tag:theconversation.com,2011:/global/topics/cell-biology-6217/articlesCell biology – The Conversation2024-02-08T13:40:17Ztag: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>
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<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>
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<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>
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<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/2125952023-10-04T12:33:20Z2023-10-04T12:33:20ZCell death is essential to your health − an immunologist explains when cells decide to die with a bang or take their quiet leave<figure><img src="https://images.theconversation.com/files/550723/original/file-20230927-27-m1brzw.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1732%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Programmed cell death such as apoptosis is a common stage of cellular life.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/cell-udergoing-lysis-process-illustration-royalty-free-illustration/1414392472">Nanoclustering/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Living cells work better than dying cells, right? However, this is not always the case: your cells often <a href="https://nigms.nih.gov/education/Inside-Life-Science/Pages/Cellular-Suicide-An-Essential-Part-of-Life.aspx">sacrifice themselves to keep you healthy</a>. The unsung hero of life is death.</p>
<p>While death may seem passive, an unfortunate ending that just “happens,” the death of your cells is often extremely purposeful and strategic. The intricate details of how and why cells die can have significant effects on your overall health. </p>
<p>There are over 10 different ways cells can “decide” to die, each serving a particular purpose for the organism. <a href="https://scholar.google.com/citations?hl=en&user=XokicmoAAAAJ">My own research</a> explores how immune cells switch between different types of programmed death in scenarios like cancer or injury.</p>
<p>Programmed cell death can be broadly <a href="https://www.the-scientist.com/sponsored-article/programmed-cell-death-mechanisms-for-cellular-self-destruction-70955">divided into two types</a> that are crucial to health: silent and inflammatory. </p>
<h2>Quietly exiting: silent cell death</h2>
<p>Cells can often become damaged because of age, stress or injury, and these abnormal cells <a href="https://theconversation.com/cells-become-zombies-when-the-ends-of-their-chromosomes-are-damaged-a-tactic-both-helpful-and-harmful-for-health-186445">can make you sick</a>. Your body runs a tight ship, and when cells step out of line, they must be quietly eliminated before they overgrow into tumors or cause <a href="https://theconversation.com/what-is-inflammation-two-immunologists-explain-how-the-body-responds-to-everything-from-stings-to-vaccination-and-why-it-sometimes-goes-wrong-193503">unnecessary inflammation</a> where your immune system is activated and causes fever, swelling, redness and pain. </p>
<p>Your body <a href="https://doi.org/10.1016%2Fj.it.2017.06.009">swaps out cells every day</a> to ensure that your tissues are made up of healthy, functioning ones. The parts of your body that are more likely to see damage, like your skin and gut, turn over cells weekly, while other cell types can take months to years to recycle. Regardless of the timeline, the death of old and damaged cells and their replacement with new cells is a normal and important bodily process.</p>
<p><a href="https://www.genome.gov/genetics-glossary/apoptosis">Silent cell death, or apoptosis</a>, is described as silent because these cells die without causing an inflammatory reaction. Apoptosis is an active process involving many proteins and switches within the cell. It’s designed to strategically eliminate cells without alarming the rest of the body.</p>
<p>Sometimes cells can detect that their own functions are failing and <a href="https://doi.org/10.1101%2Fcshperspect.a008656">turn on executioner proteins</a> that chop up their own DNA, and they quietly die by apoptosis. Alternatively, healthy cells can order overactive or damaged neighbor cells to activate their executioner proteins. </p>
<p>Apoptosis is important to maintaining a healthy body. In fact, you can thank apoptosis for your <a href="https://embryo.asu.edu/pages/apoptosis-embryonic-development">fingers and toes</a>. Fetuses initially have webbed fingers until the cells that form the tissue between them undergo apoptosis and die off. </p>
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<a href="https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of mouse foot at embryonic stage" src="https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=904&fit=crop&dpr=1 600w, https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=904&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=904&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1135&fit=crop&dpr=1 754w, https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1135&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/550728/original/file-20230927-15-kh9avn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1135&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">The toes of this embryonic mouse foot are forming through apoptosis.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Embryonic_foot_of_mouse.jpg">Michal Maňas/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>Without apoptosis, cells can grow out of control. A well-studied example of this is cancer. Cancer cells are abnormally good at growing and dividing, and those that can <a href="https://www.mskcc.org/news/what-apoptosis">resist apoptosis</a> form very aggressive tumors. Understanding how apoptosis works and why cancer cells can disrupt it can potentially improve cancer treatments. </p>
<p>Other conditions can benefit from apoptosis research as well. Your body makes a lot of immune cells that all respond to different targets, and occasionally one of these cells can accidentally target your own tissues. Apoptosis is a crucial way your body can eliminate these immune cells before they cause unnecessary damage. When apoptosis fails to eliminate these cells, sometimes because of genetic abnormalities, this can lead to <a href="https://doi.org/10.5772/48164">autoimmune diseases</a> like lupus.</p>
<p>Another example of the role apoptosis plays in health is <a href="https://medlineplus.gov/endometriosis.html">endometriosis</a>, an understudied disease caused by the overgrowth of tissue in the uterus. It can be extremely painful and debilitating for patients. Researchers have recently linked this <a href="https://doi.org/10.1210/endocr/bqad057">out-of-control growth in the uterus</a> to dysfunctional apoptosis. </p>
<p>Whether it’s for development or maintenance, your cells are quietly exiting to keep your body happy and healthy.</p>
<h2>Going out with a bang: inflammatory cell death</h2>
<p>Sometimes, it is in your body’s best interest for cells to raise an alarm as they die. This can be beneficial when cells detect the presence of an infection and need to eliminate themselves as a target while also alerting the rest of the body. This <a href="https://sitn.hms.harvard.edu/flash/2021/when-cells-die-a-fiery-death-pyroptosis-as-a-cells-response-to-damage-and-infection/">inflammatory cell death</a> is typically triggered by bacteria, viruses or stress.</p>
<p>Rather than quietly shutting down, cells undergoing inflammatory cell death will make themselves burst, or lyse, killing themselves and exploding inflammatory messengers as they go. These messengers tell your immune cells that there is a threat and prompts them to treat and fight the pathogen.</p>
<p>An inflammatory death would not be healthy for maintenance. If the normal recycling of your skin or gut cells caused an inflammatory reaction, you would feel sick a lot. This is why inflammatory death is <a href="https://doi.org/10.3390%2Fijms21041456">tightly controlled</a> and requires multiple signals to initiate. </p>
<p>Despite the riskiness of this grenadelike death, many infections would be impossible to fight without it. Many bacteria and viruses need to live around or inside your cells to survive. When specialized sensors on your cells detect these threats, they can simultaneously activate your immune system and remove themselves as a home for pathogens. Researchers call this <a href="https://cshperspectives.cshlp.org/content/12/2/a036459.full">eliminating the niche</a> of the pathogen.</p>
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<figcaption><span class="caption">Cells die in many ways, including lysis.</span></figcaption>
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<p>Inflammatory cell death plays a major role in pandemics. <a href="https://doi.org/10.1101/cshperspect.a036459"><em>Yersinia pestis</em></a>, the bacteria behind the Black Death, has evolved various ways of stopping human immune cells from mounting a response. However, immune cells developed the ability to sense this trickery and die an inflammatory death. This ensures that additional immune cells will infiltrate and eliminate the bacteria despite the bacteria’s best attempts to prevent a fight. </p>
<p>Although the Black Death is not as common nowadays, close relatives <em>Yersinia pseudotuberculosis</em> and <em>Yersinia enterocolitica</em> are behind outbreaks of <a href="https://edis.ifas.ufl.edu/publication/FS193">food-borne illnesses</a>. These infections are rarely fatal because your immune cells can aggressively eliminate the pathogen’s niche by inducing inflammatory cell death. For this reason, however, <em>Yersinia</em> infection can be more dangerous in immunocompromised people.</p>
<p>The <a href="https://doi.org/10.1016/j.it.2020.10.005">virus behind the COVID-19 pandemic</a> also causes a lot of inflammatory cell death. Studies show that without cell death the virus would freely live inside your cells and multiply. However, this inflammatory cell death can sometimes get out of control and <a href="https://theconversation.com/long-covid-19-and-other-chronic-respiratory-conditions-after-viral-infections-may-stem-from-an-overactive-immune-response-in-the-lungs-186970">contribute to the lung damage</a> seen in COVID-19 patients, which can greatly affect survival. Researchers are still studying the role of inflammatory cell death in COVID-19 infection, and understanding this delicate balance can help improve treatments. </p>
<p>In good times and bad, your cells are always ready to sacrifice themselves to keep you healthy. You can thank cell death for keeping you alive.</p><img src="https://counter.theconversation.com/content/212595/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Zoie Magri 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>Your cells die to keep you alive. Cell death does everything from fighting cancer cells and pathogens to forming your fingers and toes.Zoie Magri, Ph.D. Candidate in Immunology, Tufts 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>
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<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>
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<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/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/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>
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<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/1991482023-02-08T13:42:23Z2023-02-08T13:42:23ZCells routinely self-cannibalize to take out their trash, aiding in survival and disease prevention<figure><img src="https://images.theconversation.com/files/508693/original/file-20230207-23-r0tkni.png?ixlib=rb-1.1.0&rect=0%2C0%2C907%2C679&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Illustration of an autophagosome (light blue double-membrane to the right) engulfing cellular material.</span> <span class="attribution"><a class="source" href="https://doi.org/10.2210/rcsb_pdb/goodsell-gallery-012">David S. Goodsell and Daniel Klionsky/RCSB PDB-101</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Don’t let the textbook diagram of a simplified two-dimensional cell fool you – within this tiny structure of life is a complex universe of molecular machinery that is continually being built, put into motion and eventually broken down. </p>
<p>Cells use the thousands of different proteins within them as tools to shape their internal environment. In this environment are specialized compartments known as <a href="https://www.genome.gov/genetics-glossary/Organelle">organelles</a> that carry out the cell’s functions. Two important organelles within cells are mitochondria and the endoplasmic reticulum, which <a href="https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/04%3A_Cell_Structure_of_Bacteria_Archaea_and_Eukaryotes/4.07%3A_Internal_Structures_of_Eukaryotic_Cells/4.7B%3A_Mitochondria">produce energy</a> and <a href="https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Cells_-_Molecules_and_Mechanisms_(Wong)/11%3A_Protein_Modification_and_Trafficking/11.03%3A_Protein_Folding_in_the_Endoplasmic_Reticulum">assemble proteins</a>, respectively. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of endoplasmic reticulum surrounded by an autophagosome" src="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=749&fit=crop&dpr=1 600w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=749&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=749&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=942&fit=crop&dpr=1 754w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=942&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=942&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 an endoplasmic reticulum engulfed by an autophagosome.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1371/journal.pbio.0040442.g001">Liza Gross/PLoS Biology</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Since routine cellular activity generates toxic byproducts that can damage the cell, a disposal system is needed to degrade and recycle these molecules within cells. One of these processes is <a href="https://doi.org/10.1038/sj.cdd.4401765">autophagy</a>, a form of self-consumption cells use to eliminate and recycle abnormal or excess components, including proteins and organelles. Derived from Greek, the term literally translates to “self-eating.” In 2016, cell biologist Yoshinori Ohsumi won the <a href="https://www.nobelprize.org/prizes/medicine/2016/press-release/">Nobel Prize in Physiology or Medicine</a> for his work on autophagy. Autophagy is essential for cellular health and longevity. When this process is not working well, it’s <a href="https://doi.org/10.1056/nejmra2022774">linked to several human diseases</a>, including neurodegenerative and cardiovascular diseases and cancer. </p>
<p><a href="https://gustafssonlabucsd.org/team/">We are researchers</a> studying how autophagy is activated in cells. In our <a href="http://dx.doi.org/10.1126/scisignal.abo4457">recently published research</a>, we examined two key regulators of this process and identified a unique role one of them plays in degrading mitochondria that may serve as a potential target to treat certain diseases.</p>
<h2>Autophagy and human disease</h2>
<p>The connection between autophagy and disease is complex and not well understood. </p>
<p>For instance, autophagy appears to play a <a href="https://doi.org/10.1038/s41418-019-0474-7">paradoxical role in cancer</a>. On one hand, some studies have shown that because this process suppresses tumors by eliminating potentially harmful material, reduced or impaired autophagy can turn a cell cancerous. On the other hand, activating autophagy after a tumor has formed can promote cancer by helping it adapt and survive, potentially leading to treatment resistance.</p>
<p>These findings suggest that it is especially important to understand the precise steps and timing of autophagy when it comes to targeting this process as a cancer treatment strategy. Researchers are evaluating the anticancer effects of two malaria drugs, <a href="https://doi.org/10.3389/fphar.2020.00408">chloroquine and hydroxychloroquine</a>, that block the final steps of autophagy. So far, they have varying efficacy depending on cancer type and stage.</p>
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<figcaption><span class="caption">Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Medicine for his discoveries of the mechanisms of autophagy.</span></figcaption>
</figure>
<p>Dysfunctional autophagy also plays an important role in <a href="https://doi.org/10.1111/bpa.12545">most neurodegenerative diseases</a>. The aggregation of abnormal proteins in brain cells are common features in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS. Some scientists believe that the accumulation of these proteins is due at least in part to a decline in their degradation through autophagy.</p>
<p>Autophagy is also important for heart health. Researchers have found that autophagy in the heart <a href="https://doi.org/10.1161/CIRCRESAHA.118.312208">declines</a> <a href="https://doi.org/10.1111/acel.13187">with age</a> and contributes to cardiovascular disease. Decreased autophagy in cardiac muscle cells results in accumulating cellular garbage that can affect their ability to contract and even cause their death. With fewer cells and less contraction, the buildup of toxic material in cardiac muscle cells can ultimately lead to heart failure. </p>
<h2>Breaking down mitochondria with mitophagy</h2>
<p>For autophagy to be efficient, it needs to specifically get rid of only damaged proteins or organelles within the cell. Uncontrolled degradation would deprive a cell of its basic needs. </p>
<p>This is particularly true for mitochondria, as cells rely on them for much of their energy production. Our team has been very interested in how cells ensure that autophagy of mitochondria, also known as mitophagy, eliminates only dysfunctional mitochondria while sparing the healthy parts of the cell. Dysfunctional mitophagy has been linked to <a href="https://doi.org/10.1016/j.semcancer.2019.07.015">cancer</a>, <a href="https://doi.org/10.1111/cns.13140">neurodegeneration</a> and <a href="https://doi.org/10.1016/j.molmed.2022.06.007">cardiovascular disease</a>, among other diseases. </p>
<p>The process of autophagy starts when the cell begins to form a membrane near damaged proteins or organelles. This membrane will expand into a vesicle, or sac, known as an autophagosome, that engulfs the damaged material. It will then fuse with another internal cell structure full of acid called a lysosome that helps degrade its cargo. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting autophagy process" src="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.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">Autophagy involves the formation of a membrane around the cellular material to be eliminated. This autophagosome eventually joins with another organelle called a lysosome (orange sphere, fifth step) which releases chemicals that break down its contents.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/stages-of-autophagy-illustration-royalty-free-illustration/713780595">Kateryna Kon/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>Beclin1 is a protein known to promote the formation of autophagosomes in cells. However, its role in mitophagy is controversial, in part because very little is known about its <a href="https://doi.org/10.1016/j.cell.2013.07.035">close relative Beclin2</a>. We wanted to <a href="http://dx.doi.org/10.1126/scisignal.abo4457">disentangle the functions</a> of these two proteins and determine their role in mitophagy. To do this, we used mouse and human cell models to examine how the presence or absence of these two proteins affected autophagy. </p>
<p>We discovered that activating a region unique to Beclin1 enables it to promote autophagosome formation next to dysfunctional mitochondria, facilitating their degradation in human cells. Because a similar region isn’t found in Beclin2, this meant that only Beclin1 may be essential for mitophagy.</p>
<p>Interestingly, we also observed Beclin1 at discrete points of contact between mitochondria and endoplasmic reticulum during mitophagy. This supports <a href="https://doi.org/10.1038/s41580-020-0241-0">emerging research</a> suggesting that physical interactions between these organelles facilitate the transfer of certain molecules needed to make autophagosomes. Our work indicates that only Beclin1 promotes engulfment of damaged mitochondria at these sites. Beclin2 may perform a different role in autophagy in other conditions.</p>
<h2>Targeting autophagy for treatments</h2>
<p>Autophagy represents a potential treatment target for many different diseases. Our team is currently studying how autophagy contributes to protein aggregation and mitochondrial dysfunction in the heart, and we are working to develop new tools to measure this process in cell and animal models.</p>
<p>However, therapeutic strategies to regulate autophagy is complicated by the fact that it is a complex multi-step process that involves many different proteins. Some diseases may require targeting the early steps of autophagsosome formation, while others may require focusing on when they fuse with lysosomes. Furthermore, different disease states may benefit from either autophagy activation or inhibition. More work needs to be done to identify all of the specific proteins that regulate each step of the autophagy pathway and how cells finetune this process in both health and disease. </p>
<p>We believe that helping cells better harness the power of autophagy in a complex molecular universe can train them to follow the three Rs – reduce, reuse, recycle – to promote health and longevity.</p><img src="https://counter.theconversation.com/content/199148/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Åsa Gustafsson receives funding from NIH. </span></em></p><p class="fine-print"><em><span>Justin Quiles receives funding from The American Heart Association. </span></em></p>Cells degrade and recycle damaged parts of themselves through a process called autophagy. When this “self-devouring” goes awry, it may promote cancer and neurodegenerative disease.Åsa Gustafsson, Professor of Pharmacy and Pharmaceutical Sciences, University of California, San DiegoJustin Quiles, Postdoctoral Scholar of Pharmacy and Pharmaceutical Science, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1915592023-01-11T13:25:40Z2023-01-11T13:25:40ZTriggering cancer cells to become normal cells – how stem cell therapies can provide new ways to stop tumors from spreading or growing back<figure><img src="https://images.theconversation.com/files/503356/original/file-20230105-19-bvp86r.jpg?ixlib=rb-1.1.0&rect=6%2C6%2C2038%2C2038&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">This image shows pancreatic cancer cells (blue) growing, encased within membranes (red).</span> <span class="attribution"><a class="source" href="https://flic.kr/p/GAACEb">Min Yu/Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC via NIH/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>How cells <a href="https://doi.org/10.3390%2Fijms21186489">become cancerous</a> is a process researchers are still trying to fully understand. Generally, normal cells grow and multiply through controlled cell division, where <a href="https://doi.org/10.3389/fcell.2021.645593">old and damaged cells</a> are replaced after they die by new cells. Sometimes this process stops working, leading cells to start growing uncontrollably and develop into a tumor.</p>
<p>Traditionally, cancer treatments like chemotherapy, immunotherapy, radiation and surgery focus on killing cancer cells. Another type of treatment using stem cells called <a href="https://doi.org/10.1177/1010428317729933">differentiation therapy</a>, however, focuses on persuading cancer cells to become normal cells. </p>
<p><a href="https://scholar.google.com/citations?user=GNSivG8AAAAJ&hl=en">We are</a> <a href="https://chen.uchicago.edu/abhimanyu-thakur-ph-d/">researchers</a> who study how stem cells, or immature cells that can develop into different types of cells, behave in states of health and disease. We believe that stem cells can provide potential treatments for cancer of all types in many different ways.</p>
<h2>How do stem cells contribute to cancer?</h2>
<p><a href="https://www.the-scientist.com/university/brush-up-what-is-stemness-and-pluripotency-70571">Stem cells</a> are unspecialized cells, meaning they can eventually become any one of the various types of cells that make up different parts of the body. They can replenish cells in the skin, bone, blood and other organs during development, and regenerate and repair tissues when they’re damaged.</p>
<p>There are different types of stem cells. Embryonic stem cells are the first cells that initially form after a sperm fertilizes an egg, and can give rise to all other cell types in the human body. Adult stem cells are more mature, meaning they can replace damaged cells only in one type of organ and have a limited ability to multiply. Researchers can <a href="https://doi.org/10.1007%2Fs13238-021-00863-6">reprogram adult stem cells, or differentiated cells</a>, in the lab to act like embryonic stem cells.</p>
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<figcaption><span class="caption">Cells become specialized over the course of development.</span></figcaption>
</figure>
<p>Because stem cells can survive longer than regular cells, they have a much higher probability of accumulating genetic mutations that can result in loss of control over their growth and ability to regenerate. This is why many tumors harbor a small subpopulation of cells that <a href="https://doi.org/10.1038%2Flabinvest.2008.14">function like stem cells</a>. These so-called cancer stem cells are <a href="https://doi.org/10.1186/s13578-017-0188-9">thought to be responsible</a> at least in part for cancer initiation, progression, metastasis, recurrence and treatment resistance.</p>
<h2>What is differentiation therapy?</h2>
<p>Accumulating evidence is also showing that cancer stem cells can differentiate into multiple cell types, including noncancerous cells. Researchers are taking advantage of this fact through a type of treatment called <a href="https://doi.org/10.1177/1010428317729933">differentiation therapy</a>. </p>
<p>The concept of differentiation therapy <a href="https://doi.org/10.1038/nrc.2017.103">originated from scientists observing</a> that hormones and cytokines, which are proteins that play a key role in cell communication, can stimulate stem cells to mature and lose their ability to regenerate. It followed that forcing cancer stem cells to differentiate into more mature cells could subsequently stop them from multiplying uncontrollably, making them become normal cells.</p>
<p>Differentiation therapy has been successful in treating <a href="https://doi.org/10.1182/blood-2009-01-198911">acute promyelocytic leukemia</a>, an aggressive blood cancer. In this case, retinoic acid and arsenic are used to block a protein that stops myeloid cells, a type of blood cell derived from the bone marrow, from fully maturing. By allowing these cells to fully mature, they lose their cancerous qualities.</p>
<p>Furthermore, because differentiation therapy doesn’t focus on killing cancer cells and doesn’t surround healthy cells in the body with harmful chemicals, it can be <a href="https://doi.org/10.1182%2Fblood-2009-01-198911">less toxic</a> than traditional treatments.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of acute promyelocytic leukemia" src="https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/503362/original/file-20230105-22-8a0umi.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">Acute promyelocytic leukemia, as shown in this microscopy image, can be treated with differentiation therapy.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/acute-promyelocytic-leukemia-cells-royalty-free-image/1417347912">jarun011/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<h2>Using stem cells to treat cancer</h2>
<p>There are many other potential ways to use stem cells to treat cancer. For example, cancer stem cells can be <a href="https://doi.org/10.1038/s41392-020-0110-5">directly targeted</a> to stop their growth, or turned into “<a href="https://doi.org/10.1515/iss-2016-0005">Trojan horses</a>” that attack other tumor cells.</p>
<p><a href="https://doi.org/10.1155/2016/1740936">Quiescent cancer stem cells</a>, which don’t divide but are still alive, are another potential drug target. These cells typically play a big role in treatment resistance for various cancer types because they are able to regenerate and avoid death even better than regular cancer stem cells. Their quiescent quality can persist for decades and lead to a cancer relapse. They are also challenging to distinguish from regular cancer stem cells, making them difficult to study.</p>
<p>Researchers can also genetically engineer stem cells to express a protein that binds to a desired target in a cancer cell, increasing the efficacy of treatments by releasing drugs right at the tumor. For example, <a href="https://doi.org/10.3389%2Ffbioe.2020.00043">mesenchymal stem cells</a> derived from bone marrow naturally migrate toward and stick to tumors, and can be used to deliver cancer drugs directly to cancer cells.</p>
<p>Stem cells can also be used to make <a href="https://doi.org/10.1002/wdev.399">organoid models</a>, or miniature versions of organs, to screen potential cancer drugs and study the underlying mechanisms that lead to cancer. </p>
<h2>Challenges in stem cell therapy</h2>
<p>Although, stem cells hold numerous advantages in their use in cancer therapy, they also <a href="https://doi.org/10.18632%2Foncotarget.20798">face various challenges</a>. For example, many current stem cell therapies that aren’t used in combination with other drugs are unable to completely eliminate tumors. There are also concerns about stem cell therapies potentially promoting tumor growth.</p>
<p>Despite these challenges, we believe that stem cell technologies have the potential to open new avenues for cancer therapy. Integrating genetic engineering with stem cells can overcome the major drawbacks of chemotherapeutics, such as toxicity to healthy cells. With further research, cancer stem cell therapies may one day become part of the standard of care for many types of cancer.</p><img src="https://counter.theconversation.com/content/191559/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors 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>Many tumors have cancer stem cells that help them grow and evade treatments. Differentiation therapy forces these cells to mature, stopping growth with less toxicity than traditional treatments.Huanhuan Joyce Chen, Assistant Professor of Molecular Engineering, University of Chicago Pritzker School of Molecular EngineeringAbhimanyu Thakur, Postdoctoral Scholar in Molecular Engineering, University of Chicago Pritzker School of Molecular EngineeringLicensed 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/1761342022-03-20T11:43:17Z2022-03-20T11:43:17ZMajor study shows the need to improve how scientists approach early-stage cancer research<figure><img src="https://images.theconversation.com/files/452401/original/file-20220316-15-1tmf3hp.jpg?ixlib=rb-1.1.0&rect=726%2C0%2C4837%2C2952&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Preclinical research — the kind that takes place before testing on humans — often guides decisions about which potential treatments should continue to clinical trials. But attempts to replicate 50 studies found the odds of getting the same results were only about 50-50.</span> <span class="attribution"><span class="source">(Pexels/Artem Podrez)</span></span></figcaption></figure><iframe style="width: 100%; height: 175px; border: none; position: relative; z-index: 1;" allowtransparency="" src="https://narrations.ad-auris.com/widget/the-conversation-canada/major-study-shows-the-need-to-improve-how-scientists-approach-early-stage-cancer-research" width="100%" height="400"></iframe>
<p>Preclinical studies, the kind that scientists perform before testing in humans, don’t get as much attention as their clinical counterparts. But they are the vital first steps to eventual treatments and cures. It’s important to get preclinical findings right. When they are wrong, scientists waste resources pursuing false leads. Worse, false findings can trigger <a href="https://doi.org/10.1186/s41231-019-0050-7">clinical studies with humans</a>. </p>
<p>Last December, the Center for Open Science (COS) released the worrying results of its eight-year $US 1.5 million <em><a href="https://doi.org/10.7554/eLife.71601">Reproducibility Project: Cancer Biology</a></em> study. Done in collaboration with research marketplace <a href="https://ww2.scienceexchange.com/s/about">Science Exchange</a>, independent scientists found that the odds of replicating results of 50 preclinical experiments from 23 high-profile published studies were no better than a coin toss. </p>
<p>Praise and controversy have followed the project from the beginning. The journal <em>Nature</em> applauded the replication studies as “<a href="https://doi.org/10.1038/541259b">the practice of science at its best</a>.” But the journal <em>Science</em> noted that reactions from some scientists whose studies were chosen ranged from “<a href="https://doi.org/10.1126/science.348.6242.1411">annoyance to anxiety to outrage</a>,” impeding the replications. Although none of the original experiments was described in enough detail to allow scientists to repeat them, <a href="https://doi.org/10.7554/eLife.67995">a third of the original authors were unco-operative</a>, and some were even <a href="https://www.sciencenews.org/article/cancer-biology-studies-research-replication-reproducibility">hostile</a> when asked for assistance.</p>
<figure class="align-center ">
<img alt="A person wearing PPE using a multi-channel pipette in a laboratory" src="https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=231&fit=crop&dpr=1 600w, https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=231&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=231&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=291&fit=crop&dpr=1 754w, https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=291&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/452293/original/file-20220315-15-60adun.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=291&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">It’s important to get preclinical findings right. When they are wrong, scientists waste resources pursuing false leads.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>COS executive director Brian Nosek cautioned that the findings pose “<a href="https://www.science.org/content/article/more-half-high-impact-cancer-lab-studies-could-not-be-replicated-controversial-analysis">challenges for the credibility of preclinical cancer biology</a>.” In a tacit acknowledgement that biomedical research has not been universally rigorous or transparent, the American National Institutes of Health (NIH), the largest funder of biomedical research in the world, has announced that it will <a href="https://www.chemistryworld.com/news/replication-failures-cast-doubt-on-some-cancer-studies/4014881.article">raise requirements for both of these qualities</a>.</p>
<p>I have taught classes and written about good scientific practice in psychology and biomedicine for over 30 years. I’ve reviewed more grant applications and journal manuscripts than I can count, and I’m not surprised.</p>
<figure class="align-right ">
<img alt="A stack of journal articles, with passages highlighted in the top one, with a pen resting on top." src="https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/452304/original/file-20220315-21-1j5qntp.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">
<figcaption>
<span class="caption">Independent scientists found that the odds of replicating results of 50 preclinical experiments from 23 high-profile published studies were no better than a coin toss.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>The twin pillars of trustworthy science — transparency and dispassionate rigour — have wobbled under the stress of <a href="https://royalsocietypublishing.org/doi/10.1098/rsos.160384">incentives that</a> enhance careers at the expense of reliable science. Too often, proposed preclinical studies — and surprisingly, published peer-reviewed ones — <a href="https://doi.org/10.1161/CIRCRESAHA.114.303819">don’t follow the scientific method</a>. Too often, <a href="https://doi.org/10.1089/bio.2020.0037">scientists do not share</a> their government-funded data, even when required by the publishing journal.</p>
<h2>Controlling for bias</h2>
<p>Many preclinical experiments <a href="https://doi.org/10.1007/164_2019_279">lack the rudimentary controls against bias</a> that are taught in the social sciences, though <a href="https://www.cshlpress.com/default.tpl?cart=1646145461247203111&fromlink=T&linkaction=full&linksortby=oop_title&--eqSKUdatarq=1020">rarely in biomedical disciplines</a> such as medicine, cell biology, biochemistry and physiology. Controlling for bias is a key element of the scientific method because it allows scientists to disentangle experimental signal from procedural noise. </p>
<p>Confirmation bias, the tendency to see what we want to see, is one type of bias that good science controls by “blinding.” Think of the “double-blind” procedures in clinical trials in which neither the patient nor the research team knows who is getting the placebo and who is getting the drug. In preclinical research, blinding experimenters to samples’ identities minimizes the chance that they will alter their behaviour, however subtly, in favour of their hypothesis. </p>
<p>Seemingly trivial differences, such as whether a sample is processed in the morning or afternoon or whether an animal is caged in the upper or lower row, can also change results. This is not as unlikely as you might think. Moment-to-moment changes in the micro-environment, such as exposure to light and air ventilation, for example, <a href="https://arriveguidelines.org/arrive-guidelines/randomisation#:%7E:text=Using%20a%20validated%20method%20of,valid%20%5B4%2C5%5D">can change physiological responses</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A row of clear acrylic animal cages, each housing a white rat." src="https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=420&fit=crop&dpr=1 600w, https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=420&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=420&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=527&fit=crop&dpr=1 754w, https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=527&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/452275/original/file-20220315-15-39otqq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=527&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Seemingly trivial differences, such as whether an animal is caged in the upper or lower row, can change results.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>If all animals who receive a drug are caged in one row and all animals who do not receive the drug are caged in another row, any difference between the two groups of animals may be due to the drug, to their housing location or to an interaction between the two. You can’t honestly choose between the alternative explanations, and neither can the scientists.</p>
<p>Randomizing sample selection and processing order minimizes these procedural biases, makes the interpretation of the results clearer, and makes them more likely to be replicated. </p>
<p>Many of the replication experiments blinded and randomized, but it’s not known if the original experiments did. All that is known is that for the 15 animal experiments, only <a href="https://doi.org/10.7554/eLife.71601">one of the original studies reported randomization and none reported blinding</a>. But it would not be surprising if many of the studies neither randomized nor blinded.</p>
<h2>Study design and statistics</h2>
<p>According to one estimate, over half of the one million articles published each year <a href="https://doi.org/10.1016/S0140-6736%2809%2960329-9">have biased study designs</a>, contributing to 85 per cent of US$100-billion spent each year on (mostly preclinical) research being wasted. </p>
<p>In a widely reported commentary, industry scientist and former academic Glenn Begley reported being able to reproduce the results of only <a href="https://doi.org/10.1038/483531a">six of 53</a> academic studies (11 per cent). He listed <a href="https://doi.org/10.1038/497433a">six practices</a> of reliable research, including blinding. All six of the studies that replicated followed all six practices. The 47 studies that failed to replicate followed few or, sometimes, none of the practices. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Three people in white coats with a microscope in the foreground, superimposed with bar graphs and data points." src="https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=372&fit=crop&dpr=1 600w, https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=372&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=372&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=468&fit=crop&dpr=1 754w, https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=468&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/452283/original/file-20220315-19-vympx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=468&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Misuse of statistics is a common in biomedical research despite calls for better data analysis practices.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>Another way to bias findings is by misusing statistics. As with blinding and randomization, it’s not known which, if any, of the original studies in the reproducibility project misused statistics, because of the studies’ lack of transparency. But that, too, is common practice.</p>
<p>A dictionary of terms describes a slew of poor data analysis practices that can manufacture statistically significant (but false) findings, such as <a href="https://doi.org/10.1207/s15327957pspr0203_4">HARKing</a> (Hypothesizing After the Results are Known), p-hacking (<a href="https://doi.org/10.1177%2F0956797611417632">repeating statistical tests until a desired result is produced</a>) and following a series of data-dependent analysis decisions known as a “<a href="https://doi.org/10.1511/2014.111.460">garden of forking paths</a>” to publishable findings. </p>
<p><a href="https://link.springer.com/chapter/10.1007/164_2019_278#Sec4">These practices</a> are <a href="https://acmedsci.ac.uk/policy/policy-projects/reproducibility-and-reliability-of-biomedical-research">common in biomedical research</a>. <a href="https://doi.org/10.1136/bmj.308.6924.283">Decades of pleas</a> from <a href="https://doi.org/10.1371/journal.pmed.0020124">methodologists</a>, and an <a href="https://magazine.amstat.org/blog/2021/08/01/task-force-statement-p-value/">unprecedented statement</a> from the American Statistical Association to change data analysis practices, however, have <a href="https://doi.org/10.1111/1740-9713.01505">gone unheeded</a>.</p>
<h2>A better future</h2>
<figure class="align-center ">
<img alt="A woman wearing a lab coat and safety glasses and green gloves examining lab samples" src="https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.jpg?ixlib=rb-1.1.0&rect=353%2C0%2C4871%2C3371&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/452295/original/file-20220315-25-11qxmpb.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">
<figcaption>
<span class="caption">Incentives and standards should reward practices that produce trustworthy science and censor practices that do not, without killing innovation.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>Those who are anti-science should not take heart in these findings. Preclinical science’s accomplishments are real and impressive. Decades of preclinical research led to the <a href="https://www.nytimes.com/2022/01/15/health/mrna-vaccine.html">development of the COVID-19 mRNA vaccines</a>, for example. And most scientists are doing the best they can within a system that rewards <a href="https://www.theguardian.com/commentisfree/2013/dec/09/how-journals-nature-science-cell-damage-science">quick flashy results</a> over slower reliable ones. </p>
<p>But science is done by humans with all the strengths and weaknesses that go with it. The trick is to reward practices that produce trustworthy science and to censor practices that do not, without killing innovation. </p>
<p>Changing incentives and enforcing standards are the most effective ways to improve scientific practice. The goal is to improve efficiency by ensuring scientists who value transparency and rigour over speed and flash are given a chance to thrive. It’s been <a href="https://doi.org/10.1038/505612a">tried before</a>, with <a href="https://doi.org/10.1080/08989621.2020.1855427">minimal success</a>. This time may be different. The <em>Reproducibility Project: Cancer Biology</em> study and the NIH policy changes it prompted may be just the push needed to make it happen.</p><img src="https://counter.theconversation.com/content/176134/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Robert Nadon 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>Preclinical studies are an important part of biomedical research, often guiding future trials in humans. Failure to replicate research results suggests a need to increase the quality of studies.Robert Nadon, Associate Professor, Department of Human Genetics, Faculty of Medicine, McGill UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1729412022-02-02T13:07:37Z2022-02-02T13:07:37Z50-year-old muscles just can’t grow big like they used to – the biology of how muscles change with age<figure><img src="https://images.theconversation.com/files/443851/original/file-20220201-17-1pp1t44.jpg?ixlib=rb-1.1.0&rect=86%2C0%2C7971%2C5376&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Why is it harder to build muscle as you age?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/senior-male-bodybuilder-flexing-his-biceps-royalty-free-image/1310652763?adppopup=true"> DjelicS/iStock via Getty Images</a></span></figcaption></figure><p>There is perhaps no better way to see the absolute pinnacle of human athletic abilities than by watching the Olympics. But at the Olympics – and at almost all professional sporting events – you rarely see a competitor over 40 years old and almost never see a single athlete over 50. This is because with every additional year spent on Earth, bodies age and muscles don’t respond to exercise the same as they used to. </p>
<p>I lead a team of scientists who study the health benefits of <a href="https://hnrca.tufts.edu/mission/">exercise, strength training and diet in older people</a>. We investigate how older people respond to exercise and try to understand the underlying biological mechanisms that cause muscles to increase in size and strength after resistance or strength training.</p>
<p>Old and young people build muscle in the same way. But as you age, many of the biological processes that turn exercise into muscle become less effective. This makes it harder for older people to build strength but also makes it that much more important for everyone to continue exercising as they age.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A woman spotting someone doing a bench press." src="https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/443854/original/file-20220201-17-1ljwx0x.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">Lifting weights and doing pushups and other strength training exercises cause muscles to grow in size and strength.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/wide-shot-of-woman-spotting-friend-bench-pressing-royalty-free-image/1346267080?adppopup=true">Thomas Barwick/Digital Vision via Getty Images</a></span>
</figcaption>
</figure>
<h2>How the body builds muscle</h2>
<p>The exercise I study is the type that makes you stronger. Strength training includes exercises like pushups and situps, but also weightlifting and resistance training using bands or workout machines.</p>
<p>When you do strength training, over time, exercises that at first felt difficult become easier as your muscles increase in strength and size – a process called hypertrophy. Bigger muscles simply have larger muscle fibers and cells, and this allows you to lift heavier weights. As you keep working out, you can continue to increase the difficulty or weight of the exercises as your muscles get bigger and stronger.</p>
<p>It is easy to see that working out makes muscles bigger, but what is actually happening to the cells as muscles increase in strength and size in response to resistance training?</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing how muscle contraction can move an arm." src="https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=607&fit=crop&dpr=1 600w, https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=607&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=607&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=763&fit=crop&dpr=1 754w, https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=763&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/443857/original/file-20220201-27-l8le9c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=763&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Muscles move your limbs and body by contracting or releasing.</span>
<span class="attribution"><a class="source" href="https://openstax.org/books/anatomy-and-physiology/pages/preface">J. Gordon Betts, Kelly A. Young, James A. Wise, Eddie Johnson, Brandon Poe, Dean H. Kruse, Oksana Korol, Jody E. Johnson, Mark Womble, Peter DeSaix via OpenStax</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Any time you move your body, you are doing so by shortening and pulling with your muscles – a process called contraction. This is how muscles spend energy to generate force and produce movement. Every time you contract a muscle – especially when you have to work hard to do the contraction, like when lifting weights – the action causes <a href="https://doi.org/10.1038/s42255-020-00290-7">changes to the levels of various chemicals in your muscles</a>. In addition to the chemical changes, there are also specialized receptors on the surface of muscle cells that detect when you move a muscle, generate force or otherwise <a href="https://doi.org/10.1007/s00223-014-9921-0">alter the biochemical machinery within a muscle</a>. </p>
<p>In a healthy young person, when these chemical and mechanical sensory systems detect muscle movement, they turn on a number of specialized chemical pathways within the muscle. These pathways in turn trigger the production of more proteins that get incorporated into the muscle fibers and cause the muscle to increase in size.</p>
<p>These cellular pathways also turn on genes that code for specific proteins in cells that make up the muscles contracting machinery. This activation of gene expression is a longer-term process, with genes being <a href="https://doi.org/10.1016/j.cmet.2015.05.011">turned on or off for several hours</a> after a single session of resistance exercise. </p>
<p>The overall effect of these many exercise-induced changes is to cause your muscles to get bigger.</p>
<h2>How older muscles change</h2>
<p>While the basic biology of all people, young or old, is more or less the same, something is behind the lack of senior citizens in professional sports. So what changes in a person’s muscles as they age?</p>
<p>What my colleagues and I have found in our research is that in young muscle, a little bit of exercise produces a strong signal for the many <a href="https://doi.org/10.1152/ajpregu.00324.2003">processes that trigger muscle growth</a>. In older people’s muscles, by comparison, the <a href="https://doi.org/10.1152/japplphysiol.01383.2003">signal telling muscles to grow is much weaker</a> for a given amount of exercise. These changes begin to occur when a person reaches around 50 years old and become more pronounced as time goes on.</p>
<p>In a recent study, we wanted to see if the changes in signaling were accompanied by any changes in which genes – and how many of them – respond to exercise. Using a technique that allowed us to measure changes in thousands of genes in response to resistance exercise, we found that when younger men exercise, there are changes in the expression of more than 150 genes. When we looked at older men, we found <a href="https://doi.org/10.1096/fj.14-254490">changes in the expression of only 42 genes</a>. This difference in gene expression seems to explain, at least partly, the more visible variation between how young and old people respond to strength training.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="An older woman in a swimsuit flexing and showing off muscles." src="https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/443859/original/file-20220201-28-r1wl98.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">Strength training can help maintain overall fitness and allow you to keep doing other things you love as you age.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/older-caucasian-woman-flexing-her-muscles-on-beach-royalty-free-image/526298515">Peathegee Inc via Getty Images</a></span>
</figcaption>
</figure>
<h2>Staying fit as you age</h2>
<p>When you put together all of the various molecular differences in how older adults respond to strength training, the result is that <a href="https://doi.org/10.1093/gerona/glp146">older people do not gain muscle mass as well as young people</a>.</p>
<p>But this reality should not discourage older people from exercising. If anything, it should encourage you to exercise more as you age. </p>
<p>Exercise still remains one of the <a href="https://www.nia.nih.gov/health/exercise-physical-activity">most important activities older adults can do for their health</a>. The work my colleagues and I have done clearly shows that although the responses to training lessen with age, they are by no means reduced to zero.</p>
<p>We showed that older adults with mobility problems who participate in a regular program of aerobic and resistance exercise can <a href="https://doi.org/10.1001/jama.2014.5616">reduce their risk of becoming disabled by about 20%</a>. We also found a similar 20% reduction in risk of becoming disabled among <a href="https://doi.org/10.7326/M16-2011">people who are already physically frail</a> if they did the same workout program.</p>
<p>While younger people may get stronger and build bigger muscles much faster than their older counterparts, older people still get incredibly valuable health benefits from exercise, including improved strength, physical function and reduced disability. So the next time you are sweating during a workout session, remember that you are building muscle strength that is vital to maintaining mobility and good health throughout a long life.</p><img src="https://counter.theconversation.com/content/172941/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Roger Fielding receives funding from USDA, NIH, Biophytis, Nestle', Lonza. </span></em></p>As people age, the chemical signaling pathways in muscles become less potent, and it gets harder to build muscle and maintain strength. But the health benefits of strength training only increase with age.Roger Fielding, Senior Scientist Team Lead Nutrition Exercise Physiology and Sarcopenia Team Jean Mayer USDA Human Nutrition Research Center on Aging, Professor of Medicine, Tufts UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1722362022-01-11T19:12:15Z2022-01-11T19:12:15ZWhat’s autophagy? It’s the ultimate detox that doesn’t yet live up to the hype<figure><img src="https://images.theconversation.com/files/437902/original/file-20211215-21-1np3mq.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1000%2C666&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-photo/young-woman-recording-on-smart-phone-1585351741">Shutterstock</a></span></figcaption></figure><p>“The anti-aging MIRACLE.” “Strengthen your immune system.” “Lose weight fast.”</p>
<p>These are some of the promises of autophagy, the silver bullet wellness influencers are saying is backed by Nobel-winning science.</p>
<p>In many cases, influencers say the best way to boost autophagy – the body’s way of recycling molecules – is with a product available from their online store.</p>
<p><div data-react-class="InstagramEmbed" data-react-props="{"url":"https://www.instagram.com/p/BiNO46nhLz-","accessToken":"127105130696839|b4b75090c9688d81dfd245afe6052f20"}"></div></p>
<p>While autophagy sounds too good to be true, the scientific reality may cross over with the hype – at least in laboratory mice and some other organisms.</p>
<p>Here’s where the science is up to and what we still need to find out to see if boosting autophagy helps humans.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/research-check-can-eating-aged-cheese-help-you-age-well-68808">Research Check: can eating aged cheese help you age well?</a>
</strong>
</em>
</p>
<hr>
<h2>Autophagy is the ultimate detox</h2>
<p>Autophagy is a vital process that removes and recycles unwanted or damaged molecules from your cells. </p>
<p>The process begins with the cell marking unwanted or damaged organelles (made from molecules like proteins, carbohydrates, lipids, and DNA or RNA) for removal.</p>
<p>These marked organelles are enveloped by a membrane, sealing them inside like a garbage bag, becoming what scientists call an <a href="https://www.nature.com/articles/s41580-020-0241-0">autophagosome</a>.</p>
<p>The autophagosome then moves closer to another organelle called a <a href="https://www.genome.gov/genetics-glossary/Lysosome">lysosome</a>, a small acidic bag filled with powerful enzymes. When the two fuse, their contents mix. The enzymes break down the rubbish into recycled nutrients your cells can re-use. </p>
<p>It is the ultimate detox, and you’re doing it right now.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=356&fit=crop&dpr=1 600w, https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=356&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=356&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=448&fit=crop&dpr=1 754w, https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=448&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/436311/original/file-20211208-188518-1fyp5pw.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=448&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 autophagy works in the body. Created with BioRender.com.</span>
<span class="attribution"><span class="license">Author provided</span></span>
</figcaption>
</figure>
<h2>Mice benefit, but do humans?</h2>
<p>Removing these waste products can potentially affect age-related diseases. For example, genetically engineered mice with less autophagy <a href="https://www.nature.com/articles/s41467-019-14187-x">are more likely</a> to develop tumours. Decreased autophagy also accelerates signs of <a href="https://www.jci.org/articles/view/33585">dementia</a> and <a href="https://www.nature.com/articles/s42255-019-0162-4">heart disease</a> in mice.</p>
<p>Autophagy degrades cellular components to re-use as an <a href="https://cancerdiscovery.aacrjournals.org/content/4/8/914.long">energy source</a> during advanced stages of starvation in mice. And because autophagy is crucial for survival during starvation, it is sensitive to nutrient and energy levels. If we decrease nutrition in <a href="https://www.sciencedirect.com/science/article/pii/S0167488917301635?via%3Dihub">laboratory cells</a> and <a href="https://www.tandfonline.com/doi/full/10.4161/auto.6.6.12376">laboratory animals</a>, autophagy increases to compensate. This means diet can potentially modify autophagy.</p>
<p>It all sounds promising. But, and this is the big stumbling block, we don’t really know how it acts in humans.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/of-mice-and-men-why-animal-trial-results-dont-always-translate-to-humans-73354">Of mice and men: why animal trial results don’t always translate to humans</a>
</strong>
</em>
</p>
<hr>
<h2>How would we know if it’s the same in humans?</h2>
<p>For us to know if fasting, taking a pill or some other activity affects autophagy in humans (and our health), we need to be able to measure if autophagy is increasing or decreasing.</p>
<p>And our group <a href="https://www.tandfonline.com/doi/abs/10.1080/15548627.2020.1846302?journalCode=kaup20&">has developed</a> the first test of its kind to measure how autophagy activity varies in humans. But even that is limited to blood samples. We’re still not sure about the levels of autophagy in tissues like the brain or whether the autophagy activity we see in the blood matches elsewhere in the body. We are working on it.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/theres-no-magic-way-to-boost-your-energy-but-perineum-sunning-isnt-the-answer-150835">There's no magic way to boost your energy. But 'perineum sunning' isn't the answer</a>
</strong>
</em>
</p>
<hr>
<h2>How about those diets or pills then?</h2>
<p>We simply do not understand enough about autophagy in humans, and there has not been enough time to test whether autophagy-boosting diets or supplements actually work in people. At best this makes various claims of boosting autophagy and its benefits premature, and at worst, completely incorrect.</p>
<p>Given the positive results in animals, and because autophagy is sensitive to nutrition, it is not surprising there is no end of advice and nutritional supplements that promise to increase autophagy for healthy ageing.</p>
<p>These tend to be books or material that explain how to <a href="https://www.theselect7.com/the-select-files/wb-all-about-autophagy">diet your way to more autophagy</a> (using intermittent fasting or keto-diets for example). Or, you can <a href="https://www.ominutrition.com/what-is-autophagy-and-how-can-it-save-my-skin/">buy supplements</a> claiming to increase autophagy with ingredients such as citrus bergamot.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Woman holding up dietary supplement" src="https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/439788/original/file-20220107-13-18z5ihu.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">There is no end of advice and nutritional supplements that promise to increase autophagy for healthy ageing.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/vitamins-girl-holding-pill-cod-liver-622424405">Shutterstock</a></span>
</figcaption>
</figure>
<p>As dubious as these claims might seem, a lot of them do tend to stem from a grain of truth. Indeed, work on the mechanisms of autophagy really did <a href="https://www.nobelprize.org/prizes/medicine/2016/press-release/">win the Nobel Prize in 2016</a>.</p>
<p>But influencers’ claims wildly extrapolate from preliminary data without context. For example, a mouse can only go without food for <a href="https://www.nature.com/articles/s41580-021-00411-4">two to three days</a> before dying, while a human can go without food for weeks. </p>
<p>So exactly how much fasting is required to increase autophagy in humans is completely unknown: influencer <a href="https://www.mentalfoodchain.com/induce-autophagy/">claims of</a> 16, 24 or 48 hours are stabs in the dark.</p>
<p>This is equally true for supplements. One prominent product for sale is spermidine, which can increase autophagy in the laboratory, such as in <a href="https://www.nature.com/articles/ncb1975">yeast and cultured human cells</a>. However, nothing directly shows it can increase autophagy in humans.</p>
<p>Autophagy has only been widely studied for around 15 years. So far, we know it can slow biological ageing in laboratory animals. Because of this, it has the potential to address some of the biggest health issues our society currently faces. <a href="https://www.embopress.org/doi/full/10.15252/embj.2021108863">This includes</a> dementia, cancer and heart disease.</p>
<p>But, at the moment, we just don’t know enough about autophagy in humans to make any claims about what we can do to increase it, or any health benefits.</p>
<hr>
<p><em>Ben Lewis, science writer and communicator at the South Australian Health and Medical Research Institute, co-authored this article.</em></p><img src="https://counter.theconversation.com/content/172236/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>TJS and JB are listed as inventors on a related patent, PCT/AU2020/050908 for measurement of autophagy in humans.</span></em></p>Autophagy may be Nobel-winning research, but so far there’s no evidence that boosting how your cells recycle nutrients makes you live longer or lose weight.Tim Sargeant, Head, Lysosomal Health in Ageing research group, South Australian Health & Medical Research InstituteJulien Bensalem, Postdoctoral researcher, Lysosomal Health in Ageing research group, South Australian Health & Medical Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1632102021-06-24T18:17:22Z2021-06-24T18:17:22ZResearch that shines light on how cells recover from threats may lead to new insights into Alzheimer’s and ALS<figure><img src="https://images.theconversation.com/files/408024/original/file-20210623-27-1ckyw2a.png?ixlib=rb-1.1.0&rect=6%2C3%2C1147%2C1097&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Ubiquitin tags in cells serve different functions depending on stress conditions.</span> <span class="attribution"><span class="source">Michael Hughes</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>Our bodies contain a special protein tag that plays a role in how cells recover from specific threats to their survival, according to new research I co-authored. Understanding how this process works may be key to future treatments for neurodegenerative diseases, such as Alzheimer’s disease and some forms of dementia.</p>
<p>Cells regularly encounter potentially harmful changes in their environment, such as fluctuating temperature or exposure to UV light or toxins. To ensure survival, cells have evolved complex ways to adapt to these stressful changes. These mechanisms range from temporary changes in metabolism to wholesale shutdown of critical biological processes that might otherwise be permanently damaged. </p>
<p>For example, many cellular stresses temporarily shut down protein production while <a href="https://www.nature.com/scitable/definition/mrna-messenger-rna-160/">messenger RNAs</a>, which carry part of the DNA code through the cell, become sequestered in dense structures known as <a href="https://doi.org/10.1016/j.cell.2020.03.046">stress granules</a>. When the stress passes, the stress granules are disassembled and cells emerge from this defensive state to resume normal activities. </p>
<p>But until now, molecular biologists <a href="https://scholar.google.com/citations?user=n1F7nY8AAAAJ&hl=en&oi=sra">like me</a> didn’t understand exactly how this mechanism worked. </p>
<p>In a pair of peer-reviewed studies published in the journal Science on June 25, 2021, my colleagues and I working in <a href="https://scholar.google.com/citations?user=D8NsvBIAAAAJ&hl=en&oi=ao">J. Paul Taylor</a>’s cell and molecular biology lab explain how a protein known as <a href="https://www.healthline.com/health/ubiquitin#where-its-found">ubiquitin</a> is responsible for getting cells back up and running once the coast is clear.</p>
<p><a href="https://science.sciencemag.org/content/372/6549/eabc3593/tab-article-info">In the first study</a>, I discovered that different types of stress lead to specific proteins in cells getting tagged with ubiquitin in distinct ways. I exposed cells to either heat stress or a toxic chemical, then blocked the ubiquitin-tagging process after seemingly identical stress granules formed. To my surprise, blocking ubiquitin tagging only prevented stress granule disassembly for heat shock. Importantly, I also found that cells were unable to restart key biological processes like protein production and transport when these stress granules remained present, even after a return to normal temperatures.</p>
<p><a href="https://science.sciencemag.org/content/372/6549/eabf6548/tab-article-info">In the second study</a>, my colleague <a href="https://scholar.google.com/citations?user=hUDqV14AAAAJ&hl=en">Youngdae Gwon</a> looked closer into this process. He discovered that heat stress triggers ubiquitin tagging of a key protein that allows an enzyme to disassemble stress granules. This enzyme grabs onto the ubiquitin tag and uses it as a handle to pull the structure apart.</p>
<h2>Why it matters</h2>
<p>Researchers have linked stress granule biology and the stress response process in general to <a href="https://doi.org/10.1126/science.abb8032">several neurodegenerative diseases</a>, including Alzheimer’s disease, ALS or Lou Gehrig’s disease, and some forms of dementia. </p>
<p>For example, mutations in the the same protein, which we found to be necessary to dissemble stress granules, can cause inherited neurodegenerative diseases. Understanding how stress granules are regulated is critical to getting a better grasp on how these diseases work and potentially finding new treatments for them. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/piBTwMdXjBQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Stress granules play a role in the development of neurodegenerative diseases like ALS.</span></figcaption>
</figure>
<h2>What still isn’t known</h2>
<p>Although we identified several key factors in the role ubiquitin plays in the disassembly of stress granules, many molecular details of this process remain unknown. To gain further insight, scientists will need to identify which enzymes are responsible for putting the ubiquitin tag on proteins during stress in the first place. Additionally, it will be important to understand how mutations that lead to neurodegenerative diseases might also affect the stress recovery process.</p>
<h2>What other research is being done</h2>
<p>Researchers are investigating various aspects of stress granule biology and its links to neurodegenerative disease. Some are working to <a href="https://doi.org/10.1083/jcb.202009079">recreate stress granules in a test tube</a> to explore questions not easily answered by working in cells. And others are looking inside live neurons, mice and fruit flies to understand how disease mutations affect stress recovery in living cells and creatures.</p>
<p>[<em><a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-corona-important">The Conversation’s most important coronavirus headlines, weekly in a science newsletter</a></em>]</p><img src="https://counter.theconversation.com/content/163210/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Brian Andrew Maxwell receives funding from NIH and the St. Jude George Mitchell Fellowship </span></em></p>Insight on how a unique protein plays a role in cellular stress responses may provide more clues on how to treat diseases like ALS and Alzheimer’s.Brian Andrew Maxwell, Scientist in Cell Biology, St. Jude Children’s Research Hospital Graduate School of Biomedical SciencesLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1177272019-07-05T12:22:07Z2019-07-05T12:22:07ZSo far cultured meat has been burgers – the next big challenge is animal-free steaks<figure><img src="https://images.theconversation.com/files/282365/original/file-20190702-126382-pchbd2.jpg?ixlib=rb-1.1.0&rect=479%2C455%2C4501%2C3038&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Meat of the future might be quite different from meat of the past.</span> <span class="attribution"><a class="source" href="https://www.loc.gov/pictures/item/2004671592/">Stanley Kubrick, photographer, LOOK Magazine Photograph Collection, Library of Congress, Prints & Photographs Division, LC-USZ6-2352.</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>The meat you eat, if you’re a carnivore, comes from animal muscles. But animals are composed of a lot more than just muscle. They have organs and bones that most Americans do not consume. They require food, water, space and social connections. They produce waste.</p>
<p>Farmers spend a lot of energy and resources to grow complex organisms, creating waste in the process, only to focus on the profitable cuts of meat they can harvest.</p>
<p>It would be easier, more humane, less wasteful, to <a href="https://vimeo.com/78403188">produce just the parts people want</a>. And with cell biology and tissue engineering, it is possible to grow just muscle and fat tissue. It’s called cultured meat. Scientists provide cells with the same inputs they need to grow, just outside an animal: nutrients, oxygen, moisture and molecular signals from their cell neighbors.</p>
<p>So far researchers have <a href="https://youtu.be/slslQLZL2EI">cultivated bunches of cells</a> that can be turned into processed meat like a burger or a sausage. This cultured meat technology is still in the early phases of research and development, as prototypes are scaled-up and fine-tuned to prepare for the challenges of commercialization. But already bioengineers are taking on the next tougher challenge: growing structured cuts of meat like a steak or a chicken cutlet.</p>
<h2>What meat’s made of</h2>
<p>If you look at a piece of raw meat under the microscope, you can see what you’re eating on the cellular level. Each bite is a matrix of muscle and fat cells, interlaced with blood vessels and enrobed by connective tissue.</p>
<p>The muscle cells are full of proteins and nutrients and the fat cells are full of, well, fats. These two cell types contribute to most of the taste and mouth-feel a carnivore experiences when biting into a burger or steak. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=677&fit=crop&dpr=1 600w, https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=677&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=677&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=850&fit=crop&dpr=1 754w, https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=850&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/279615/original/file-20190614-158945-158jkci.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=850&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Section of turkey stained to show cellular-level organization skeletal muscle tissue – also known as meat.</span>
<span class="attribution"><span class="source">Natalie Rubio</span></span>
</figcaption>
</figure>
<p>The blood vessels supply an animal’s tissue with nutrients and oxygen while it’s alive; after slaughter, the blood adds a unique, metallic, umami nuance to the meat.</p>
<p>The connective tissue, composed of proteins like collagen and elastin, organizes the muscle fibers into aligned bundles, oriented in the direction of contraction. This connective tissue changes during cooking and adds texture – and gristle – to meat.</p>
<p>The challenge for cellular agriculture researchers is to emulate this complexity of meat from the bottom up. We can grow muscle and fat cells in a petri dish – but blood vessels and connective tissue don’t spontaneously generate as they do in an animal. How can we engineer biomaterials and bioreactors to provide nutrient diffusion and induce organization so we end up with a thick, structured cut of meat?</p>
<h2>Cultured-meat burgers are the first step</h2>
<p>To create any cultured meat, researchers take small – think marble-sized – amounts of tissue from a cow, pig or chicken and isolate individual cells. Then, bioengineers like me put the cells in plastic flasks and give them nutrients, oxygen and moisture while housing them at body temperature. The cells are happy and can divide exponentially, creating more and more cells. </p>
<p>When grown on plastic, the cells will continue to divide until they exist on all of the available surface area. This results in a crowded layer that’s one cell thick. Once the cells stop dividing, they start to mature. Muscle cells fuse together to create long muscle fibers and fat cells begin to produce lipids. Researchers can combine a bunch of these cells together to create processed meat products, like burgers, hot dogs and sausages.</p>
<p>Animal cells alone can replicate most of the meat experience. But without blood vessels and connective tissue, you don’t end up with an organized, three-dimensional tissue – and that’s what you need for structured cuts of meat, like steak, chicken breast and bacon. </p>
<p>To overcome this challenge, scientists can use biomaterials to replicate the structure and function of blood vessels (for nutrient and oxygen transfer) and connective tissue (for organization and texture). This area of research is called <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/scaffolds-for-tissue-engineering">scaffold development</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=473&fit=crop&dpr=1 600w, https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=473&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=473&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=594&fit=crop&dpr=1 754w, https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=594&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/282551/original/file-20190703-126400-8iv3fh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=594&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Providing some structure for cells to grow on will get cultured meat from hamburger to steaks.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/high-angle-rear-view-female-butcher-242663623">Tyler Olson/Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>Scaffolds are the secret ingredient for steaks</h2>
<p>The concept of scaffolds originates in the field of <a href="https://doi.org/10.1016/B978-008045154-1.50021-6">tissue engineering for medical applications</a>. Scientists combine cells and scaffolds to produce functional biomaterials for research, toxicology screening or <a href="https://www.sciencedaily.com/releases/2019/06/190607193705.htm">implants</a>.</p>
<p>These biomaterials can take different forms – films, gels, sponges – depending on what properties are desired in the resulting tissue. For example, you could <a href="https://technobleak.com/regenerative-artificial-skin-new-technology-booming-worldwide/">grow skin cells on a flat collagen film</a> to create a skin graft to help burn victims or <a href="https://www.sciencedaily.com/releases/2019/05/190516155338.htm">bone cells in a hydroxyapatite sponge</a> for bone regeneration.</p>
<p>For medical applications, scaffolds generally need to be safe for implantation, must not induce a response from the body’s immune system, be degradable and capable of supporting cell growth. </p>
<p>For food applications, the design considerations of scaffolds are different. They should still support cell growth, but it’s also important that they are inexpensive, edible and environmentally friendly to produce. Some common biomaterials for food applications include cellulose from plants, a carbohydrate called chitosan from mushrooms and a carbohydrate called alginate from algae.</p>
<p>Here’s one “recipe” for cultured meat that I’ve worked on in the lab. First, create an appropriate scaffold. Isolate chitosan from mushrooms and dissolve it in water to create a viscous gel. Put the gel in a tube and expose one end to a cold substance, like dry ice or liquid nitrogen. The whole tube of gel will slowly freeze, starting at the cold end. The frozen gel can then be freeze-dried by a vacuum pulling on the gel at very low temperatures, ultimately creating a dry sponge-like material. The <a href="https://doi.org/10.1021/acsbiomaterials.8b01261">directional freezing process creates a sponge</a> with small, long, aligned pores resembling a bundle of straws – and also muscle tissue.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=116&fit=crop&dpr=1 600w, https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=116&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=116&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=146&fit=crop&dpr=1 754w, https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=146&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/282536/original/file-20190703-126400-19y7moh.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=146&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 simplified process for creating a chitosan sponge with aligned pores.</span>
<span class="attribution"><span class="source">Natalie Rubio</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>Then, instead of growing meat on flat plastic, you can transfer the cells to this three-dimensional sponge to provide more surface area for growing thicker tissue. The pores can also help distribute nutrients and oxygen throughout the tissue. So far with this technique, my lab has been able to produce small bits of meat less than a centimeter square – a little small for a cookout but a strong start.</p>
<p>Other scaffold possibilities include growing cells within alginate-based fibers, gels or sponges. Or technicians can rinse plant cells off of plants in a process called decellularization and <a href="https://medium.com/neodotlife/meat-on-a-leaf-glenn-gaudette-9b2765a861f0">repopulate the cellulose framework that’s left behind with animal cells</a>.</p>
<p>Once researchers find materials and methods that work really well, we’ll work on creating larger batches. At that point, it’ll be a game of scaling up the process and bringing down the cost so cultured meat products can be cost-competitive with farmed meat products.</p>
<p>It’s always exciting to see startup companies debut their cultured meatballs, sausages and burgers. But I’m looking ahead to what’s next. With a bit more research, time, funding and luck, the cultured meat menu 2.0 will include the steak and pork chops many carnivores know and love.</p><img src="https://counter.theconversation.com/content/117727/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Natalie R. Rubio is funded by New Harvest and is an advisor for Bond Pet Foods.</span></em></p>It’s relatively easy to grow a bunch of animal cells to turn into a burger. But to grow a steak made of cultured meat is a trickier task. Bioengineers must create organized, three-dimensional tissues.Natalie R. Rubio, Cellular Agriculture PhD Candidate, Tufts UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1186722019-07-04T20:12:35Z2019-07-04T20:12:35ZTo cure brain diseases, neuroscientists must collaborate: That’s why I’m giving my data away<figure><img src="https://images.theconversation.com/files/282155/original/file-20190702-164980-1tmcg6y.jpg?ixlib=rb-1.1.0&rect=137%2C122%2C4779%2C3076&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Thomas Durcan's lab is using pluripotent stem cells to grow human brain neurons in a dish, in search of a cure for Parkinson's disease. </span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Since watching <em>Jurassic Park</em> for the first time as a kid, I’ve been fascinated by the biology of cells and DNA, and the potential to make a dinosaur for real. While this particular dream is a long way off, my life as a research scientist has shown me all the other exciting possibilities that cells offer.</p>
<p>These days, my <a href="https://mcgill.ca/ipsquebec-mni/">lab at the Montréal Neurological Institute and Hospital</a> is growing stem cells in a dish to develop better treatments for <a href="https://theconversation.com/parkinsons-disease-scientists-find-the-earliest-roots-in-the-brain-119030">Parkinson’s disease</a>.</p>
<p>Parkinson’s disease is an age-related movement disorder, characterized by rigidity and tremor, caused a loss of dopaminergic neurons over time. L-DOPA remains the <a href="https://www.pharmaceutical-journal.com/opinion/comment/levodopa-still-the-gold-standard-after-40-years-of-successful-treatment/10047817.articlehttps://www.pharmaceutical-journal.com/opinion/comment/levodopa-still-the-gold-standard-after-40-years-of-successful-treatment/10047817.article">most effective therapy for Parkinson’s</a>. But it was discovered back in the 1960s and no other disease-modifying therapy has emerged since then. </p>
<p>This is partly due to the complexity of the disease, but also because we haven’t done a good enough job <a href="https://theconversation.com/opening-up-the-future-of-psychedelic-science-101303">sharing our protocols and data in an open and accessible manner</a>, so others can take the next step forward and avoid making the same mistakes or repeating the same experiments over and over again.</p>
<p>That’s why I’m giving my lab’s standard methods away over the next year — making them available to anyone who would like to access them.</p>
<h2>A cure for Parkinson’s disease</h2>
<p>You’d think I would keep this knowledge a secret. Science is a competitive field, and finding a way to cure a major disease can be the ticket to rarified air, access to major grant funding, papers in top journals, invitations to be a keynote speaker anywhere in the world and even a drug patent worth millions of dollars — all with the potential gold ticket to a <a href="https://www.nobelprize.org">Nobel Prize</a>.</p>
<p>But modern science doesn’t work like that, at least not neuroscience. Diseases of the brain are incredibly complex and getting even close to halting the disease progression — and developing a potential cure — takes a massive amount of fundamental research done through collaborations. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/282156/original/file-20190702-105200-1i3frms.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">
<figcaption>
<span class="caption">The symptoms of Parkinson’s disease include stiffness, slowness and shaking, as well as memory problems.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>Any breakthrough will come from a diverse team of collaborators who share data, so others can build on it. Only then will <a href="https://m4kpharma.com/">something ground-breaking emerge that can enter the clinic</a> to offer patients a new lease on life, free of the worse effects of the disease. </p>
<p>I know that if my work is to make any kind of difference, it has to be put out into the public domain so it can be added to databases, then analyzed and reproduced by others in the field to ensure findings are consistent across labs.</p>
<h2>We are growing 3D mini-brains</h2>
<p>My lab works with <a href="https://stemcells.nih.gov/info/basics/6.htm">human-induced pluripotent stem cells</a>, or hiPSCs, which can be reprogrammed from the skin, blood or urine of any person. A pluripotent stem cell can be used to make any cell in the human body, all it needs are the right ingredients and some loving care.</p>
<p>In my group, we are <a href="https://doi.org/10.12688/mniopenres.12816.1">using these cells to grow human neurons on a dish</a>, so we can replicate the neurons affected in Parkinson’s disease, amyotrophic lateral sclerosis and neurodevelopmental disorders.</p>
<p>Not only are we generating neurons on 2D dishes, but we have been growing 3D neuronal organoids, or mini-brains, by the thousands, mimicking the human brain more closely then anything seen with 2D cultures.</p>
<p>At the same time, we have been fortunate that <a href="https://theconversation.com/opening-pandoras-box-gene-editing-and-its-consequences-108003">CRISPR genome editing</a> has emerged, providing us with the tools to edit a gene at the base pair level. With all these tools now at our disposal, the time is ripe for new discoveries, but only by working with other academics, start-ups and large pharmaceutical companies — all with the main goal of treating these devastating disorders.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/opening-up-the-future-of-psychedelic-science-101303">Opening up the future of psychedelic science</a>
</strong>
</em>
</p>
<hr>
<p>We are covering new ground, and other labs can learn from our experience. Industry and government spend trillions every year on scientific research, when much of it has already been done. This duplication happens because <a href="https://www.newsweek.com/2014/11/21/medical-science-has-data-problem-284066.html">researchers keep data to themselves, especially negative results</a>. If they do publish the data openly, it’s often impossible to find or use in any practical way, so we need to try something different.</p>
<h2>I hope others will pay it forward</h2>
<p>Over the next year, I will publish my lab’s protocols and methods <a href="https://openlabnotebooks.org/modelling-diseases-of-the-brain-through-stem-cells/">on this blog</a>, where many groundbreaking scientists around the world are sharing their lab notebooks online. </p>
<p>Our results will also be shared openly, in keeping with our <a href="https://www.mcgill.ca/neuro/open-science-0">Open Science policy</a>, which I hope will encourage others to pay it forward and make their results and methods available, leading to a truly open and collaborative scientific community that benefits everyone.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/282150/original/file-20190702-164980-qkbzf3.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">
<figcaption>
<span class="caption">The movie Jurassic Park inspired the author’s interest in cell biology as a child.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>I hope my decision opens new avenues and helps me develop new collaborations. As a scientist, I will benefit from an open environment where I can use the data of others in my work. But more than that, we owe it to patients with neurological disease to be as open with our data and methods as much as possible.</p>
<p>So, please be my guest and use the methods and protocols from my group to help with your own work. And don’t forget to pay it forward.</p>
<p>And if you discover how to bring back the dinosaurs, just like in <em>Jurassic Park</em>, please name the first one after me, the Tommosaurus Rex.</p><img src="https://counter.theconversation.com/content/118672/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Thomas Durcan receives funding from McGill Healthy Brains for Healthy Lives and Parkinson's Canada. </span></em></p>Thomas Durcan’s lab is growing 3D mini-brains in the search for a cure for Parkinson’s disease. Over the next year he is giving all his lab’s protocols, methods and results away.Thomas Durcan, Assistant Professor, Neurodegenerative disorders, McGill UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/783972017-06-26T20:07:57Z2017-06-26T20:07:57ZData visualisation isn’t just for communication, it’s also a research tool<figure><img src="https://images.theconversation.com/files/173232/original/file-20170610-21746-2s25da.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A collage of biological data visualisations. </span> <span class="attribution"><span class="source">Image from C. Stolte, B.F. Baldi, S.I. O'Donoghue, C. Hammang, D.K.G. Ma, and G.T. Johnson</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>At the heart of the scientific method lies the ability to make sense from data. </p>
<p>However, this is a challenge in the fast-moving field of biotechnology, where new experimental methods are creating huge amounts of complex data. These data promise to revolutionise healthcare, food and agriculture, but it can be difficult to extract answers to specific research questions from these sets of numbers. </p>
<p>Data visualisation can help. Our eyes deliver information <a href="http://www.cell.com/current-biology/abstract/S0960-9822(06)01639-3">very rapidly</a> to our brains, and then <a href="http://bigthink.com/endless-innovation/humans-are-the-worlds-best-pattern-recognition-machines-but-for-how-long">sophisticated pattern recognition abilities</a> take over. Well-designed visualisation tools can reveal discoveries that would otherwise remain buried. </p>
<p>Below we highlight three data visualisation tools we have developed to help life scientists find relevant and useful information amongst the noise. The <a href="https://vizbi.org/Videos/26205288">visualisation principles</a> used in these tools are general and help in many complex data challenges.</p>
<h2>Managing large data sets</h2>
<p>Proteins and other molecules in our bodies exist as <a href="https://pdb101.rcsb.org/motm/motm-about">complex 3D structures</a> that constantly change shape and interact with each other. Mapping out the many possible ways that proteins can be structured helps scientists understand how biological processes work, and may inform drug development and treating diseases such as cancer. </p>
<p>Thanks to decades of research worldwide, we now have reliable, evidence-based 3D structures for <a href="https://en.wikipedia.org/wiki/Protein_Data_Bank">tens of thousands of proteins</a>, plus more than <a href="https://www.garvan.org.au/news-events/news/powerful-tool-promises-to-change-the-way-scientists-view-proteins">100 million models of protein structures</a>. </p>
<p>These models are useful for learning about life’s molecular processes – such as how <a href="https://www.wehi.edu.au/wehi-tv/dna-central-dogma-part-1-transcription">RNA</a> and <a href="https://www.wehi.edu.au/wehi-tv/dna-central-dogma-part-2-translation">proteins</a> are made – however, the large number of models can make it difficult for scientists to pin down which specific models can help answer a particular research question.</p>
<p>To address this difficulty, one of us (Seán O’Donoghue) and colleagues developed <a href="http://youtu.be/FAQ3yVGYSzY">Aquaria</a>, a tool using the visualisation principle of “<a href="https://doi.org/10.1109/VL.1996.545307">overview first, details on demand</a>”. By using a technique called “<a href="https://en.wikipedia.org/wiki/Cluster_analysis">clustering</a>”, Aquaria creates a concise visual overview of all structural models available for any specific protein. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=716&fit=crop&dpr=1 600w, https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=716&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=716&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=899&fit=crop&dpr=1 754w, https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=899&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/173240/original/file-20170610-4794-otmifm.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=899&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">An overview of all 3D structural models available for p53, a protein that protects against cancer. Image created using Aquaria.</span>
<span class="attribution"><span class="source">S.I. O’Donoghue and C. Stolte</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>The image above shows this overview for p53, a protein that protects against cancer. Each cluster of related 3D models can be interactively expanded and explored (bottom of the image), helping scientists find the most useful models suited to address a specific research question.</p>
<p>Once a suitable model is found it is shown (top of the image), with dark colouring used to indicate regions where the structure of the model is less certain. In addition, yellow, blue and green are used to highlight different shapes within the structure, which helps scientists understand how the protein is arranged in three dimensions.</p>
<h2>Viewing connections between different datasets</h2>
<p>Sometimes, we need to look at data from multiple viewpoints. This is particularly true for a field of research known as <a href="https://www.genome.gov/10001177/dna-sequencing-fact-sheet/">sequencing</a>. Sequencing involves determining the precise order of the chemical building blocks that make up <a href="https://www.genome.gov/25520880/deoxyribonucleic-acid-dna-fact-sheet/">DNA</a>, RNA and protein. Knowing these sequences and comparing how they vary between individuals can tell us about mutations that cause disease and reveal how we evolved. </p>
<p>One of the most widely used tools for visualising sequences is <a href="http://www.jalview.org/training/Training-Videos">Jalview</a>, <a href="https://doi.org/10.1093/bioinformatics/btp033">co-developed by one of us (James Procter)</a>, which brings together the huge amounts of data that are created through sequencing. </p>
<p>Jalview employs two principles - “<a href="http://www.infovis-wiki.net/index.php?title=Linking_and_Brushing">linking and brushing</a>” and “<a href="https://www.cs.umd.edu/hcil/snap/">multiple coordinated views</a>” - to bring together different types of information. Jalview also allows other tools to be connected, enabling scientists to navigate through complex, interrelated datasets.</p>
<p>The example below shows a family of proteins known as Aquaporins, which are molecular channels important for water balance and nutrient transport in cells. Aligning these protein’s sequences (close up on right) allows them to be clustered into a tree (shown top-left, with birds-eye view of the protein alignment next door). DNA mutations are mapped onto the protein alignment (shown in red), and these colours also locate the mutations in protein structure (bottom left).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/173234/original/file-20170610-21746-tcavh5.png?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">Linked brushing and multiple data visualisations allow potential disease mutations to be identified at the core of Aquaporin, a protein important for water balance and nutrient transport. Image created using Jalview linked with UCSF Chimera.</span>
<span class="attribution"><span class="source">J.B. Procter</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<h2>Visualising networks that change over time</h2>
<p>Scientists are aiming to unravel diseases – such as obesity – by studying small changes that take place within our cells.</p>
<p>For example, food that we eat triggers the release of insulin into our blood stream, which then tells fat cells to store rather than release energy. This process ultimately influences our body weight.</p>
<p>Cells are tiny, but they are hives of activity. Thanks to recent advances in techniques such as <a href="https://en.wikipedia.org/wiki/Mass_spectrometry">mass spectrometry</a>, we can now map the tens of thousands of events that are <a href="https://en.wikipedia.org/wiki/Phosphoproteomics">happening within each of our cells</a> in response to hormones such as insulin.</p>
<p>The difficulty for scientists is to try to view this huge amount of information in an accurate and simple way, and one that reflects the chain of events in a cell that matter to our overall health. </p>
<p>One of us (Seán O’Donoghue) and colleagues developed <a href="http://cell.com/cell/enhanced/odonoghue">Minardo</a>, an approach that creates a sort of timeline of events that happen inside a cell. Minardo uses the principle that position on a viewing screen is <a href="http://www.infovis-wiki.net/index.php?title=Visual_Variables#Visual_Variables_2">the most effective visualisation strategy</a>. The resulting visualisation helps scientists identify exactly what is going on inside a healthy cell, and what might be different in a diseased cell. </p>
<p>The image here shows (beginning top left, then clockwise) the sequence of events that take place after insulin (in pink) binds to the surface of a fat cell. The consequences of insulin binding include switching off the release of energy stores from the cell (around 1 minute after insulin binds), and switching on energy storage (around 5 minutes after insulin binds). </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=381&fit=crop&dpr=1 600w, https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=381&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=381&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=479&fit=crop&dpr=1 754w, https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=479&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/173235/original/file-20170610-4774-1otxmuc.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=479&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 sequence of key events within a human fat cell following insulin binding to its receptor (top left, pink). Image created using Minardo.</span>
<span class="attribution"><span class="source">D.K.G. Ma, C. Stolte, J.R. Krycer, D.E. James, and S.I. O’Donoghue</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<h2>VIZBI, an international visualisation community</h2>
<p>In building these tools, we aim to visualise data as clearly as possible, so the viewer can focus on the science. </p>
<p><a href="http://youtu.be/FAQ3yVGYSzY">Aquaria</a>, <a href="http://www.jalview.org/training/Training-Videos">Jalview</a> and <a href="http://cell.com/cell/enhanced/odonoghue">Minardo</a> are freely accessible and used by tens of thousands of scientists and students worldwide - an accomplishment that we are proud of. </p>
<p>However, our tools address only three specific research questions – biology has thousands more. Tailored visualisations of this kind need an interdisciplinary team, take months to prototype and require years to develop into robust and usable tools. </p>
<p>Realising this, in 2010, we created an international initiative called <a href="https://vizbi.org">VIZBI</a> to connect tool-builders and raise the standard of <a href="http://www.nature.com/news/the-visualizations-transforming-biology-1.20201">data visualisation in biology</a>. In June 2017, <a href="http://vizbi.org/2017/">VIZBI</a> and associated events came to the Asia-Pacific region for the first time. </p>
<p>With the overwhelming complexity of biological data, substantial time and effort is required to create effective visualisation tools not just for communication but also for research itself.</p><img src="https://counter.theconversation.com/content/78397/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Seán I. O’Donoghue works for CSIRO and the Garvan Institute of Medical Research.</span></em></p><p class="fine-print"><em><span>James B. Procter's work on Jalview in the Barton Group at the University of Dundee is supported by funding from the UK's Biotechnology and Biological Sciences Research Council and Wellcome Trust.
</span></em></p>The daunting complexity of biological data requires tailored visualisation tools to reveal buried insights.Seán I. O’Donoghue, Senior Faculty Member at the Garvan Institute, Conjoint Professor at UNSW, and Senior Principal Research Scientist, CSIROJames B. Procter, Jalview Coordinator, Bioinformatician and Open Source Software Developer, University of DundeeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/735442017-03-10T11:05:47Z2017-03-10T11:05:47ZMaths: why many great discoveries would be impossible without it<figure><img src="https://images.theconversation.com/files/159775/original/image-20170307-14932-o8tzu4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">There are some great uses.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/man-dark-business-suit-drawing-algebraic-414380566?src=KCvjNrjtxmWatDNSXW1_ZQ-1-21">Shutterstock</a></span></figcaption></figure><p>Despite the fact that mathematics is often described as the underpinning science, it is often not given enough credit when scientific discoveries are presented. But the contribution of mathematics and statistics is essential and has transformed entire areas of research – many discoveries would not have been possible without it. In fact, as a mathematician, I have contributed to scientific discoveries and provided solutions to problems that biology was yet to solve.</p>
<p>Seven years ago, I attended a lecture on some biological research that was taking place at Heriot-Watt University. My colleagues had an unsolved problem which related to the movement of bag-like structures called <a href="http://study.com/academy/lesson/vesicles-definition-function-quiz.html">vesicles</a> which move hormones and <a href="http://www.neurogistics.com/the-science/what-are-neurotransmitters">neurotransmitters</a> such as insulin or <a href="http://www.healthline.com/health/mental-health/serotonin">serotonin</a> around cells and the body. </p>
<p>Their problem lay in that vesicles were known to follow specific tracks along the <a href="https://www.khanacademy.org/science/biology/structure-of-a-cell/tour-of-organelles/a/the-cytoskeleton">cell skeleton</a> which lead to special molecules which then caused the vesicle to release its contents into the cell. However, when the biologists themselves tried to find these tracks, they were not in the expected places. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=675&fit=crop&dpr=1 600w, https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=675&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=675&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=848&fit=crop&dpr=1 754w, https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=848&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/159776/original/image-20170307-14934-ur22sk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=848&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A bag that carries hormones to their location.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File%3A0310_Exocytosis.jpg">OpenStax</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>It is important to understand how vesicles behave, or in fact misbehave, as they have been linked to conditions such <a href="http://www.nature.com/nrn/journal/v6/n1/full/nrn1583.html">diabetes and neurological disorders</a>. The biologists were struggling to find a way to understand the vesicles – but I had a solution in my mathematical toolkit.</p>
<h2>Maths can beat biology</h2>
<p>After two years of collaboration I told my colleagues: “my model and computer experiments are better than your microscope!” </p>
<p>What I meant by this rather confident statement was that by using mathematics to model how molecules move in a cell we could predict and run multiple experiments on a computer at a smaller scale and faster rate than a microscope. It could allow us to uncover things that the biologist’s resources could not, and might even point us in the direction of target molecules for future treatments of diabetes and neurological disorders.</p>
<p>The mathematical model allowed us to recognise that the movement of vesicles requires energy – and the maths models it through an energy landscape. It imagined a vesicle to be like a cyclist riding a bicycle – the landscape may have easy level sections but also hills that require more energy input to get over them, and so we wanted to test whether they actually avoided these hills.</p>
<p>After seven years of working in partnership with the biologists, my colleagues and I <a href="http://www.sciencedirect.com/science/article/pii/S0960982216314488">proved our hypothesis</a> was correct. Vesicles do follow lower energy “valleys” in the landscape, avoiding molecules which create the high energy hills in the energy landscape – taking the easiest path. The overall result is just the same as the biologists had found – the vesicles end up in the same end location and they reuse similar routes over and over again. But the difference lies in the way in which they do it, and it was not by following the cell skeleton as biologists had first believed – they take an easier route. It really shows the power of maths and how it can change the way we see things.</p>
<p>Mathematical models allow you to capture many gigabytes of raw data in a compact form in a way that is impossible for a biologist with a microscope. You can make modifications to the model easily and show how vesicle behaviour may change during disease, when they are disrupted or mutated. It could then reveal which molecules to target in future treatment studies – and lay the groundwork for larger and more thorough modelling of complex biological processes. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=320&fit=crop&dpr=1 600w, https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=320&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=320&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=402&fit=crop&dpr=1 754w, https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=402&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/160318/original/image-20170310-3676-qqk95l.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=402&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A modelled energy landscape.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/abstract-digital-landscape-flowing-particles-cyber-512664334?src=1Jj96ZspibYIcnaBGgSXpQ-1-3">Shutterstock</a></span>
</figcaption>
</figure>
<p>The integration of cutting-edge microscopy with cell biology and mathematical modelling could be applied to many other problems in bio-medicine and will accelerate discovery in the years to come. The movement of molecules and other cell components is just one example of where the power of mathematics is unrivalled, but it is by no means its limit. </p>
<h2>Useful is an understatement</h2>
<p>Maths is often criticised by the public for lacking in “real-world” applications, but it is being applied to many real-world problems all the time. <a href="https://www.sciencedaily.com/releases/2012/11/121128143541.htm">Groundwater contamination</a>, <a href="https://ercim-news.ercim.eu/en78/special/introduction-modern-mathematics-for-finance-and-economics">financial and economic forecasting</a>, <a href="https://books.google.co.uk/books?id=kfi3CgAAQBAJ&pg=PA59&lpg=PA59&dq=plume+height+maths&source=bl&ots=2PxPQoHjvg&sig=0Jc4XxFwybn9tJQn57sGUKsBl4o&hl=en&sa=X&ved=0ahUKEwjLiuPdjtPSAhVFKcAKHbYvBjsQ6AEIUjAI#v=onepage&q=plume%20height%20maths&f=false">plume heights</a> in volcanic eruptions, the modelling of biological processes and <a href="http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.605.5690&rep=rep1&type=pdf">drug delivery</a> are just a few places where maths is making a huge difference.</p>
<p>I’m proud to say that I co-authored a paper with my biology colleagues, and I hope to see more mathematicians coming to the fore for science research in the future. Mathematics plays a central role in so many of the world’s scientific breakthroughs and deserves a headline role in more academic publications. Power to the mathematician – they’re behind more discoveries than you think.</p><img src="https://counter.theconversation.com/content/73544/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gabriel Lord receives funding from EPSRC. </span></em></p>Maths is often a quiet contributor to problems in subjects like biology.Gabriel Lord, Professor of Mathematics, Heriot-Watt UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/594832016-05-20T12:53:30Z2016-05-20T12:53:30ZHow the hidden mathematics of living cells could help us decipher the brain<figure><img src="https://images.theconversation.com/files/122716/original/image-20160516-15930-5nnsna.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Simulating the human brain is proving tricky. But could mathematics based on symmetries help?</span> <span class="attribution"><span class="source">youtube</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Given how much they can actually do, computers have a surprisingly simple basis. Indeed, the logic they use has worked so well that we have even started to think of them as analogous to the human brain. Current computers basically use two basic values – 0 (false) and 1 (true) – and apply simple operations like “and”, “or” and “not” to compute with them. These operations can be combined and scaled up to represent virtually any computation. </p>
<p>This “binary "or "Boolean” logic was introduced by <a href="http://www-groups.dcs.st-and.ac.uk/%7Ehistory/Biographies/Boole.html">George Boole</a> in 1854 to describe what he called “the laws of thought”. But the brain is far from a binary logic device. And while programmes such as the <a href="https://theconversation.com/after-years-of-conflict-huge-project-could-help-scientists-decipher-the-brain-42581">Human Brain Project</a> seek to model the brain using computers, the notion of what computers are is also constantly changing.</p>
<p>So will we ever be able to model something as complex as the human brain using computers? After all, biological systems use symmetry and interaction to do things that even the most powerful computers cannot do – like surviving, adapting and reproducing. This is one reason why binary logic often falls short of describing how living things or human intelligence work. But <a href="http://rsta.royalsocietypublishing.org/content/roypta/373/2046/20140223.full.pdf">our new research</a> suggests there are alternatives: by using the mathematics that describe biological networks in the computers of the future, we may be able to make them more complex and similar to living systems like the brain.</p>
<p>Living organisms do not live in a world of zeroes and ones. And if binary logic doesn’t naturally describe their activity, what kind of mathematics does? I was involved in an international project which studied whether mathematical structures called “<a href="https://plus.maths.org/content/os/issue41/features/elwes/index">Simple Non-Abelian Groups</a>” (SNAGs) may describe complex processes in living cells. SNAGs are commonly in mathematics and physics, and are based on the principles of symmetry and interaction. SNAGs offer a potentially powerful alternative to binary logic for computation.</p>
<h2>Helpful SNAGs</h2>
<p>There are infinitely many kinds of SNAGs. They were conjured by the brilliant 19th-century French mathematician <a href="http://www-groups.dcs.st-and.ac.uk/history/Biographies/Galois.html">Évariste Galois</a>, who tragically died aged 20 in a fatal duel over a romantic interest. Indeed, he wrote much of his ground-breaking theory during a feverish night before the duel. </p>
<p>The smallest SNAG – A5 – describes the symmetries of two beautiful 3D shapes known since the time of the ancient Greeks: the icosahedron (made of 20 triangles) and the dodecahedron (made of 12 pentagons). SNAGs can be thought of as the “multiplication tables” of how symmetries interact, rather than for how to multiply numbers. </p>
<p><img src="https://upload.wikimedia.org/wikipedia/commons/7/73/Dodecahedron.gif">
<img src="https://upload.wikimedia.org/wikipedia/commons/e/e2/Icosahedron.gif"><br>
Dodecahedron and Icosahedron (Platonic Solids): <br>3D shapes with SNAG symmetry</p>
<p><img>
<img></p>
<p>Unlike the ones and zeros used in binary logic with just two values, the SNAG for each of these shapes have 60 values – or “symmetries”. These symmetries operate like rotations that can be combined. Performing a rotation and following it with a second can have the same effect as another kind of rotation, giving a kind of “multiplication table” for these 60 symmetries. For example, if you rotate the icosahedron (the figure below) five times by 72 degrees clockwise around the axis through its centre and any vertex (corner) it will get back to the starting configuration. </p>
<p>The structure of SNAGs is a natural kind of basis for computation that is <a href="http://www.sciencedirect.com/science/article/pii/S0019995866902294/part/first-page-pdf">just as powerful as binary logic</a>, but presents a very different view about which computations are easy. To compute with SNAGs, nature (or humans or future computers) can use sequences of SNAG symmetries combined according to the rules. Patterns of events and interactions determine which symmetries occur in the sequence’s variable positions.</p>
<h2>Symmetries in nature</h2>
<p>We have <a href="http://rsta.royalsocietypublishing.org/content/roypta/373/2046/20140223.full.pdf">for the first time shown</a> that there are SNAGs hidden in common biological networks. To do this, we analysed the internal workings of cells (their gene regulation and metabolism) using mathematics, computers and models from systems biology. We found that SNAG symmetries accurately describe potential activities in the genetic regulatory network that controls a cell’s response to certain kinds of stress – such as radiation and DNA damage. This may be hugely important as it means SNAGs can describe cellular processes intimately involved in self-repair, “cell suicide”, and cancer. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=500&fit=crop&dpr=1 600w, https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=500&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=500&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=628&fit=crop&dpr=1 754w, https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=628&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/123378/original/image-20160520-4463-51xv6t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=628&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Multiphoton fluorescence image of so-called HeLa cells using a laser scanning microscope.</span>
<span class="attribution"><span class="source">NIH</span></span>
</figcaption>
</figure>
<p>The specific SNAG involved in this gene network is A5. The 60 symmetries in this case are the result of particular sequences of manipulations by the cell’s genetic regulatory network to transform ensembles of proteins into other forms. For example, when a set of five concentration levels of proteins is manipulated, it can be transformed to another set. When this is done many times, it can break some of the proteins down, join some together or synthesise new types of proteins. But after a specific number of manipulations the original five concentration levels of proteins will eventually return. </p>
<p>It doesn’t stop at cellular damage control processes. We have also shown mathematically that nearly all biological reaction networks must have <a href="http://www.biomicsproject.eu/file-repository/category/11-public-files-deliverables?download=264:d3-1-2-modelling-methods-for-interaction-computing.pdf#page=24">numerous embedded SNAG components</a>. However, lab work is still needed to explain how and to what extent cells exploit SNAGs in their activity. </p>
<p>Computation with SNAGs has never yet been exploited in conventional computers, but we are hoping to use it. In the future, new kinds of computers and software systems may deploy resources the way some living organisms do, in robust adaptive responses. Driven by interaction with their environment, including human users, they could grow new structures, divide up tasks among different types of computational “cells” such as hardware units or software processes, allow old structures to wither and be reabsorbed if unused.</p>
<p>Understanding how living things and brains use interaction-based computations, which are all around us, may radically reshape not only our computers and the internet, but the existing models of the brain and living organisms. SNAG-based computations may finally help us build better and more predictive working models of cells and of the brain. But we have only sighted the first examples, and so have a long way to go. After all, <a href="http://shakespeare.mit.edu/hamlet/full.html">as Shakespeare</a> and this discovery of SNAG-computation in cells remind us: “There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy.”</p><img src="https://counter.theconversation.com/content/59483/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The work of the author reported here was supported by funding from the European Commission Future and Emerging Technologies (FET) Project BIOMICS (Biological and Mathematical Basis of Interaction
Computing), Grant no. 318202.</span></em></p>Scientists uncover hidden mathematical structures controlling how living cells operate. If this could be used by computers of the future, we may one day be able to understand the brain.Chrystopher Nehaniv, Professor of Mathematical and Evolutionary Computer Science, University of HertfordshireLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/345382015-01-13T03:48:44Z2015-01-13T03:48:44ZSun damage and cancer: how UV radiation affects our skin<figure><img src="https://images.theconversation.com/files/68667/original/image-20150112-23795-4hcca3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Sun exposure that doesn't result in burning may still damage the skin cells.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/rainbreaw/3686462313">Rain/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Around 30 Australians are <a href="http://www.melanoma.org.au/understanding-melanoma/">diagnosed</a> with melanoma every day and more than <a href="http://www.melanoma.org.au/understanding-melanoma/">1,200 die</a> from the disease each year. </p>
<p>While small amounts of ultraviolet (UV) radiation are required for the <a href="https://theconversation.com/how-to-protect-your-skin-while-getting-enough-vitamin-d-34143">production of vitamin D</a> to keep bones and muscles strong and healthy, skin can burn from just 15 minutes of exposure to the summer sun. </p>
<p>In 2009, the World Health Organization (WHO) <a href="http://www.iarc.fr/en/media-centre/iarcnews/2009/sunbeds_uvradiation.php">classified</a> the whole ultraviolet spectrum and the use of solariums as carcinogenic to humans, placing them in the same category as asbestos and tobacco. The majority of skin cancers in Australia are thought to be caused by exposure to UV radiation in sunlight. </p>
<p>The sun emits three different types of UV radiation: UVA, UVB and UVC. While UVC rays are filtered by the ozone, 10% of UVB and 95% of UVA rays reach the earth’s surface. </p>
<h2>Cell damage</h2>
<p>The UV effects on the skin are largely dependent on the type of UV rays (proportion of UVB and UVA), the amount and intensity of UV, and the stage at which the cells on the skin are in during their normal division and renewal process. </p>
<p>UV can produce a number of effects within the cell including specific types of DNA damage in skin cells and, with extreme UV exposure, cell death. Some of these types of <a href="http://www.fasebj.org/content/17/10/1195.full">oxidative DNA</a> and <a href="http://en.wikipedia.org/wiki/Nucleotide_excision_repair">nucleotide</a> damage, and failure of the cells to repair this damage can prompt cells to mutate, leading to the development of skin cancers.</p>
<p>With some cancers that develop on skin exposed to excessive sunlight, DNA damage can be identified through UV-specific DNA mutations within the tumour. </p>
<p>But sun exposure that doesn’t result in burning may still damage the skin cells. Research suggests that regular exposure to UV radiation year after year can also lead to <a href="http://www.cancer.org.au/about-cancer/types-of-cancer/skin-cancer.html">skin cancer</a>. </p>
<h2>Repairing DNA</h2>
<p>When cells are actively dividing and proliferating they are particularly vulnerable to DNA damage. So cells are equipped with mechanisms to respond to and repair DNA damage within the cell to restore the DNA structure before they continue dividing.</p>
<p>The cells respond by delaying progression through the cell cycle through the cooperation of cell cycle checkpoints and several biochemical pathways. This allows sufficient time for repair before the critical phases of the cell division process proceed. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/68772/original/image-20150113-23795-7sas6g.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">
<figcaption>
<span class="caption">To reduce your exposure to UV, use a high-sun protection factor, water-resistant sunscreen that blocks both UVA and UVB rays, and reapply every two hours.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-42892540/stock-photo-close-up-of-women-hands-receiving-sunblock-cream-lotio.html?src=wF8G3QOfqZgn8N3vGm-XrQ-1-1&ws=1">ostill/Shutterstock</a></span>
</figcaption>
</figure>
<p>In the event the DNA damage is too severe, the cells kill themselves off, preventing DNA damage being transferred to the daughter cells. </p>
<p>If these checkpoints are defective and do not delay the cell cycle progression to enable repair, the result may be an increase in DNA mutations and chromosomal defects. This can cause uncontrolled growth, transformation of the cell and the development of cancer. </p>
<p>In the rare hereditary disease <a href="http://ghr.nlm.nih.gov/condition/xeroderma-pigmentosum">xeroderma pigmentosum</a> (XP), which is caused by defects in some of the normal DNA repair genes, patients display approximately 3000-fold increases in the rate of skin cancer. This emphasises how critical the DNA response and repair process is to UV induced DNA damage.</p>
<h2>Skin cancer growth</h2>
<p>The top layer of skin, the epidermis, contains three different kinds of cells: </p>
<ul>
<li>squamous cells that make up the top outer layer of the skin</li>
<li>basal cells that make up the lower layer and produce new skin cells as old ones die off</li>
<li>melanocytes are the bottom layer of the epidermis that produce pigment called melanin, which gives the skin its colour.<br></li>
</ul>
<p>Cancer begins when normal cells change and grow uncontrollably. The tumour can be benign (non-cancerous) or malignant (cancerous, and can spread to other parts of the body). </p>
<p>The three major types of skin cancer – <a href="http://www.cancer.org.au/about-cancer/types-of-cancer/skin-cancer.html">melanoma</a>, <a href="http://www.cancer.org.au/about-cancer/types-of-cancer/skin-cancer/non-melanoma.html">squamous cell carcinoma (SCC) and basal cell carcinoma (BCC)</a> – are defined by the cell type of the skin from where they develop.</p>
<p><strong>Melanoma</strong></p>
<p>Melanocytes cluster together in the skin during childhood to form moles, and are the cells that produce melanin to help protect the skin from UV radiation. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=460&fit=crop&dpr=1 600w, https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=460&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=460&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=578&fit=crop&dpr=1 754w, https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=578&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/68654/original/image-20150112-23782-xm8k93.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=578&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"></span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-237617614/stock-vector-melanoma-or-skin-cancer-this-rare-type-of-skin-cancer-originates-from-melanocytes-layers-of-the.html?src=SAJLwoBr03ptKZAAQYM3zw-1-6">Designua/Shutterstock</a></span>
</figcaption>
</figure>
<p><a href="http://www.cancer.org.au/about-cancer/types-of-cancer/skin-cancer/melanoma.html">Melanoma</a> develops in melanocytes, and is the most dangerous and aggressive form of skin cancer, accounting for 3% of all skin cancers. Melanomas can grow very quickly if left untreated and can spread to other parts of the body. </p>
<p>Melanoma of the skin can appear as a new or existing spot, freckle or mole that changes in colour, size or shape and can have dark coloured pigment or no colour in the lesion. They can grow anywhere on the body, not just in areas exposed to the sun. </p>
<p><strong>Non-melanoma skin cancers</strong></p>
<p>Non-melanoma skin cancers are the most common cancers in Australia, and refer to all the types of cancer that occur in the skin that are not melanoma. The two main types are squamous cell carcinomas (SCC) and basal cell carcinomas (BCC), in addition to other rarer forms.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=473&fit=crop&dpr=1 600w, https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=473&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=473&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=595&fit=crop&dpr=1 754w, https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=595&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/68658/original/image-20150112-23810-bmknrv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=595&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"></span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-241007965/stock-photo-squamous-cell-carcinoma-or-squamous-cell-cancer.html?src=9Gq5aRJzqOulxoMi1HsfrA-1-7">Designua/Shutterstock</a></span>
</figcaption>
</figure>
<p>Approximately 28% of skin cancers are SCCs, arising from the squamous cells of the epidermis. This type of skin cancer is mainly caused by UV radiation either from sun exposure or solariums, but it can appear on skin that has been burned, damaged by chemicals, or exposed to x-rays. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=459&fit=crop&dpr=1 600w, https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=459&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=459&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=577&fit=crop&dpr=1 754w, https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=577&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/68657/original/image-20150112-23792-1mncmn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=577&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"></span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-237520735/stock-vector-skin-cancer-basal-cell-carcinoma-or-basal-cell-cancer-bcc-schematic-representation-of-skin.html?src=pp-same_artist-237617614-SAJLwoBr03ptKZAAQYM3zw-1">Designua/Shutterstock</a></span>
</figcaption>
</figure>
<p>About 68% of skin cancers are BCCs, arising in the basal cells in the epidermis. BCCs are mainly caused by long-term exposure to UV radiation from the sun or can develop in people who received radiation therapy as children. This type of skin cancer usually grows slowly.</p>
<h2>Protecting against UV damage</h2>
<p>A number of environmental factors influence the amount of UV radiation we are exposed to throughout the day, including the earth’s latitude, height of the sun throughout the day, cloud cover and reflection of surfaces. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=700&fit=crop&dpr=1 600w, https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=700&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=700&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=880&fit=crop&dpr=1 754w, https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=880&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/68767/original/image-20150112-23810-3xazgt.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=880&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"></span>
<span class="attribution"><span class="source">Reproduced with the permission of the Bureau of Meteorology</span></span>
</figcaption>
</figure>
<p>Most Australians need sun protection when the UV index is three or above. UV radiation levels in northern states are higher than southern states, so in some parts of Australia, sun protection is needed all year around at certain times of the day. </p>
<p>To reduce your exposure to UV, cover up when outdoors and use a high-sun protection factor, water-resistant sunscreen that blocks both UVA and UVB rays, and reapply every two hours.</p>
<p>In Australia, we need to balance the risk of skin cancer from too much sun exposure with maintaining adequate vitamin D levels. During summer, most people can maintain adequate vitamin D levels from a few minutes of exposure to sunlight on their face, arms and hands or the equivalent area of skin in the morning or late afternoon when the UV index is below three. </p>
<p>You can check the <a href="http://www.sunsmart.com.au/uv-sun-protection/uv">UV index</a> in the weather section of daily newspapers, on the <a href="http://www.bom.gov.au/uv/">Bureau of Meteorology website</a> or by using the <a href="http://www.bom.gov.au/uv/iphoneapp.shtml">SunSmart app</a>.</p>
<hr>
<p><em><strong>Further reading:</strong></em> </p>
<ul>
<li><em><a href="https://theconversation.com/spot-the-difference-harmless-mole-or-potential-skin-cancer-33674">Spot the difference: harmless mole or potential skin cancer?</a></em></li>
<li><em><a href="https://theconversation.com/how-to-protect-your-skin-while-getting-enough-vitamin-d-34143">How to protect your skin while getting enough vitamin D</a></em></li>
</ul><img src="https://counter.theconversation.com/content/34538/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sandra Pavey receives funding from the NHMRC, Cancer Council Australia, and the University of Queensland.</span></em></p>Around 30 Australians are diagnosed with melanoma every day and more than 1,200 die from the disease each year. While small amounts of ultraviolet (UV) radiation are required for the production of vitamin…Sandra Pavey, Postdoctoral Research Fellow, Diamantina Institute, The University of QueenslandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/254552014-04-11T09:34:25Z2014-04-11T09:34:25ZPlant powerhouses are more than just energy producers<figure><img src="https://images.theconversation.com/files/46132/original/gcqdv5wm-1397145472.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Powerhouse and secret communicator.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/arwing3/6946034795">arwing3</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>For more than a billion years, plants have had an internal dialogue, and we are just beginning to learn the words. The unusual dialogue occurs between two compartments within plant cells – the nucleus and the chloroplast. It is a dialogue that continues today, and, according to research just published in <a href="http://dx.doi.org/10.1126/science.1250322">Science</a>, it shapes the productivity of plants.</p>
<p>All living organisms are made of cells. These cells contain many compartments, a bit like organs in an animal body. Each plant cell contains many chloroplasts, which are responsible for producing energy.</p>
<p>A billion years ago, the ancestors of chloroplasts existed as free-living individual cells, able to convert energy from light into sugar. But in a spectacular evolutionary event, these early chloroplasts were consumed by larger cells, where they eventually took up residence, supplying them with sugar. The legacy of that merger is evident around us every day in the green tissues of plants.</p>
<p>The fate of every plant cell is inextricably tied to the interaction between chloroplasts and other compartments of the plant cell. The most important of these interactions is with the nucleus.</p>
<p>The nucleus is the home of the genetic material for the plant – its genome. The genome contains all of the plant’s genes, written in DNA code. Like human beings, plants have tens of thousands of genes in the nucleus.</p>
<p>Each gene encodes a specific set of instructions – a recipe of sorts – for a particular cell component. The nucleus is like a non-circulating library for all of the plant’s genetic recipes. All the information is there, but it can’t leave the nucleus to be used elsewhere in the cell. In order to use the information in the recipe library, it has to be transcribed into a different kind of information molecule – an <a href="http://en.wikipedia.org/wiki/Messenger_RNA">RNA transcript</a>. The transcript is then transported out of the nucleus, where it is used as instructions to create a particular piece of cellular machinery.</p>
<p>Some of the genes in the nucleus are recipes for cellular machinery needed for the chloroplast to do its job – to undertake photosynthesis. It is important that the nucleus transcribes these genes in response to appropriate cues, especially daylight.</p>
<p>Light effects the transcription of one in every five plant genes. Intriguingly, some genes are transcribed based on a signal that comes from the chloroplast. The chloroplast informs the nucleus that certain genes need to be transcribed. Signalling from the chloroplast to the nucleus is called <a href="http://en.wikipedia.org/wiki/Retrograde_signaling">retrograde signalling</a>. It has <a href="http://journal.frontiersin.org/Journal/10.3389/fpls.2012.00135/full">fascinated scientists for decades</a> because the nature of the signal from the chloroplast is unknown.</p>
<p>Now this story has become even more intriguing. According to the Science paper, authored by Ezequiel Petrillo at the University of Buenos Aires and colleagues, it seems that this form of signalling from chloroplasts can do more than direct the transcription of genes – it can also direct modifications of the RNA transcribed from the genes. These transcripts are modified by <a href="http://www.dnalc.org/resources/animations/rna-splicing.html">splicing the RNA</a>, which removes bits of superfluous information from them. Without splicing, most RNAs wouldn’t be able to encode proteins.</p>
<p>Petrillo and colleagues found a transcript that is spliced in different ways depending on whether light is present or not, and showed that the switch depended on the chloroplast’s signalling. The transcript in question encodes part of the cell’s splicing machinery, so the splicing process itself is regulated by a retrograde signal. That means that the effects can be broader than simply this one protein.</p>
<p>Whatever signal the chloroplast is producing, it must be able to move not just within the cell but also throughout the plant. If they shone light on the leaves, cells in the roots contained the spliced transcript. If they shone light on roots that do not contain active chloroplasts, the root cells did not contain the spliced transcript. This implies that the signal must travel from other tissues to the roots – so that the entire plant body is informed that the leaves have perceived light.</p>
<p>Finding out what this signal is would help researchers understand more about the process and perhaps exploit it for applications such as engineering plants that work in low light. One hypothesis was that the signal could be the sugars produced by chloroplasts, but that idea was shot down. Sugar-starved plants growing in the dark failed to produce any spliced transcript, as expected. But supplying them with sugars didn’t restore the splicing.</p>
<p>The signal has to be something new. Some have suggested candidate retrograde signals involved in other aspects of <a href="http://journal.frontiersin.org/Journal/10.3389/fpls.2012.00135/full">chloroplast communication with the nucleus</a>, but we will have to wait for further studies to see if those are involved in the regulation of transcript splicing too.</p>
<p>Chloroplasts have resided in cells with a nucleus for about a billion years now. That the chloroplasts have discovered ways of communicating to the nucleus is not entirely surprising. That they communicate using a mechanism that remains a mystery is fascinating. Learning the “words” of their language, such as the retrograde signal for splicing, will provide illuminating discoveries for the coming years.</p><img src="https://counter.theconversation.com/content/25455/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Malcolm Campbell receives funding from the Natural Science and Engineering Research Council (NSERC) of Canada, and Genome Canada.</span></em></p>For more than a billion years, plants have had an internal dialogue, and we are just beginning to learn the words. The unusual dialogue occurs between two compartments within plant cells – the nucleus…Malcolm Campbell, Professor & Vice-Principal Research, University of TorontoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/169192013-08-13T05:27:13Z2013-08-13T05:27:13Z‘Mitotic spindles’ could help develop better chemo drugs<figure><img src="https://images.theconversation.com/files/29073/original/9bdwbfy9-1376302663.jpg?ixlib=rb-1.1.0&rect=1%2C0%2C1022%2C683&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A good yarn: chromosomes are shared out to dividing cells by mitotic spindles.</span> <span class="attribution"><span class="source">Triesquid</span></span></figcaption></figure><p>Cells use a tiny machine called the mitotic spindle to share genetic material equally between cells when they divide. But when this process goes wrong it can lead to cancer. </p>
<p>For many years we’ve been interested in how the spindle divides up genetic material accurately. When a cell divides it must make sure that each daughter cell receives just one copy of each chromosome, which carries DNA to the new cell. Defects in this process can lead to cells having the wrong amount of chromosomes, which can lead to cancer or birth defects.</p>
<p>Anti-cancer drugs have been developed which target the mitotic spindle and destroy dividing cells in tumours. But these drugs have significant side effects. In my lab, we’re trying to understand how the mitotic spindles work in order to develop drugs that are more targeted and have fewer side effects.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=447&fit=crop&dpr=1 600w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=447&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=447&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=562&fit=crop&dpr=1 754w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=562&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=562&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Mitotic spindle: chromosomes in blue, microtubles in green.</span>
<span class="attribution"><span class="source">Wikimedia Commons/Afunguy</span></span>
</figcaption>
</figure>
<p>Chromosomes are allocated by the mitotic spindle, which is made up of many thin filaments called microtubules. These are held together in bundles and these bundles share the chromosomes equally during mitosis.</p>
<p>Colleagues and I at Warwick Medical School have shown <a href="http://bit.ly/1boixL1">in a paper published</a> in The Journal of Cell Biology that a team of three proteins - called the TACC3–ch-TOG–clathrin complex - work to hold the spindle’s microtubules together and stabilise the bundle through a system of “bridges”. Drugs such as Taxol (Paclitaxel) have been used very effectively in chemotherapy because they poison microtubles and inhibit the mitotic spindle. This stops cancer cells from dividing and causes them to die. </p>
<p>However, the disadvantage is that microtubules are needed for many functions in non-cancerous cells. This means that existing treatments don’t discriminate between cancerous and normal cells. So the use of Taxol and others in its family, for example, cause side effects such as nerve damage. If we could target the mitotic spindle proteins, rather than microtubules, we may be able to develop effective anti-cancer drugs with far fewer side effects.</p>
<p>We’ve found that in cancer cells, the amount of the protein complex is either too low or too high. This suggests that these proteins could be targeted for potential anti-cancer therapies in the future.</p>
<p>Our research group, together with Richard Bayliss’ lab at the University of Leicester, have recently described how the proteins in the TACC3–ch-TOG–clathrin complex bind to one another. In turn this led us to understand how the complex binds to microtubules. By taking out the TACC3 protein, the clathrin loses its function and is no longer able to create some of the bridges that bind the microtubles. </p>
<p>It’s important as we can use this information to think of ways to break the complex apart or to prevent it binding microtubules. From this, we may be able to disrupt the function of the protein complex in dividing cells and inhibit the sharing of chromosomes during mitosis, causing the death of cancerous cells. </p>
<p>The research is in the early stages, but we have also discovered that an enzyme called Aurora A kinase controls the assembly of the protein complex. Aurora A is often amplified in tumours and clinical trials into inhibiting its role are already underway into drugs that cause the TACC3-ch-TOG-clathrin complex to fall apart and actually break away from the mitotic spindle altogether. </p>
<p>When treating cancer we still often cause damage in other areas. Understanding and controlling the action of the mitotic spindle could help us to better target treatment by directly shutting down defective cells.</p><img src="https://counter.theconversation.com/content/16919/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Steve Royle is a Senior Fellow for Cancer Research UK which funds his lab at Warwick University.</span></em></p>Cells use a tiny machine called the mitotic spindle to share genetic material equally between cells when they divide. But when this process goes wrong it can lead to cancer. For many years we’ve been interested…Steve Royle, Associate Professor, University of WarwickLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/151692013-06-26T21:00:53Z2013-06-26T21:00:53ZExplainer: what is RNA?<figure><img src="https://images.theconversation.com/files/26034/original/y4myx2vv-1372035024.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">RNA is similar to DNA in lots of ways. But an extra oxygen atom makes all the difference.</span> <span class="attribution"><span class="source">Image from shutterstock.com</span></span></figcaption></figure><p>Our genetic material is encoded in DNA (<a href="http://en.wikipedia.org/wiki/DNA">deoxyribonucleic acid</a>). DNA is famous. But you may also have also heard of RNA (<a href="http://en.wikipedia.org/wiki/RNA">ribonucleic acid</a>). So, what is RNA, and what is it good for? </p>
<p>Quite a lot really. In fact, it is possible that early life used RNA as its genetic material and also used folded RNAs as chemical tools to survive. This is called the <a href="http://www.princeton.edu/%7Eachaney/tmve/wiki100k/docs/RNA_world_hypothesis.html">RNA world hypothesis</a>.</p>
<p>RNA is similar to DNA in lots of ways. It is a long chain of sugars linked together by phosphate groups. There is a cyclic base attached to each sugar and the bases can pair with matching partners to make a double helix.</p>
<p>This resembles DNA but the helix is a bit contorted and often RNAs are folded into complex structures stabilised by short helices interspersed with long single-stranded loops.</p>
<p>The really important difference is that RNA has an extra oxygen atom. This makes RNA less stable than DNA.</p>
<figure class="align-center ">
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<figcaption>
<span class="caption">Ribose, on the left, has one extra oxygen atom compared to deoxyribose, right.</span>
<span class="attribution"><span class="source">Wikimedia Commons</span></span>
</figcaption>
</figure>
<p>You might think that being unstable is a bad thing, but there are advantages. Organisms that need to change rapidly tend to use RNA as their genetic material. Viruses, such as influenza and HIV, <a href="http://en.wikipedia.org/wiki/RNA_virus">choose RNA</a> rather than the more stable alternative of DNA so they can change and keep one step ahead of the immune system of their hosts. </p>
<p>Many factors contribute to the high mutation rates in RNA viruses, including the instability of RNA and the poor proof reading activity in the enzymes that replicate RNA.</p>
<h2>Messenger service</h2>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=891&fit=crop&dpr=1 600w, https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=891&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=891&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1120&fit=crop&dpr=1 754w, https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1120&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/26037/original/ydny99br-1372035585.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1120&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Like DNA, RNA is a long chain of sugars.</span>
<span class="attribution"><span class="source">Sponk</span></span>
</figcaption>
</figure>
<p>As well as serving as genetic material, RNA has another critical function in virtually all organisms: it acts as a messenger; a short-lived intermediate communicating the information contained in our genes to the rest of the cell. </p>
<p>Many genes need to be turned on in bursts. Think of a football fan shouting out at a key point in a game - we don’t want the message to last forever.</p>
<p>Genes do last a lifetime, so how do we provide short-lived messages? </p>
<p>We make RNA copies of our DNA genes. The messages, or <a href="http://en.wikipedia.org/wiki/Messenger_RNA">mRNAs</a>, reflect the sequence of bases in our DNA and travel out of the nucleus (where our DNA is stored) into the cytoplasm where they are translated into proteins. The proteins go on to do jobs in the cell and the unstable mRNAs simply decay or are degraded.</p>
<p>So RNA can act as a messenger in the process of ensuring genes are translated into proteins – the tools of the cell, things such as haemoglobin to carry oxygen round the body. </p>
<p>But how does this mysterious translation occur? Does it rely on chemical tools such as proteins? </p>
<p>It certainly does, but it seems that the proteins are not the key players. It is a remarkable fact that the really important players in triggering the chemical reactions to produce protein chains from the mRNA code are not other proteins, but specially folded RNA molecules - RNA enzymes or ribozymes. </p>
<p>The machinery for reading a protein from a messenger RNA is contained in a complex RNA enzyme and the functional parts are RNA molecules called ribosomal RNAs or <a href="http://en.wikipedia.org/wiki/Ribosomal_RNA">rRNAs</a>.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/8dsTvBaUMvw?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">RNA enzymes or ribozymes trigger the mRNA translation process.</span></figcaption>
</figure>
<h2>Securing information</h2>
<p>How come RNA can trigger chemical reactions but DNA doesn’t seem to? It is partly the extra oxygen and partly the special ability RNA has to fold up into complex shapes to form tools that can do things, whereas the double helix is regular and stable. The DNA double helix holds information securely but doesn’t do much else. </p>
<p>In 1989 <a href="http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1989/">Sidney Altman and Thomas Cech </a>shared the Nobel Prize in Chemistry for demonstrating that RNAs could catalyze chemical reactions.</p>
<p>You might wonder how a chain of sugars and bases such as mRNA can even serve as a template for forming a protein chain. The answer is complicated but it involves some clever adaptors. Amazingly, those adaptors are also made of RNA, they’re called transfer RNAs or <a href="http://en.wikipedia.org/wiki/Transfer_RNA">tRNAs</a>. They use their cyclic bases to pair to their mirror images in the mRNA and line up the right amino acids to make the protein, while the rRNA triggers the reaction to do the joining.</p>
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<figcaption>
<span class="caption">Structure of a transfer RNA (tRNA) molecule.</span>
<span class="attribution"><span class="source">Image from shutterstock.com</span></span>
</figcaption>
</figure>
<p>The finding that absolutely essential functions such as encoding information, having a short-lived messenger to express it, and converting it into a set of functional protein tools, all involve RNA has led people to hypothesise that early life was made up of RNA. </p>
<p>In the beginning RNA possibly did the lot. But then gradually DNA took over as a more stable genetic material and proteins took over as more stable chemical tools. And RNA was gradually forgotten by some researchers, at least until recently.</p>
<h2>Future of RNA</h2>
<p>In 1998, American biologists Andy Fire and Craig Mello <a href="http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/">discovered RNA inhibition</a> – how RNA can switch off genes. </p>
<p>We now know that a new class of small inhibitory RNAs (<a href="http://www.ncbi.nlm.nih.gov/pubmed/16013959">siRNAs</a> which are about 20 residues long), fine tune the output from messenger RNAs. As mentioned RNA can form double strands - this allows siRNAs to bind messenger RNAs and interfere with their function. </p>
<p>These interfering RNAs are essentially “digital” inhibitors that are base for base mirror images of the messenger RNA. So it possible to make artificial inhibitors now. Thus a new industry has been born as researchers strive to turn genes off for experimental purposes and medical researchers investigate whether this can be used for therapies, such as turning off viruses or other harmful genes.</p>
<p>There has also been another interesting discovery – researchers have found that although only a small part of our genome encodes protein, around 2%, <a href="http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000371">a much larger proportion is still copied into RNA</a>. </p>
<p>The function of many of these long non-protein coding RNAs, called <a href="http://www.nature.com/nrg/journal/v10/n3/abs/nrg2521.html">lncRNAs</a>, is still being investigated but it seems that some act to catalyse chemical reactions and that others are involved in turning genes on or off either by binding messenger RNAs or by binding directly to the DNA genes they match.</p>
<p>If the world began with RNA then it is not really surprising that echoes of that RNA world remain and that RNAs are still involved in key life processes and are fundamentally important in gene regulation. </p>
<p>New classes of RNA molecules will continue to be discovered and it is seems likely that further insights into fundamental biology will emerge from this fertile ground in the future.</p><img src="https://counter.theconversation.com/content/15169/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley receives funding from the University of New South Wales, the Australian Research Council and the National Health and Medical Research Council.</span></em></p>Our genetic material is encoded in DNA (deoxyribonucleic acid). DNA is famous. But you may also have also heard of RNA (ribonucleic acid). So, what is RNA, and what is it good for? Quite a lot really…Merlin Crossley, Dean of Science and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.