span><a href="mailto:elke.hebisch@ftf.lth.se">elke.hebisch@ftf.lth.se</a> receives funding from a seedling project grant through NanoLund; for the research study, my supervisor <a href="mailto:christelle.prinz@ftf.lth.se">christelle.prinz@ftf.lth.se</a> receives funding from the ERC-CoG grant NanoPokers (662206); the Swedish Foundation for Strategic Research (ITM17 grant), the Swedish Research Council, the Crafoord Foundation, and NanoLund. Also it is to be mentioned that one of our co-authors (Martin Hjort) is Chief Technology Officer at Navan Technologies, Inc., a startup commercializing nanostraws.</span></em></p>Nanodiamonds aren’t just cellular bling: they could be used to better understand the development of cancer in our cells.Elke Hebisch, Researcher, Department of Solid State Physics, Lund UniversityLicensed as Creative Commons – attribution, no derivatives.