tag:theconversation.com,2011:/fr/topics/proteins-1910/articlesProteins – The Conversation2024-03-14T12:43:02Ztag:theconversation.com,2011:article/2229442024-03-14T12:43:02Z2024-03-14T12:43:02ZProteins in milk and blood could one day let doctors detect breast cancer earlier – and save lives<figure><img src="https://images.theconversation.com/files/581419/original/file-20240312-28-8qcsls.jpg?ixlib=rb-1.1.0&rect=18%2C91%2C5398%2C3982&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">What if a simple blood test could diagnose otherwise undetected breast cancer?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/vascular-testing-in-research-laboratories-royalty-free-image/1443155227">Srinophan69/Moment via Getty Images</a></span></figcaption></figure><p>Doctors may someday be able to use bodily fluids to noninvasively detect breast cancer in patients earlier than is possible now.</p>
<p>Breast cancer is the <a href="https://doi.org/10.3322/caac.21763">most commonly diagnosed cancer among women</a> in the U.S. and is currently one of the leading <a href="https://www.cancer.org/cancer/risk-prevention/understanding-cancer-risk/cancer-facts/cancer-facts-for-women.html">causes of cancer deaths</a>. Earlier diagnosis and treatment <a href="https://doi.org/10.1002/cncr.32887">lead to better prognoses</a> for breast cancer patients. But mammograms have proved to be <a href="https://www.cancer.org/cancer/types/breast-cancer/screening-tests-and-early-detection/mammograms/limitations-of-mammograms.html">less effective for those under age 40</a>, as their breast tissue is denser and screening and biopsies can be unpleasant to endure.</p>
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<p>In breast milk and blood serum, researchers, including <a href="https://people.clarkson.edu/%7Ecdarie/">those in my lab group</a>, have identified proteins that are involved in tumor development. Eventually, biochemists like my colleagues <a href="https://scholar.google.com/citations?user=GH2M7ZEAAAAJ&hl=en">and I</a> hope we can use these cancer-related proteins to create a <a href="https://doi.org/10.3390/proteomes10040036">biomarker panel</a> that physicians can use to detect breast cancer earlier, therefore aiding in diagnosis and treatment.</p>
<h2>Proteins as biomarkers for what’s happening</h2>
<p>Researchers can analyze the proteins present in a variety of tissues, from biopsies of tumors to biological fluids including blood, saliva, urine, tears or breast milk. This technique is an example of studying a sample’s proteome – all the proteins in a particular cell, organism or species. The field is called <a href="https://doi.org/10.4331/wjbc.v12.i5.57">proteomics</a>. </p>
<p><a href="https://doi.org/10.1016/S1672-0229(07)60018-7">Proteomics can be a powerful tool</a> when researchers compare the proteomes of individuals from different groups, such as in blood from healthy people versus those with breast cancer. This kind of case-control comparison can identify a single protein or a group of proteins and their variants that are specific to one condition.</p>
<p>That’s what my colleagues and I are looking for: proteins that are present only in the samples from people who have breast cancer. Scientists call them <a href="https://www.britannica.com/science/biomarker">biomarkers</a> because they signal that a patient has a particular condition. Once our candidates are verified by large-scale clinical trials that include many patients, we hope that particular proteins can then be used to assess someone’s future risk of developing the disease.</p>
<p>Doctors can currently use <a href="https://doi.org/10.5493/wjem.v2.i5.86">biomarkers for breast cancer</a> to gauge a patient’s response to treatment. For instance, the molecules cancer antigen 15-3 (CA 15-3) and carcinoemybronic antigen (CEA) are elevated in breast cancer patients, so monitoring their levels can let physicians know whether treatment is working. </p>
<p>Inherited variants of the BRCA1/2 genes can increase the likelihood of developing cancer; they can act as biomarkers in screening for cancer risk. </p>
<p>None of these biomarkers aid in diagnosis of breast cancer, though.</p>
<p>Researchers prefer proteins as cancer biomarkers over the genetic materials DNA and RNA because proteins provide a snapshot of what is happening in a patient’s body at the time a sample is collected. DNA and RNA can tell you whether a certain gene is turned on or off, but not the active form of the protein it codes for or the relative abundance of <a href="https://doi.org/10.1016/j.heliyon.2023.e13323">proteins</a>. Protein analysis can also reveal changes the protein has undergone and <a href="https://doi.org/10.1016/S1672-0229(07)60018-7">protein-protein interactions</a> that can alter the way a protein functions.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="diagram showing nursing mother and breast milk bag, and a blood draw and test tube" src="https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=368&fit=crop&dpr=1 600w, https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=368&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=368&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=463&fit=crop&dpr=1 754w, https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=463&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/581402/original/file-20240312-18-og1u88.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=463&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Looking for biomarker proteins in breast milk or blood serum could detect the presence or absence of cancer.</span>
<span class="attribution"><span class="source">Danielle Whitham</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Benefits of milk and serum biomarkers</h2>
<p>Breast milk and blood serum are two bodily fluids that can be collected noninvasively and that give information about what is happening in the body when collected.</p>
<p><a href="https://doi.org/10.1002/elps.201700123">Breast milk contains</a> secreted proteins, immune cells and sloughed cells of the milk ducts. During lactation, the breast is actively working to create milk to feed an infant. Any abnormalities in the breast milk reflect the current situation in the body. Some proteins in breast milk also circulate throughout the body and can be found in blood serum as well.</p>
<p>Serum is the <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/serum">liquid part of the blood</a> after red blood cells have been removed. It contains all the same proteins found in the blood, minus the clotting factors, therefore allowing circulating protein levels to be monitored. Narrowing in on a serum-based biomarker would mean it could be used to screen every woman, not just one who is currently lactating.</p>
<p><a href="https://doi.org/10.3390/proteomes10040036">The proteins we’ve found</a> <a href="https://doi.org/10.3390/proteomes10040036">in breast milk and identified as being</a> <a href="https://doi.org/10.1002/elps.202300040">out of whack in breast cancer</a> are involved in the cancer cells’ ability to divide, multiply and spread throughout the body. They all promote disease progression.</p>
<p>My colleagues and I currently consider these breast milk proteins to be <a href="https://doi.org/10.1080/14789450.2024.2320158">a draft biomarker for breast cancer</a>. Our group is currently working on using blood serum to identify proteins that could be involved with breast cancer. Moving from breast milk to blood serum would allow people of any age and reproductive status to be screened for the disease, rather than just those who are lactating.</p><img src="https://counter.theconversation.com/content/222944/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The Biochemistry and Proteomics Laboratories at Clarkson University receives funding from National Cancer Institute of the National Institutes of Health under Award Number R15CA260126.</span></em></p>Identifying proteins that are only present in bodily fluids when a patient has breast cancer could provide a way to screen healthy people for the disease.Danielle Whitham, Ph.D. Candidate in Chemistry and Biochemistry, Clarkson UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2217202024-03-11T21:26:04Z2024-03-11T21:26:04ZAllergen warning: “Vegan” foods may contain milk and eggs<figure><img src="https://images.theconversation.com/files/570731/original/file-20240112-29-t9z77z.jpg?ixlib=rb-1.1.0&rect=4%2C0%2C989%2C667&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">When buying pre-packaged foods, consumers with allergies rely on the declarations in the list of ingredients to identify safe foods.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>The popularity of vegan diets continues to increase around the world. Indeed, in 2023, the vegan food market grew to <a href="https://www.expertmarketresearch.com/reports/vegan-food-market">more than US$27 billion</a>.</p>
<p>The term “vegan” usually refers to foods that contain no animal ingredients (meat, poultry, eggs, milk, fish, seafood).</p>
<p>While some consumers consider them to be healthier, vegan foods are also an interesting alternative for consumers concerned about the environment, sustainable development, and animal welfare.</p>
<p>But another type of consumer may be turning to these products for a completely different reason: people who are allergic to proteins of animal origin, such as cow’s milk and eggs.</p>
<p>In view of this, <a href="https://parera.ulaval.ca">our research group</a>, a leader in food allergen risk analysis in Canada, decided to explore <a href="https://link.springer.com/article/10.1186/s13223-023-00836-w">the following two questions</a>:</p>
<ul>
<li><p>Do consumers who are allergic to animal proteins consider vegan products to be safe?</p></li>
<li><p>And, if so, are these products truly safe for them?</p></li>
</ul>
<h2>What’s in it for consumers with allergies?</h2>
<p>The answers to these questions are crucial for people with food allergies who risk suffering potentially severe reactions (anaphylaxis) from consuming these products.</p>
<p>Food allergies affect around <a href="https://www.jaci-inpractice.org/article/S2213-2198(19)30912-2/fulltext">six per cent of Canadians</a>, including 0.8 per cent who are allergic to eggs, and 1.1 per cent to milk.</p>
<p>Despite the fact that different forms <a href="https://foodallergycanada.ca/living-with-allergies/allergy-treatments-and-therapies/treatments-and-therapies/">of immunotherapy or allergen desensitization</a> have shown promising results, the most effective strategy for avoiding allergic reactions is still to refrain from eating foods that may contain allergens.</p>
<p>When buying pre-packaged foods, consumers with allergies rely on declarations in the list of ingredients to identify foods that are safe for them. Regulatory authorities who are responsible for the quality and safety of food recognize the importance of accurate ingredients declarations for allergic consumers. Thus, it is <a href="https://www.canada.ca/en/health-canada/services/food-nutrition/food-labelling/allergen-labelling.html">mandatory</a> to list every allergen that has been voluntarily added to a pre-packaged food item.</p>
<p>However, when it comes to ingredients that may be unintentionally present — for example, as due to cross-contact during food processing — there is a regulatory gap. These ingredients are generally identified with the warning “may contain,” which is used (or sometimes <a href="https://www.sciencedirect.com/science/article/abs/pii/S2213219818300102">overused</a>) voluntarily and randomly by food processors.</p>
<p>Furthermore, the term “vegan” is neither standardized nor defined in Canadian regulations. In fact, <a href="https://inspection.canada.ca/food-labels/labelling/industry/composition-and-quality/eng/1625516122300/1625516122800?chap=2">the Canadian Food Inspection Agency</a> notes that, with regard to the use of the term “vegan,”</p>
<blockquote>
<p>…companies can apply additional criteria or standards that take account of other factors in addition to the ingredients of the food.</p>
</blockquote>
<p>However, details or examples of these elements are not provided. This lack of a precise regulatory definition prevents the implementation of compliance requirements.</p>
<p>Yet, most <a href="https://recalls-rappels.canada.ca/en/search/site?search_api_fulltext=vegan">recalls</a> of products marketed as “vegan” are due to the presence of undeclared ingredients of animal origin, in particular milk and eggs.</p>
<h2>What do consumers with food allergies say?</h2>
<p>In this context, and as part of a <a href="https://www.researchsquare.com/article/rs-2583779/v1">survey</a> of consumers with allergies conducted in collaboration with <a href="https://foodallergycanada.ca">Food Allergy Canada</a>, we asked participants who indicated that they were allergic (or were the parents of a child who was allergic) to eggs or milk if they bought products marketed as “vegan.”</p>
<p>Of the 337 respondents, 72 per cent said they sometimes included these products in their purchases, 14 per cent said they always did, and 14 per cent never.</p>
<p>These <a href="https://link.springer.com/article/10.1186/s13223-023-00836-w">results</a> suggest that these consumers do, indeed, consider the claim “vegan” as an indicator of the absence of animal proteins — an absence which, again, is not supported by any regulatory requirement or definition.</p>
<p>Since the absence of these ingredients is not guaranteed, these consumption habits could put people who are allergic to eggs and/or milk at risk.</p>
<p>An education campaign to clarify that the term “vegan” is an indicator of dietary <em>preferences</em> and not <em>risks</em> would therefore be important for this community.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="dark chocolate" src="https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=372&fit=crop&dpr=1 600w, https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=372&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=372&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=467&fit=crop&dpr=1 754w, https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=467&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/569134/original/file-20240112-29-5nq5bg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=467&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Some dark chocolate bars marketed as ‘certified vegan’ contain milk proteins.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<h2>Do vegan products contain ingredients of animal origin?</h2>
<p>The fact that 86 per cent of survey respondents buy “vegan” products suggests that the incidence of allergic reactions linked to these foods is potentially rare.</p>
<p>We therefore <a href="https://link.springer.com/article/10.1186/s13223-023-00836-w">analyzed</a> the egg and milk protein content of “vegan” and “plant-based” products marketed in Québec.</p>
<p>A total of 124 products were analyzed for the presence of egg (64) and/or milk (87) proteins.</p>
<p>Egg protein was not detected in any samples, but five samples contained milk proteins: these included four dark chocolate bars marketed as “certified vegan” and a supermarket brand chestnut cake.</p>
<p>These five products declared the potential presence of milk with a warning, “may contain milk.”</p>
<p>We used the concentrations of milk proteins quantified in these products, combined with the quantities of the food that would be consumed in a single eating occasion, to calculate an exposure dose, in milligrams of allergen protein. We then estimated the probability of these doses provoking a reaction in the allergic populations concerned by using <a href="https://www.sciencedirect.com/science/article/pii/S0278691520307213">correlation models</a>. Our results show that the calculated doses could trigger reactions in six per cent of milk-allergic consumers, for the chocolate bars, and one per cent, for the cake.</p>
<h2>How can consumers with food allergies protect themselves?</h2>
<p>Although this level of risk may be perceived as low, it is likely to vary without notice. And this will remain the case until regulatory requirements are put in place.</p>
<p>In fact, rather than attributing it to the presence of a “vegan” or “plant-based” claim, this level of risk most likely reflects <a href="https://www.cell.com/heliyon/pdf/S2405-8440(22)02590-7.pdf">good allergen management practices</a>, characteristic of the North American food manufacturing sector.</p>
<p>Thus, even if a statement “may contain milk” seems contradictory in a “vegan” or “plant-based” product, people allergic to milk should interpret it as an indication that this product may pose a risk to their health.</p><img src="https://counter.theconversation.com/content/221720/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Samuel Godefroy's research activities are funded by the Natural Sciences and Engineering Research Council of Canada, the Foreign Agriculture Service of the United States Department of Agriculture, R-Biopharm GmbH and R-Biopharm Canada Inc. He acts as an expert advisor to members of the food and beverage industry, international organizations (the Food and Agriculture Organization of the United Nations, the United Nations Industrial Development Organization and the World Bank), international food regulatory bodies such as the China National Centre for Food Safety Risk Assessment and consumer organizations such as Food Allergy Canada. Godefroy is Chairman of the Board of the Global Food Regulatory Science Society (GFoRSS).</span></em></p><p class="fine-print"><em><span>Jérémie Théolier et Silvia Dominguez ne travaillent pas, ne conseillent pas, ne possèdent pas de parts, ne reçoivent pas de fonds d'une organisation qui pourrait tirer profit de cet article, et n'ont déclaré aucune autre affiliation que leur poste universitaire.</span></em></p>Vegan foods are considered by most consumers to have no ingredients of animal origin, but they may actually contain milk proteins.Silvia Dominguez, Professionnelle de recherche en sciences des aliments, Université LavalJérémie Théolier, Professionel de recherche en sciences des aliments, Université LavalSamuel Godefroy, Professeur titulaire - Sciences des aliments, Université LavalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2202342024-02-07T15:41:14Z2024-02-07T15:41:14ZCould protecting our proteins help us prevent ageing?<figure><img src="https://images.theconversation.com/files/566856/original/file-20231102-21-co328v.jpg?ixlib=rb-1.1.0&rect=41%2C236%2C4643%2C2641&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">What if protecting our proteins helped us to age well?</span> <span class="attribution"><a class="source" href="https://unsplash.com/fr/photos/donna-sorridente-VMGAbeeJTKo">Ravi Patel/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Existing theories on the chemistry of ageing are being turned on their head, thanks in particular to a small ultra-resistant bacterium capable of “coming back to life” after extremely harmful attacks.</p>
<p>This is <a href="https://presse.inserm.fr/wp-content/uploads/2017/01/2006_09_27_CP_Deinococcus_Resurrec.pdf"><em>Deinococcus radiodurans</em></a>, one of the most resistant bacteria known to date, which lives in arid environments such as desert sand. It survives in canned meat after the “shock” treatment of gamma radiation sterilisation. It can also overcome an irradiation dose 5,000 times greater than the lethal dose for humans.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Transmission electron microscopy of an extremophilic bacterium" src="https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=690&fit=crop&dpr=1 600w, https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=690&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=690&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=867&fit=crop&dpr=1 754w, https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=867&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/553213/original/file-20231011-25-suiwlh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=867&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"><em>Deinococcus radiodurans</em> is an extremophilic bacterium and one of the most radiation-resistant organisms known. Here it is seen by transmission electron microscopy.</span>
<span class="attribution"><a class="source" href="https://fr.wikipedia.org/wiki/Deinococcus_radiodurans#/media/Fichier:Deinococcus_radiodurans.jpg">Michael Daly, Uniformed Services University, US Department of Energy</a></span>
</figcaption>
</figure>
<p>Studies have shown that <a href="https://pubmed.ncbi.nlm.nih.gov/26871429/">this bacterium survives even if its DNA is damaged and broken into several hundred fragments</a> as a result of violent stress. In just a few hours, it reconstitutes its entire genetic make-up and returns to life. Its DNA isn’t resistant, it’s simply repaired immediately by proteins that are indestructible in the face of this extreme radiation.</p>
<p>Hence the secret of the robustness of this extremophilic bacterium depends on the robustness of its “proteome” – the sum of all its proteins – and in particular its DNA repair proteins.</p>
<p>This suggests a new paradigm: to increase longevity, particularly in humans, it is the proteome – rather than DNA – that we need to protect.</p>
<p>An organism’s survival depends on the activity of its proteins. If we act against the alteration of the proteome, which is at the root of ageing, we are simultaneously acting on all its consequences: for example, cell survival and function; and we are avoiding mutations induced by radiation.</p>
<h2>The keys to ageing</h2>
<p><a href="https://www.medecinesciences.org/en/articles/medsci/full_html/2020/11/msc200258/msc200258.html">Ageing</a> is characterised by the accumulation of events that deteriorate the functions of our organs and, as a consequence, there’s an <a href="https://pubmed.ncbi.nlm.nih.gov/30914006/">exponential increase in the risk of death and disease over time</a>.</p>
<p>Numerous models have been proposed to explain the molecular basis of ageing, such as the theory of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344376/">cellular senescence</a>, the reduction in DNA repair capacity, <a href="https://www.inserm.fr/c-est-quoi/ca-use-ca-use-c-est-quoi-telomeres/">telomere shortening</a>, mitochondrial dysfunction and <a href="https://www.medecinesciences.org/en/articles/medsci/full_html/2006/04/medsci2006223p266/medsci2006223p266.html">oxidative stress</a> or <a href="https://www.medecinesciences.org/en/articles/medsci/full_html/2020/11/msc200019/msc200019.html">chronic inflammation</a>.</p>
<p>These different models all attempt to understand the consequences of ageing, not the causes. The scientific dogma “DNA -> RNA -> proteins,” which refers to the relationships between DNA, RNA and proteins and asserts that this relationship is unidirectional (that is, from DNA to proteins via RNA), now deserves to be reconsidered.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/553215/original/file-20231011-24-r1aap0.jpeg?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">
<figcaption>
<span class="caption">Triple helix of collagen, a structural protein that contributes to skin resistance.</span>
<span class="attribution"><span class="source">Naos</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<p>Indeed, rather than focusing on our DNA and trying to protect it to slow down our ageing, what if <a href="https://pubmed.ncbi.nlm.nih.gov/36660191/">we protected our proteome</a>?</p>
<h2>What is the proteome?</h2>
<p>The term <a href="https://www.inserm.fr/actualite/proteomique-code-vie-traduit-plus-90/"><em>proteome</em></a> refers to all the proteins present in a cell or organism. Proteins – from the Greek <em>protos</em> meaning “first” – are only exceeded as a constituent of the human body by water, and account for <a href="https://legacy.foresight.org/Nanomedicine/Ch03_1.html">around 20%</a> of its mass.</p>
<p>The term was coined by analogy with the genome: the proteome being to proteins what the genome is to genes, i.e. the set of genes/proteins of an individual – this protein set varying according to the activity of the genes.</p>
<p>The proteome is a dynamic entity, constantly adapting to the needs of the cell and its environment. Proteins are essential molecules in the construction and functioning of all living organisms. <a href="https://www.aquaportail.com/definition-15276-interactome.html">Around 650,000 interactive protein-protein networks</a> have been identified in various organisms, including around 250,000 in humans.</p>
<p>Proteins perform a <a href="https://www.futura-sciences.com/sante/definitions/biologie-proteine-237/">wide variety of functions</a>:</p>
<ul>
<li><p>A structural role: many proteins are central to the maintenance and cohesion of our tissues. For example, actin and tubulin are involved in cell architecture. Keratin is involved in the architecture of our epidermis, hair and nails. Collagen is a protein that plays an important role in the structure of bones, cartilage and skin.</p></li>
<li><p>A functional role: enzymatic (for example, proteases are involved in cleaning up dysfunctional proteins and in desquamation), hormonal (for example, insulin regulates glycaemia), transport (for example, aquaporins transport water in the different layers of the skin) or defence (for example, immunoglobulins are involved in the immune response). All vital functions are thus ensured by the activity of proteins.</p></li>
</ul>
<h2>Carbonylation, the leading cause of irreparable damage to our proteome</h2>
<p>The balance between the synthesis of new proteins and their breakdown is called <a href="https://cordis.europa.eu/article/id/435462-maintaining-proteostasis-may-slow-ageing-and-related-diseases/fr"><em>proteostasis</em></a>. It’s necessary for our body to function, but this state of equilibrium is sensitive. It is under constant threat, because protein synthesis and degradation also depend on proteins. Over time and as a result of external aggression, the proteome is subjected to <a href="https://www.medecinesciences.org/en/articles/medsci/full_html/2017/02/medsci20173302p176/medsci20173302p176.html">various alterations</a>, the most formidable of which is <em>carbonylation</em>, irreversible damage linked to the oxidation of proteins.</p>
<p>Carbonylated proteins are permanently modified and can no longer perform their biological functions properly. When they are irreparably damaged, proteins must be recycled or eliminated by the body. With age, this elimination becomes more difficult, and they can accumulate in the form of toxic aggregates that interfere with cellular physiology and accelerate ageing. Above a certain threshold, these aggregates are harmful to the body: a state of <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/proteotoxicity">proteotoxicity</a> sets in.</p>
<p>The <a href="https://www.nature.com/articles/s41580-019-0101-y">loss of proteostasis</a>, i.e. the balance between the synthesis of new proteins and their degradation, due to the accumulation of protein aggregates, is the central cause of ageing and degenerative diseases. These carbonylated protein aggregates are found in most age-related diseases, as well as in the main signs of skin ageing.</p>
<p>Until now <a href="https://pubmed.ncbi.nlm.nih.gov/26871429/">our view of ageing has been centred on the genome</a>, but recent research on the proteome introduces the importance of the accumulation of damaged proteins as a key factor in the ageing process as a whole.</p>
<h2>Antioxidant chaperone molecules to act on the causes of ageing</h2>
<p>To correctly perform their many jobs, <a href="https://sitn.hms.harvard.edu/flash/2010/issue65/">proteins need to fold into a range of shapes</a> and are helped out by specialised proteins called “chaperones”. These help out the proteins after their synthesis by ribosomes, or their correct folding after stress, such as heat.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=365&fit=crop&dpr=1 600w, https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=365&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=365&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=459&fit=crop&dpr=1 754w, https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=459&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/553218/original/file-20231011-23-at0nwd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=459&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Illustration of the extraction of bacterioruberins from the bacterium <em>Arthrobacter agilis</em>. Bacterioruberins are antioxidant biological pigments with a chaperone effect, protecting the proteome (NAOS).</span>
<span class="attribution"><span class="source">Naos</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<p>The term <em>chaperone molecule</em> – of French origin although proposed by <a href="https://pubmed.ncbi.nlm.nih.gov/2695089/">John Ellis and Sean Hemmingsen</a> – has been adopted because their role is to prevent undesirable interactions and to break any incorrect bonds that may form, like a human chaperone. In short, chaperones (protein or chemical) are the doctors of malformed proteins.</p>
<p>Returning to the bacterium <em>Deinococcus radiodurans</em>, chaperones play a key role in protecting proteins against carbonylation, by preventing their amino acids from being exposed to free radicals or reactive oxygen species (ROS). In this way, they reduce their susceptibility to damage. At the same time, their antioxidant effectiveness neutralises the causes of carbonylation.</p>
<p>In collaboration with the NAOS laboratories, it was established that these antioxidant chaperone proteins therefore constitute an effective means of protecting the proteome, by providing both physical protection for the functional structure of proteins and an antioxidant shield linked to proteins that protects against damage such as carbonylation.</p>
<p>In <em>Deinococcus radiodurans</em>, because its proteome is protected against oxidative damage by <a href="https://pubmed.ncbi.nlm.nih.gov/23818498/">chaperone molecules</a>, it remains intact and can then able to repair damage to its genome. <em>In fine</em>, within a few hours it can be resuscitated.</p>
<p>Beyond the genome, protection of our proteome – that is to say, our proteins – can now be seen as the key to our health and longevity.</p><img src="https://counter.theconversation.com/content/220234/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Miroslav Radman is founder and scientific director of the Mediterranean Institute for Life Sciences (MedILS). The MedILS has received funding from the NAOS company for several research collaborations. He is a consultant and member of the NAOS Scientific Committee.</span></em></p>Bacteria that are resistant to phenomenal amounts of radiation are prompting us to rethink our understanding of the mechanisms underlying ageing.Miroslav Radman, Professeur, InsermLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2196832024-02-05T23:06:31Z2024-02-05T23:06:31ZGenetic diseases: How scientists are working to make DNA repair (almost) a piece of cake<figure><img src="https://images.theconversation.com/files/564984/original/file-20231101-27-722eas.jpg?ixlib=rb-1.1.0&rect=5%2C0%2C992%2C561&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An error in DNA is called a mutation.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>I have always been fascinated by genetics, a branch of biology that helps explain everything from the striking resemblance between different members of a family to the fact that strawberry plants are frost-resistant. It’s an impressive field!</p>
<p>I also have a personal connection to genetics. Growing up, I learned that members of my family had a form of <a href="https://doi.org/10.3390/jcm12186011">muscular dystrophy</a> called dysferlinopathy. I watched as my mother gradually lost the ability to climb stairs and had to use a cane, then a walker, and finally a wheelchair to get around. Her leg muscles were less and less able to repair themselves and became weaker with time.</p>
<p>My parents explained to me that all these changes were due to the error of a single letter among the billions of letters in a long DNA sequence. This error prevents the production of the protein <a href="https://doi.org/10.3390/jcm12144769">responsible for repairing arm and leg muscles</a>.</p>
<p>Today, I am a doctoral research student in molecular medicine. I study the treatment of hereditary diseases in order to be able to help families like my own. In this article, I will demystify hereditary diseases and show what research is being carried out to treat them.</p>
<h2>A piece of cake? Not quite</h2>
<p>Let’s start by imagining DNA as a recipe book. Each gene represents a different recipe. The page with the chocolate cake recipe has a nice picture, but there is some information missing. The recipe says to preheat the oven and measure the flour, but the rest of the page is torn. So it is impossible to make the cake. We go ahead and serve our meal made from all the other recipes, but there is no chocolate cake even though this is a particularly important part of the meal.</p>
<p>The same is true for hereditary diseases. In this case, the body can make all the proteins it needs except one. In dysferlinopathy, which affects my family, the missing recipe is the protein that repairs the muscles of the arms and legs. Each hereditary disease has its own damaged page in its recipe book.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=426&fit=crop&dpr=1 600w, https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=426&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=426&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=535&fit=crop&dpr=1 754w, https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=535&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/580032/original/file-20240305-21577-nvf7ba.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=535&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A mutation can cause the absence of a protein that has its own function.</span>
<span class="attribution"><span class="source">(Camille Bouchard)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<p>To be precise, an error in the DNA is called a mutation. There are different types of mutations. Some are caused by adding letters, like adding an ingredient to the recipe. This addition could lead to a delicious chocolate cake with strawberries, or to a cake that is no longer edible because we added motor oil to it.</p>
<p>Other mutations are caused by the removal (or elimination) of one or more letters (or ingredients), or by substitutions that replace one letter with another. All of these modifications can lead to favourable or non-impactful changes, such as the appearance of the first blue eyes in evolution, or the ability to breathe outside of water. But these modifications can also bring about unfavourable results, such as a hereditary disease or cancer.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=616&fit=crop&dpr=1 600w, https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=616&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=616&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=774&fit=crop&dpr=1 754w, https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=774&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/565888/original/file-20231214-19-3u3el2.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=774&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 are different types of mutations.</span>
<span class="attribution"><span class="source">(Camille Bouchard)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<h2>Repairing DNA</h2>
<p>From a young age, I understood that my mother was sick due to the error of a gene, but that I would not develop the disease because my father did not have the same error. This is called a recessive disease, since there must be an error in the gene of each of the two parents in order for the disease to manifest. Other hereditary diseases are dominant, meaning that a mutation in the DNA passed down from just one parent is enough to impair the production of a protein.</p>
<p>As part of my research, I look at the DNA sequence of each dysferlinopathy patient to see where the error is.</p>
<p>To try to correct it, I use <a href="https://doi.org/10.3390/cells12040536">Prime editing</a>, a technique which makes it possible to cut the DNA near the mutation and rewrite the sequence correctly. Prime editing is a version of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975809/">CRISPR-Cas9</a>, a technique that allows DNA to be cut at a particular location.</p>
<p>Prime editing uses a protein called Cas9, which occurs naturally in bacteria. This protein allows bacteria to destroy the DNA sequences of viruses that could infect them. The mission of the Cas9 protein is to recognize a sequence and cut it.</p>
<p>When we use Cas9 in our human cells, we attach it to another protein, which rewrites the DNA sequence based on a template. In other words, we give the cell an error-free sequence so that it can go ahead and manufacture the protein on its own. It’s a bit like recovering the original page of the recipe book so you can finally serve the chocolate cake.</p>
<h2>A step in the right direction</h2>
<p>So why aren’t we hearing about Prime editing, when it could be used to treat a variety of diseases? Because the technology is not yet fully developed. At the moment we are able to repair DNA directly in cells in the laboratory, but we lack the means to deliver the two large proteins (Cas9 and the one that rewrites) to the cells to be treated (for example, to the centre of the affected muscles).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=434&fit=crop&dpr=1 600w, https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=434&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=434&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=546&fit=crop&dpr=1 754w, https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=546&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/565889/original/file-20231214-21-z2b726.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=546&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Prime editing is a technique being studied to correct mutations in different genes.</span>
<span class="attribution"><span class="source">(Camille Bouchard)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<p>In other words, we have found the chocolate cake recipe, but it’s written on a page that is too large to fit in an email or put in an envelope. Many laboratories, including mine, are looking for an efficient and safe vehicle that will be able to deliver these proteins.</p><img src="https://counter.theconversation.com/content/219683/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Camille Bouchard received funding from the Jain Foundation and the Fondation du CHU de Québec.</span></em></p>Many people know someone with a genetic disease, but few understand how gene mutations work.Camille Bouchard, Étudiante au doctorat en médecine moléculaire (correction génétique de maladies héréditaires), Université LavalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2110472023-09-05T01:29:56Z2023-09-05T01:29:56ZEver wonder how your body turns food into fuel? We tracked atoms to find out<figure><img src="https://images.theconversation.com/files/545890/original/file-20230901-25-gm1k02.jpeg?ixlib=rb-1.1.0&rect=0%2C50%2C8500%2C4135&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/chain-amino-acid-bio-molecules-called-1733742605">Shutterstock</a></span></figcaption></figure><p>Inside our bodies at every moment, our cells are orchestrating a complex dance of atoms and molecules that uses energy to create, distribute and deploy the substances on which our lives depend.</p>
<p>And it’s not just in <em>our</em> bodies: all animals carry out this dance of metabolism, and it turns out none of them do it quite the same way.</p>
<p>In <a href="https://doi.org/10.1126/sciadv.adg1549">new research</a> published in Science Advances, we analysed specific carbon atoms in amino acids – the building blocks of proteins – to discover distinctive fingerprints of the metabolism of different species.</p>
<p>These fingerprints reveal how different creatures meet the demands of survival, growth and reproduction – and offer a whole new way to understand metabolism in unprecedented detail.</p>
<h2>A more detailed picture</h2>
<p>We have developed a new way to study metabolism – the chemical processes inside your body that keep you alive and functioning – that reveals much more detail than previous methods. Our new technique looks at isotopes inside amino acids to see how metabolism is working.</p>
<p>Isotopes are versions of the same chemical element with different masses. For example, the most common kind of carbon is carbon-12, but there is also an isotope called carbon-13 that is a little heavier. We can measure the ratio of heavy to light isotopes in biological molecules such as proteins to learn about the organism that produced them.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-an-isotope-10688">Explainer: what is an isotope?</a>
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<p>Traditionally, scientists would analyse the overall isotope ratio of the entire protein. This can reveal some information, particularly about what kinds of things an animal eats, but it is like averaging out a complex TV image into a single pixel of light – you lose all the detailed information. </p>
<p>More recently, scientists have been able to measure isotopes in <a href="http://dx.doi.org/10.1016/j.scijus.2014.07.002">each of the 20 individual amino acids</a> that make up proteins. This is like having 20 dots of light – better, but still not very nuanced.</p>
<p>Our new method goes even further, by measuring isotopes in a particular carbon atom on each amino acid. It’s like seeing every pixel in the TV image, which gives us amazingly detailed metabolic info.</p>
<h2>Finding the right carbon</h2>
<p>We used a chemical called ninhydrin to chop off and isolate the carbon atom we wanted from each amino acid. We then sent these carbon atoms – from a very metabolically active part of the amino acid called the carboxyl group – through a machine called a mass spectrometer to read their isotope fingerprints.</p>
<p>This research began more than a decade ago, and developed into a collaborative project between Griffith University and Queensland Health. In 2018, working with colleagues in Japan, we were able to <a href="https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/rcm.8126">demonstrate</a> that we could indeed use nihydrin to isolate the carbon atoms we wanted from amino acids.</p>
<p>The next stage was to combine our nihydrin technique with a process called high-performance liquid chromatography, which can separate out different kinds of amino acids. </p>
<p>In 2019, we were able to <a href="https://www.ncbi.nlm.nih.gov/pubmed/31658286">report</a> position-specific isotope analysis for several different mammals. We found we could distinguish a clear metabolic “fingerprint” of each mammal.</p>
<h2>The four phases of metabolism</h2>
<p>In our latest work, we tested a broader range of animals including oysters, scallops, prawns, squid and fish. We found the patterns of isotopes in the amino acids could be tracked back to the biochemistry of mitochondria, the tiny energy-providing powerhouses in the cells of all animals and plants, as well as many other organisms. </p>
<p>We identified four distinct phases of metabolism: creating fats, destroying fats, creating proteins, and destroying proteins. Animals combine these phases in distinct ways to accomplish growth and reproduction.</p>
<p>For example, adult mammals use fats as a pantry to regulate their temperature, whereas adult prawns cannibalise their own proteins to make the fats they need for reproduction.</p>
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<strong>
Read more:
<a href="https://theconversation.com/why-are-bigger-animals-more-energy-efficient-a-new-answer-to-a-centuries-old-biological-puzzle-188724">Why are bigger animals more energy-efficient? A new answer to a centuries-old biological puzzle</a>
</strong>
</em>
</p>
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<p>We also found that the humans we studied showed a very balanced, steady state metabolism, which is perhaps unsurprising given our generally stable and nutritious diets. Interestingly, this was quite similar to what we found in an oyster sample. </p>
<p>In this work, we studied individuals with generally normal metabolisms. Future applications might include studies of groups with abnormal metabolism such as cancer, obesity and starvation. </p>
<p>By peering deep into the isotopes of amino acids, we will be able to understand eukaryote metabolism like never before, in animals, plants and fungi.</p><img src="https://counter.theconversation.com/content/211047/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 organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Tracing isotopes of carbon inside amino acid molecules has revealed the ‘metabolic fingerprints’ of how different animals store and use energy.James Carter, Adjunct Research Fellow, Griffith UniversityBrian Fry, Emeritus Professor, Griffith UniversityKaitlyn O'Mara, Research Fellow, Australian Rivers Institute, Griffith UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2094712023-07-27T12:25:03Z2023-07-27T12:25:03ZYour genetic code has lots of ‘words’ for the same thing – information theory may help explain the redundancies<figure><img src="https://images.theconversation.com/files/538088/original/file-20230718-19-gbku0q.jpg?ixlib=rb-1.1.0&rect=136%2C136%2C1677%2C1105&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The same amino acid can be encoded by anywhere from one to six different strings of letters in the genetic code.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/and-binary-code-illustration-royalty-free-illustration/545863911?adppopup=true">Andrzej Wojcicki/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Nearly all life, from bacteria to humans, uses the same <a href="https://www.genome.gov/genetics-glossary/Genetic-Code#">genetic code</a>. This code acts as a dictionary, translating genes into the amino acids used to build proteins. The <a href="https://doi.org/10.1146/annurev-genet-120116-024713">universality of the genetic code</a> indicates a common ancestry among all living organisms and the essential role this code plays in the structure, function and regulation of biological cells.</p>
<p>Understanding how the genetic code works is the foundation of <a href="https://www.sciencedirect.com/topics/neuroscience/genetic-engineering">genetic engineering</a> and <a href="https://www.genome.gov/about-genomics/policy-issues/Synthetic-Biology">synthetic biology</a>. But there are still many unsolved mysteries, such as why the code is important for various biological processes such as <a href="https://theconversation.com/when-researchers-dont-have-the-proteins-they-need-they-can-get-ai-to-hallucinate-new-structures-173209">protein folding</a>.</p>
<p>As a <a href="https://scholar.google.com/scholar?start=10&q=s+kak+%26+subhash+kak&hl=en&as_sdt=0,37">scholar working at the interface of biology and physics</a>, I apply information theory – the mathematics of how information is stored and communicated – to study some of these intriguing questions. Just as computers need strings of binary code to function, <a href="https://www.ncbi.nlm.nih.gov/books/NBK9843/">biological processes</a> also rely on bits of information. </p>
<p>In my <a href="https://doi.org/10.1007/s12064-023-00396-y">recent research</a>, I propose that <a href="https://doi.org/10.1007/s00034-020-01583-8">optimization theory</a> may provide a potential explanation for a long-standing mystery about a certain redundancy in how amino acids are encoded.</p>
<h2>Different words for the same thing</h2>
<p>The genetic codebook is made of “words” composed of four letters: A, C, G and U. Each of these letters stands for a different chemical building block <a href="https://www.genome.gov/genetics-glossary/Nucleotide">called a nucleotide</a>: adenine, cytosine, guanine and uracil. A molecular machine <a href="https://www.genome.gov/genetics-glossary/Ribosome">called a ribosome</a> reads the codebook to translate genes into proteins.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Circular diagram encoding all 64 possible combinations of the letters A, C, G, and U, which are colored red, yellow, blue, and green, respectively. Abbreviations for different codons are listed around the outer edge of the circle." src="https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=441&fit=crop&dpr=1 600w, https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=441&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=441&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=554&fit=crop&dpr=1 754w, https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=554&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/538605/original/file-20230720-23211-1do6c1.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=554&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 codon sequence is read from the center of the wheel of genetic code.</span>
<span class="attribution"><span class="source">Mouagip via Wikimedia Commons</span></span>
</figcaption>
</figure>
<p>Ribosomes read three-letter words <a href="https://www.genome.gov/genetics-glossary/Codon">called codons</a>, and there are 64 different possible combinations of the four letters that make different codons. In this list of 64 words, 61 <a href="https://www.acs.org/education/whatischemistry/landmarks/geneticcode.html">encode amino acids</a>, and three signal the ribosome to stop protein synthesis in the cell. For example, “AUG” codes for the amino acid methionine and also indicates the start of a protein.</p>
<p>But just as in any other language, there are synonyms – different codons can encode the same amino acid. In fact, since there are only 20 amino acids but 61 different words to encode them, there is quite a lot of overlap. An amino acid can have anywhere from one to six different codons that encode it. There are only two amino acids that have <a href="https://www.genome.gov/sites/default/files/media/images/tg/Genetic-code.jpg">exactly one codon</a>, methionine and trytophan. This redundancy helps ribosomes perform their tasks correctly even when there’s a <a href="https://doi.org/10.3389/fgene.2014.00140">typo in the genetic code</a>.</p>
<h2>Engineering nature’s guidelines</h2>
<p>Why certain amino acids have more synonyms than others is a mystery that has puzzled scientists for decades. Is there a pattern to this variability, or is it random? To answer this question, scientists study the rules that govern nature’s decision-making.</p>
<p>If a human engineer designed the genetic code, they would want to make sure that each amino acid had a similar degree of redundancy to protect against errors and to promote uniformity. The mapping of the 61 codes onto the the 20 amino acids would be roughly equal, with each amino acid assigned three codons.</p>
<p>But nature has different priorities. <a href="https://theconversation.com/simulating-evolution-how-close-do-computer-models-come-to-reality-57538">Evolutionary models of natural systems</a> like bacteria demonstrate that nature is always <a href="https://doi.org/10.1038/nature03842">striving for optimization</a>. Not only does the final form of a protein need to be optimal, but so do its intermediate forms. Optimization ensures that natural systems can adapt to different environments.</p>
<p>Scientists understand some of the guidelines that nature follows when engineering the genetic code. For instance, the <a href="https://doi.org/10.1002/iub.146">spatial arrangement of atoms and molecules</a> within and surrounding the genetic code can affect its function, as well as the <a href="https://doi.org/10.3389/fgene.2014.00140">coevolution of other cellular structures</a> involved in creating proteins.</p>
<h2>Information theory and genetics</h2>
<p><a href="https://doi.org/10.1007/s12064-023-00396-y">My research indicates</a> that there may be two other significant factors that natural systems consider: the information-theoretic nature of the genetic code and the principle of maximum entropy. </p>
<p>Paralleling how the computer processes data consisting of 0s and 1s, life processes the genetic code based on data consisting of the four letters A, C, G and U. Mathematically, however, the most energy-efficient way to represent data isn’t binary (or base 2) – using 0s and 1s, as computers do – <a href="https://doi.org/10.1007/s00034-020-01480-0">but rather base e</a>. <a href="https://theconversation.com/pi-gets-all-the-fanfare-but-other-numbers-also-deserve-their-own-math-holidays-200046">Short for Euler’s number</a>, e is an irrational number – meaning that there’s no way to write down its exact value using fractions or decimals (although it’s approximately 2.718). </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="The Mandelbrot set, a mathematical fractal, shown in black against a blue background. The edges of the fractal are blue and white" src="https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/536904/original/file-20230711-16-bunaau.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Mandelbrot set is a mathematically generated fractal.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Mandelbrot20210909_ABC02_65535x65535.png">PantheraLeo1359531 via Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Nature’s affinity for optimization using this irrational number is responsible <a href="https://theconversation.com/mathematics-of-scale-big-small-and-everything-in-between-115890">for the infinitely repeating fractals</a> seen in <a href="https://fractalfoundation.org/OFC/OFC-10-4.html">jagged shorelines</a>, <a href="https://www.smithsonianmag.com/innovation/fractal-patterns-nature-and-art-are-aesthetically-pleasing-and-stress-reducing-180962738/">fern leaves, snowflakes and trees</a>. <a href="https://doi.org/10.1007/s40819-022-01251-2">Beyond biology</a>, information optimization using e also has applications in <a href="https://doi.org/10.1007/s00034-021-01726-5">mathematics</a> and <a href="https://doi.org/10.1038/s41598-020-77855-9">cosmology</a>. </p>
<p>Another principle operating in the natural world is that of <a href="https://doi.org/10.1016/1355-2198(95)00022-4">maximum entropy</a>. Entropy is a measure of disorder in a system, and the maximum entropy principle states that systems evolve to states of greater disorder. This principle allows researchers to <a href="https://doi.org/10.1016/j.heliyon.2018.e00596">make inferences</a> from limited data and has been used to explain how <a href="https://doi.org/10.1103/PhysRevLett.100.078102">amino acids interact in proteins</a>. </p>
<p>In the context of codon groupings, the maximum entropy principle implies that nature is scrambling data as much as possible – meaning the function that describes the distribution of codon groupings should be mathematically difficult to undo. Studying how to maximize the mathematical complexity of this function <a href="https://www.britannica.com/science/Fibonacci-number">reveals potential patterns</a> underlying the codon groupings.</p>
<p>I believe these two principles may <a href="https://doi.org/10.1007/s12064-023-00396-y">help describe</a> the distribution of the codon groups in the genetic code and point to the usefulness of mathematics in analyzing natural systems. Although there are many biological mysteries that scientists have yet to solve, information theory can be a powerful tool to help crack the genetic code.</p><img src="https://counter.theconversation.com/content/209471/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Subhash Kak 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 of the amino acids that make up proteins are encoded by genetic material in more than one way. An information theorist explains how principles of nature may account for this variance.Subhash Kak, Professor of Electrical and Computer Engineering, Oklahoma State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2012902023-03-08T03:35:37Z2023-03-08T03:35:37ZCrocodiles are uniquely protected against fungal infections. This might one day help human medicine too<figure><img src="https://images.theconversation.com/files/514088/original/file-20230308-14-j29qn9.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4920%2C2921&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Anthony D. Williams</span>, <span class="license">Author provided</span></span></figcaption></figure><p>Over the millions of years crocodiles and their relatives have roamed our planet, they have evolved robust immune systems to help combat the potentially harmful microbes in the swamps and waterways they call home. </p>
<p><a href="https://www.nature.com/articles/s41467-023-36280-y">Our study</a>, recently published in Nature Communications, takes a closer look at antimicrobial proteins called defensins, found in saltwater crocodiles. These proteins play a key role in the reptiles’ first line of defence against infectious disease.</p>
<p>As the threat of antibiotic-resistant microbes grows, so does our need for new and effective treatments. Could the defensins of these beasts hold the answers to help create a new wave of life-saving therapeutics?</p>
<h2>What are defensins?</h2>
<p>Defensins are small proteins produced by all plants and animals. In plants, defensins are usually made in the flowers and leaves, whereas animal defensins are made by white blood cells and in mucous membranes (for example in the lungs and intestines). Their role is to protect the host by killing infectious organisms.</p>
<p>Research into the <a href="https://link.springer.com/article/10.1007/s00018-016-2344-5">defensins of different plant and animal species</a> has found they can target a broad range of disease-causing pathogens. These include <a href="https://apsjournals.apsnet.org/doi/10.1094/MPMI-08-18-0229-CR?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed">bacteria</a>, <a href="https://www.science.org/doi/full/10.1126/sciadv.aat0979?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org">fungi</a>, <a href="https://www.sciencedirect.com/science/article/pii/S0022283613006220?via%3Dihub">viruses</a> and even <a href="https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.201802540R">cancer cells</a>.</p>
<p>The most common way defensins kill these pathogens is by attaching themselves to the outer membrane – the layer that holds the cell together. Once there, defensins create holes in the membrane, causing the cell contents to leak out, killing the cell in the process. </p>
<h2>What’s special about crocodile defensins?</h2>
<p>Despite living in dirty water, crocodiles rarely develop infections even though they often get wounded while hunting and fighting for territory. This suggests crocodiles have a potent immune system. We wanted to better understand how their defensins have adapted over time to protect them in these harsh environments. </p>
<p>By searching through the genome of the saltwater crocodile, we found that one particular defensin, named CpoBD13, was effective at killing the fungus <em><a href="https://www.cdc.gov/fungal/diseases/candidiasis/index.html">Candida albicans</a></em> – the leading cause of human fungal infections worldwide. Although some plant and animal defensins have previously been shown to target <em>Candida albicans</em>, the mechanism behind CpoBD13’s antifungal activity is what makes it unique.</p>
<p>That’s because CpoBD13 can self-regulate its activity based on the pH of the surrounding environment. At neutral pH (for example, in the blood) the defensin is inactive. However, when it reaches a site of infection which has a lower, acidic pH, the defensin is activated and can help clear the infection. This is the first time this mechanism has been observed in a defensin.</p>
<p>Our team discovered this mechanism by revealing the structure of CpoBD13 using a process called X-ray crystallography. This involves “shooting” lab-grown protein crystals with high-powered X-rays, which we were able to do at <a href="https://www.ansto.gov.au/facilities/australian-synchrotron">the Australian Synchrotron</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A green-yellow crocodile swimming past some green lilypads in dark water" src="https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=347&fit=crop&dpr=1 600w, https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=347&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=347&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=436&fit=crop&dpr=1 754w, https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=436&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/514129/original/file-20230308-14-db6qwm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=436&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Saltwater crocodiles can live in pretty murky waters.</span>
<span class="attribution"><span class="source">Atosan/Shutterstock</span></span>
</figcaption>
</figure>
<h2>Are fungi really a threat to human health?</h2>
<p>In comparison to bacterial and viral infections, fungal infections are often not seen as serious. After all, <a href="https://onlinelibrary.wiley.com/doi/10.1111/apm.13098">pandemics throughout human history</a> have only ever been caused by the former. Indeed, fungi are most commonly known in the general public for causing athlete’s foot and toenail infections – hardly life-threating conditions.</p>
<p>But fungi can pose severe problems to human health, particularly in people with impaired immune systems. Globally, <a href="https://www.sciencedirect.com/science/article/pii/S1369527422000820#bib2">approximately 1.5 million deaths per year</a> are attributed to fungal infections. </p>
<p>Our current arsenal of antifungals is <a href="https://www.nature.com/articles/nrd.2017.46/">limited to only a handful of drugs</a>. Furthermore, we haven’t had a new class of antifungal treatments since the early 2000s. To make matters even worse, overuse of the antifungal medicines we do have has led to some <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519031/">drug-resistant fungal strains</a>.</p>
<p>Rising global temperatures have also made once cooler regions more hospitable to pathogenic fungi. <a href="https://microbiologysociety.org/publication/past-issues/life-on-a-changing-planet/article/impact-of-climate-change-on-fungi.html">Climate change</a> has even been linked with the emergence of new drug-resistant species, such as <em>Candida auris</em>. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-candida-auris-and-who-is-at-risk-115293">Explainer: what is Candida auris and who is at risk?</a>
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<h2>A long way from crocs to the clinic</h2>
<p>In the hunt for new medicines, our study and those like it are important for finding potential future antibiotics. By characterising the defensins of crocodiles, we have provided the groundwork needed to develop CpoBD13 into an effective antifungal. However, undertaking clinic trials is a long and costly process. From the initial discovery, it can take between <a href="https://www.nature.com/articles/d41573-021-00190-9">five and 20 years to get a new drug approved</a>. </p>
<p>Currently, protein-based treatments can sometimes unintentionally <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684887/">harm a person’s healthy cells</a>. By using our knowledge of the crocodile’s defensins, we could potentially engineer other proteins to take on CpoBD13’s pH-sensing mechanism. Thus, they would only “turn on” upon reaching the infection.</p>
<p>Although there is much work to do before we see crocodile defensins in the clinic, we hope to one day harness the unique primal power of the crocodile’s immune system to aid in the global fight against infectious disease.</p><img src="https://counter.theconversation.com/content/201290/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Hulett receives funding from the Australian Research Council, National Health and Medical Research Council, Medical Research Future Fund.</span></em></p><p class="fine-print"><em><span>Scott Williams 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>Despite the filthy waters they often reside in, saltwater crocodiles don’t get sick that often. Perhaps we could one day harness the special proteins that help them.Scott Williams, PhD Candidate in Biochemistry, La Trobe UniversityMark Hulett, Professor and Head of Department, La Trobe UniversityLicensed 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>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/cj8dDTHGJBY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<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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<iframe width="440" height="260" src="https://www.youtube.com/embed/hr8-ZWmVG0Y?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Neurites are long, thin branches extending from the body of a neuron.</span></figcaption>
</figure>
<p>We started by breaking eight mouse neurite-localized RNAs into about 10,000 smaller chunks, each about 250 nucleotides long. We then appended each of these chunks to an unrelated firefly RNA that mouse cells are unlikely to recognize, and watched for chunks that caused the firefly RNA to be transported to neurites. To extend the mail analogy, we took 10,000 blank envelopes (firefly RNAs) and wrote a different ZIP code (pieces of neurite-localized RNA) on each one. By observing which envelopes were delivered to neurites, we were able to discover many new neurite ZIP codes.</p>
<p>We still didn’t know the identity of the protein that acted as the “mail carrier,” however. To figure this out, we purified RNAs containing the newly identified ZIP codes and observed what proteins were purified along with them. The idea was to catch the mail carrier in the act of transport while bound to its target RNA.</p>
<p>We found that one protein that regulates neurite production, named <a href="https://doi.org/10.1101%2Fgad.258483.115">Unkempt</a>, repeatedly appeared with ZIP code-containing RNAs. When we depleted cells of Unkempt, the ZIP codes were no longer able to direct RNA transport to neurites, implicating Unkempt as the “mail carrier” that delivered these RNAs.</p>
<h2>Toward a universal language</h2>
<p>With this work, we identified ZIP codes that sent RNAs to neurites (in our analogy, the bank). But where would an RNA containing one of these ZIP codes end up if it were in a cell that didn’t have neurites (a city that didn’t have a bank)? </p>
<p>To answer this, we looked at where RNAs were in a <a href="https://doi.org/10.7554/eLife.80040">completely different cell type, epithelial cells</a> that line the body’s organs. Interestingly, the same ZIP codes that sent RNAs to neurites sent them to the bottom of epithelial cells. This time we identified another mail carrier, a protein called LARP1, responsible for the transport of RNAs containing a particular ZIP code to both neurites and the bottom end of epithelial cells.</p>
<p>How could one ZIP code and mail carrier transport an RNA to two different locations in two very different cells? It turns out that both of these cell types contain structures called microtubules that are oriented in a very particular way. Microtubules can be thought of as cellular streets that serve as tracks to transport a variety of cargo in the cell. Importantly, these microtubules are polarized, meaning they have ingrained “plus” and “minus” ends. Cargo can therefore be transported in specific directions by targeting to one of these ends.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/mBo_o0iO68U?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<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/1982222023-02-06T15:32:17Z2023-02-06T15:32:17ZChocolate chemistry – a food scientist explains how the beloved treat gets its flavor, texture and tricky reputation as an ingredient<figure><img src="https://images.theconversation.com/files/506622/original/file-20230126-33474-ipuq4s.jpg?ixlib=rb-1.1.0&rect=260%2C164%2C5030%2C3794&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">In what form do you eat your annual share of the approximately 5 million tons of cocoa produced worldwide?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/chocolate-chunks-frosting-with-beaters-and-cocoa-royalty-free-image/1209981740">Tracey Kusiewicz/Foodie Photography/Moment via Getty Images</a></span></figcaption></figure><p>Whether it is enjoyed as creamy milk chocolate truffles, baked in a devilishly dark chocolate cake or even poured as hot cocoa, Americans on average consume almost <a href="https://www.statista.com/forecasts/1236087/per-capita-consumption-of-chocolate-in-united-states">20 pounds (9 kilograms) of chocolate</a> in a year. People have been enjoying chocolate for <a href="https://theconversation.com/the-history-of-chocolate-when-money-really-did-grow-on-trees-196173">at least 4,000 years</a>, starting with Mesoamericans who brewed a drink from the seeds of cacao trees. In the 16th and 17th centuries, both the <a href="https://theconversation.com/the-history-of-chocolate-when-money-really-did-grow-on-trees-196173">trees and the beverage spread across the world</a>, and chocolate today is <a href="https://www.statista.com/forecasts/983554/global-chocolate-confectionery-market-size">a trillion-dollar global industry</a>.</p>
<p><a href="https://scholar.google.com/citations?user=5iZjEckAAAAJ&hl=en&oi=ao">As a food scientist</a>, I’ve conducted research on the volatile molecules that make chocolate taste good. I also developed and taught a very popular college course on the science of chocolate. Here are the answers to some of the most frequent questions I hear about this unique and complex food.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="hands hold a split cacao pod, displaying the seeds inside" src="https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=397&fit=crop&dpr=1 600w, https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=397&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=397&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=499&fit=crop&dpr=1 754w, https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=499&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/506623/original/file-20230126-24317-g0khzq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=499&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’s a lot of processing that happens between cacao beans in a pod and the chocolate at your table.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/fresh-red-cocoa-fruits-royalty-free-image/1067662062?adppopup=true">Gustavo Ramirez/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>How does chocolate get its characteristic flavor?</h2>
<p>Chocolate starts out as a rather dull-tasting bean, packed into a pod that grows on a cacao tree. Developing the characteristic flavor of chocolate requires two key steps: fermentation and roasting.</p>
<p>Immediately after harvest, the beans are piled under leaves and <a href="https://theconversation.com/chocolates-secret-ingredient-is-the-fermenting-microbes-that-make-it-taste-so-good-155552">left to ferment for several days</a>. Bacteria create the chemicals, called precursors, needed for the next step: roasting.</p>
<p>The flavor you know as chocolate is formed during roasting by something chemists call the <a href="https://theconversation.com/kitchen-science-from-sizzling-brisket-to-fresh-baked-bread-the-chemical-reaction-that-makes-our-favourite-foods-taste-so-good-58577">Maillard reaction</a>. It requires two types of chemicals – sugar and protein – both of which are present in the fermented cacao beans. Roasting brings them together under high heat, which causes the sugar and protein to react and <a href="https://doi.org/10.1111/j.1750-3841.2010.01984.x">form that wonderful aroma</a>.</p>
<p>Roasting is something of an art form. Different temperatures and times will produce different flavors. If you sample a few chocolate bars on the market, you will quickly realize that some companies roast at a much higher temperature than others. Lower temperatures maximize the floral and fruity notes, while higher temperatures create more caramel and coffee notes. Which is better is really a matter of personal preference.</p>
<p>Interestingly, the Maillard reaction is also what creates the flavor of freshly baked bread, <a href="https://theconversation.com/what-makes-smoky-charred-barbecue-taste-so-good-the-chemistry-of-cooking-over-an-open-flame-184206">roasted meat</a> and coffee. The similarity between chocolate and coffee may seem fairly obvious, but bread and meat? The reason those foods all smell so different is that the flavor chemicals that get formed depend on the exact types of sugar and protein. Bread and chocolate contain different types, so even if you roasted them in exactly the same manner, you wouldn’t get the same flavor. This specificity is part of the reason it’s so hard to make a good artificial chocolate flavor.</p>
<h2>How long can you store chocolate?</h2>
<p>Once the beans are roasted, that wonderful aroma has been created. The longer you wait to consume it, the more of the volatile compounds responsible for the smell evaporate and the less flavor is left for you to enjoy. Generally you have <a href="https://damecacao.com/how-to-store-chocolate/">about a year to eat milk chocolate</a> and two years for dark chocolate. It’s not a good idea to store it in the refrigerator, because it picks up moisture and odors from the other things in there, but you can store it tightly sealed in the freezer.</p>
<h2>What’s different about hot chocolate?</h2>
<p>To make powdered hot chocolate, the beans are soaked in alkali to increase their pH before roasting. Raising the pH to be more basic helps make the powdered cocoa more soluble in water. But when the beans are at a higher pH during roasting, it changes the Maillard reaction so that <a href="https://doi.org/10.1111/j.1750-3841.2009.01455.x">different flavors are formed</a>.</p>
<p>The flavor of hot chocolate is described by experts as a smooth and mellow flavor with earthy, woodsy notes, while regular chocolate flavor is sharp, with an almost citrus fruit finish.</p>
<h2>What creates the texture of a chocolate bar?</h2>
<p>Historically, chocolate was consumed as a drink because the ground beans are very gritty – far from the smooth, creamy texture people can create today.</p>
<p>After removing the shells and grinding the beans, modern chocolate makers add additional cocoa butter. Cocoa butter is the fat that occurs in the cacao beans. But there isn’t enough fat naturally in the beans to make a smooth texture, so chocolate makers add extra.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="millstones of an industrial machine smashing cocoa powder" src="https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/506625/original/file-20230126-33788-3xo4uj.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">Machines can pulverize the beans to a very fine texture.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/millstones-of-industrial-melanger-grind-cocoa-in-royalty-free-image/1182864674">Евгений Харитонов/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>Next the cacao beans and cocoa butter undergo <a href="https://www.sciencedirect.com/topics/food-science/conching">a process called conching</a>. When the process was first invented, it took a team of horses a week walking in a circle, pulling a large grinding stone, to pulverize the particles small enough. Today machines can do this grinding and mixing in about eight hours. This process <a href="https://doi.org/10.1111/j.1745-4549.2008.00272.x">creates a smooth texture</a>, and also drives off some of the undesirable odors.</p>
<h2>Why is chocolate so difficult to cook with?</h2>
<p>The chocolate you buy in a store has been tempered. Tempering is a process of heating up the chocolate to just the right temperature during production, before letting it cool to a solid. This step is necessary because of the fat.</p>
<p>Cocoa butter’s fat can naturally exist in six different crystal forms when it is a solid. Five of these are unstable and want to convert into the most stable, sixth form. Unfortunately, that sixth form is white in appearance, gritty in texture and is commonly called “bloom.” If you see a chocolate bar with white spots on it, it has bloomed, which means the fat has rearranged itself into that sixth crystal form. It is still edible but doesn’t taste as good.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="lighter colored circular pattern of bloom on a brown chocolate surface" src="https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/506626/original/file-20230126-35457-102fb3.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">Careful chocolate prep tries to hold off the most stable – but undesirable – version of the fat in cocoa butter, which is called bloom.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/bloomed-chocolate-royalty-free-image/92094613">nbehmans/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>You can’t prevent bloom from happening, but you can slow it down by heating and cooling the chocolate through a series of temperature cycles. This process causes all the fat to crystallize into the second-most stable form. It takes a long time for this form to rearrange itself into the white, gritty sixth form.</p>
<p>When you melt chocolate at home, you break the temper. The day after you’ve created your confection, <a href="https://theconversation.com/whats-the-white-stuff-on-my-easter-chocolate-and-can-i-still-eat-it-181274">the chocolate usually blooms</a> with an unattractive gray or white surface.</p>
<h2>Is chocolate an aphrodisiac or antidepressant?</h2>
<p>The <a href="https://theconversation.com/mondays-medical-myth-chocolate-is-an-aphrodisiac-4980">short answer is, sorry, no</a>. Eating chocolate may make you feel happier, but that’s because it tastes so good, not because it is chemically changing your brain.</p><img src="https://counter.theconversation.com/content/198222/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sheryl Barringer 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>There’s a lot of interesting science behind the fermenting, roasting, grinding and melting that turns chocolate into the bars, bonbons and baked goods you know and love.Sheryl Barringer, Professor of Food Science and Technology, The Ohio State UniversityLicensed 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/1960162022-12-13T22:56:16Z2022-12-13T22:56:16ZWhy does the Alzheimer’s brain become insulin-resistant?<figure><img src="https://images.theconversation.com/files/499100/original/file-20221205-26-1etuem.jpg?ixlib=rb-1.1.0&rect=7%2C7%2C988%2C555&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Type 2 diabetes, characterised in its advanced stages by insulin resistance, is an important risk factor for Alzheimer's disease.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>As the population ages, the number of people with <a href="https://braininstitute.ca/research-data-sharing/neurodegenerative-disorders">neurodegenerative diseases</a>, such as <a href="https://alzheimer.ca/en/about-dementia/what-alzheimers-disease">Alzheimer’s disease</a>, increases. Approximately <a href="https://www.canada.ca/en/public-health/services/publications/diseases-conditions/dementia-highlights-canadian-chronic-disease-surveillance.html">75,000 Canadians</a> are diagnosed with Alzheimer’s disease each year and experience a decline in their cognitive abilities. The ordeal usually lasts for several years while their family members watch helplessly.</p>
<p>Neurodegenerative diseases are characterized by <a href="https://www.sciencedirect.com/science/article/abs/pii/S0924977X13001107">proteinopathies</a> — abnormal accumulations of proteins in the brain that impair the functioning of <a href="https://cancer.ca/en/cancer-information/resources/glossary/n/neuron">neurons</a>. The most widely studied therapeutic approach to developing drugs for Alzheimer’s is to try to reduce the aggregation of <a href="https://canjhealthtechnol.ca/index.php/cjht/article/view/eh0103/683">amyloid-beta peptide</a> and <a href="https://nouvelles.umontreal.ca/en/article/2022/10/20/unlocking-the-mysteries-of-tauopathies-a-protein-that-gives-hope/">tau protein</a> in neurons.</p>
<p>However, in order to reach their targets, the drugs must first cross the <a href="https://www.theglobeandmail.com/canada/article-toronto-researchers-look-at-new-approach-for-treating-alzheimers/">blood-brain barrier</a> (BBB) from the blood to the brain. This is because <a href="https://www.biorxiv.org/content/10.1101/2020.12.10.419598v1.full">endothelial cells</a>, cells that line the tiniest blood vessels in the brain, regulate the exchange between blood and the brain. They maintain a balance that allows access to essential molecules such as glucose, but restrict the passage of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494002/">most pharmaceuticals</a>, including the new and <a href="https://www.ft.com/content/32478dbf-7270-4eb6-a576-663a47a3603e">much-hyped</a> drug <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2212948">lecanemab</a>.</p>
<p>When these brain endothelial cells become diseased, the balance is upset. The brain struggles to get the substances it needs back into the circulation and rejects those that might harm it.</p>
<p>The brain and the other organs of the body are thus in constant communication, while in health or in disease.</p>
<p>As experts in neurodegenerative diseases and the BBB, we have conducted a study on insulin receptor dysfunction in Alzheimer’s disease.</p>
<h2>Insulin and the brain</h2>
<p><a href="https://www.healthlinkbc.ca/health-topics/types-insulin">Insulin</a> is an essential hormone for life. It is best known for its effect on the regulation of <a href="https://www.diabetescarecommunity.ca/living-well-with-diabetes-articles/blood-sugar-levels-in-canada/?gclid=Cj0KCQiAyracBhDoARIsACGFcS4fee8N8dfBJj9HKxpUiGlNO6RANNF9BiZN52dsd6oxqgLCW7Od_WsaArF9EALw_wcB">blood sugar</a> and remains an essential part of the pharmaceutical treatment of <a href="https://www.healthlinkbc.ca/health-topics/types-insulin">diabetes</a>. In recent decades, researchers have noted vascular and metabolic abnormalities <a href="https://pubmed.ncbi.nlm.nih.gov/30022099/">in a high proportion of patients with dementia</a>.</p>
<p>Indeed, Type 2 diabetes, characterized in the later stages by <a href="http://www.diabetesclinic.ca/en/diab/1basics/insulin_resistance.htm">insulin resistance</a>, is a major risk factor for Alzheimer’s disease. There is some evidence to suggest that the <a href="https://pubmed.ncbi.nlm.nih.gov/29377010/">Alzheimer’s brain is less responsive to insulin</a>. Conversely, studies have shown that insulin can <a href="https://pubmed.ncbi.nlm.nih.gov/32730766/">improve memory</a>, prompting the development of clinical trials on the effect of insulin on Alzheimer’s disease.</p>
<p>Yet we still don’t know what cell types and mechanisms are involved in the action — and loss of action — of insulin in the brain. The vast majority of insulin is produced by the <a href="https://pancreaticcancercanada.ca/the-pancreas/">pancreas</a> and secreted into the bloodstream. Therefore, to affect the brain, insulin must first interact with the BBB and its endothelial cells, which are in contact with the blood and can take up insulin through <a href="https://pubmed.ncbi.nlm.nih.gov/36280236/">receptors</a>.</p>
<h2>Alzheimer’s and the insulin receptor</h2>
<p>In order to measure the amount of these insulin receptors in the brain, <a href="https://doi.org/10.1093/brain/awac309">we performed analyses directly in human tissues</a>. These samples came from a <a href="https://www.rushu.rush.edu/research/departmental-research/religious-orders-study">cohort</a> of over a thousand people who agreed to donate their brains after death. We have access to them through a partnership with researchers at Rush University in Chicago.</p>
<p>We found that the <a href="https://healthenews.mcgill.ca/new-insights-into-how-insulin-interacts-with-its-receptor/">insulin-binding receptor</a> is predominantly located in the microvessels, so, within the BBB itself. Moreover, the abundance of this receptor is decreased in Alzheimer’s patients. This decrease could lead to the loss of insulin response in the Alzheimer brain.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="schematic" src="https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=781&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=781&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=781&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=982&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=982&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=982&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 brain insulin receptor is located mainly at the BBB, and its ability to respond to blood insulin is diminished in Alzheimer’s disease.</span>
<span class="attribution"><span class="source">(Manon Leclerc)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<h2>Insulin receptor dysfunction</h2>
<p>In order to better control the experimental variables and measure the response of the insulin receptor, we then tested our hypotheses in mice. The <em>in situ</em> cerebral perfusion technique consists of injecting insulin directly into the carotid artery (an artery located in the neck) so that it reaches the brain in its entirety. We have shown that circulating insulin mainly activates receptors located on the cerebral microvessels.</p>
<p>Although it was generally accepted that insulin crosses the BBB to reach cells such as neurons deeper in the brain tissue, our results show that the proportion of insulin that crosses the BBB is low.</p>
<p>These two observations thus confirm that the majority of insulin must interact with cells in the BBB before it can exert an action on the brain.</p>
<p>We then applied the same method to <a href="https://www.criver.com/products-services/research-models-services/genetically-engineered-model-services/transgenic-mouse-rat-model-creation/transgenic-mice?region=3601">transgenic mice</a>, which were genetically modified to model Alzheimer’s disease. We found that the response to insulin at the BBB was dysfunctional, with no activation of the insulin receptor in these diseased mice.</p>
<p>Thus, in both humans and rodents, the brain insulin receptor is located primarily at the BBB, and its ability to respond to blood insulin is impaired in Alzheimer’s disease.</p>
<h2>A significant breakthrough</h2>
<p>In sum, our results suggest that alterations in the number, structure and function of insulin receptors at the level of BBB endothelial cells may contribute to the cerebral insulin resistance observed in Alzheimer’s disease.</p>
<p>Alzheimer’s research efforts are currently focused on drugs that, in order to reach their therapeutic target, the neurons, must first cross the BBB, which severely restricts their passage. By targeting the metabolic dysfunction of the brain instead, we propose a research alternative that has two major advantages.</p>
<p>The first is that we can use treatments that do not have to cross the BBB barrier, since it is the endothelial cells themselves that become the therapeutic target. The second involves <a href="https://www.nature.com/articles/nrd.2018.168">“drug repurposing,”</a> which consists of taking advantage of the phenomenal therapeutic arsenal already approved to fight diabetes and obesity, but using this in the context of Alzheimer’s.</p>
<p>It should be remembered that the few drugs available to us provide only a modest improvement in symptoms. Combating insulin resistance in the brain would make it possible to break the vicious circle between neuropathology (disease that affects the brain) and diabetes, and in theory slow down the progression of the disease.</p>
<h2>The work is not finished</h2>
<p>On the basic research side, we will continue to study the mechanisms downstream from the microvessels to understand the action of insulin on the deep layers of the brain.</p>
<p>We hope that clinical research will follow suit with human studies to repurpose drugs that target certain metabolic diseases, such as diabetes, towards fighting Alzheimer’s.</p>
<p>In the meantime, while waiting for pharmaceutical solutions, each of us would do well to adopt the preventive cocktail that we all know well: a healthy diet combined with frequent physical and mental exercise.</p><img src="https://counter.theconversation.com/content/196016/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Frederic Calon has received funding from: Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Fonds de la recherche du Québec en santé (FRQS), Alzheimer Society of Canada.</span></em></p><p class="fine-print"><em><span>Manon Leclerc has received scholarships from the Fondation du CHU de Québec and the Fonds de Recherche du Québec - Santé (FRQS).</span></em></p><p class="fine-print"><em><span>Vincent Emond ne travaille pas, ne conseille pas, ne possède pas de parts, ne reçoit pas de fonds d'une organisation qui pourrait tirer profit de cet article, et n'a déclaré aucune autre affiliation que son organisme de recherche.</span></em></p>Impaired insulin receptors in the blood vessels between the blood and the brain may contribute to the insulin resistance observed in Alzheimer’s disease.Frederic Calon, Professeur, Université LavalManon Leclerc, PhD student, Université LavalVincent Emond, Professionnel de recherche, Université LavalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1937052022-11-22T13:25:50Z2022-11-22T13:25:50ZScientists uncovered the structure of the key protein for a future hepatitis C vaccine – here’s how they did it<figure><img src="https://images.theconversation.com/files/496217/original/file-20221118-14-r6a8me.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1999%2C1499&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Imaging the proteins on the surface of HCV has been challenging because of the virus's shape-shifting nature.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/hepatitis-c-virus-particles-illustration-royalty-free-illustration/1042127452">Juan Gaertner/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The <a href="https://www.cdc.gov/hepatitis/hcv/index.htm">hepatitis C virus, or HCV</a>, causes a chronic liver infection that can lead to permanent liver scarring and, in dire cases, cancer. It affects around <a href="https://doi.org/10.1007/s42399-020-00588-3">71 million people worldwide</a> and causes approximately 400,000 deaths each year. While <a href="https://www.uptodate.com/contents/direct-acting-antivirals-for-the-treatment-of-hepatitis-c-virus-infection">treatments are available</a> for HCV-related infections, they are expensive, hard to access and do not protect against reinfection. A vaccine that can help prevent HCV infection is a major unmet medical and public health need. </p>
<p>One major reason there hasn’t been an HCV vaccine yet is that scientists have yet to identify the proper antigen, or the part of the virus would trigger a protective immune response in the body.</p>
<p>Decades of research have pinpointed <a href="https://doi.org/10.1038/nrmicro3098">HCV E1E2</a>, the only protein on the surface of the virus, as the most promising vaccine candidate. However, developing an HCV vaccine based on that protein is limited by uncertainty around what it looks like. Knowing the structure of the protein is necessary to figure out how the immune system responds to the virus.</p>
<p>So how do researchers capture the structure of single protein on a shape-shifting virus? </p>
<p>We are researchers who specialize in <a href="https://scholar.google.com/citations?user=Xejfx54AAAAJ&hl=en">microscopy</a> and <a href="https://scholar.google.com/citations?user=iQj9rSwAAAAJ&hl=en">vaccine design</a>. With new technology, we were able to <a href="https://doi.org/10.1126/science.abn9884">visualize the molecular details</a> of this elusive protein, unlocking key insights into how this virus works and offering a potential blueprint for a future vaccine.</p>
<p>This is how we did it.</p>
<h2>Challenges of capturing a shape-shifting virus</h2>
<p>One reason it has been so difficult to capture the structure of the HCV E1E2 protein is that it is both <a href="https://doi.org/10.1016/j.celrep.2022.110859">flexible and fragile</a>. It changes its shape so often and is so easily broken that it’s challenging to purify. </p>
<p>As an analogy, imagine a bowl of spaghetti drenched in tomato sauce. Now imagine trying to take a picture of each individual piece of spaghetti in the same position over time while the bowl is shaking. Hard to do, right? That’s what it was like to image the full E1E2 protein.</p>
<p>There were also <a href="https://doi.org/10.1126/science.1251652">technological barriers</a>. Until recently, available imaging techniques were limited in their ability to view microscopic proteins. <a href="https://chem.libretexts.org/Bookshelves/Analytical_Chemistry/Supplemental_Modules_(Analytical_Chemistry)/Instrumentation_and_Analysis/Diffraction_Scattering_Techniques/X-ray_Crystallography">X-ray crystallography</a>, for instance, is unable to capture molecules that frequently change and shape-shift, like HCV. Moreover, other options, such as <a href="https://chem.libretexts.org/Bookshelves/Analytical_Chemistry/Physical_Methods_in_Chemistry_and_Nano_Science_(Barron)/04%3A_Chemical_Speciation/4.07%3A_NMR_Spectroscopy">nuclear magnetic resonance spectroscopy</a>, required cutting large parts of the protein or chemically manipulating it in a way that would transform its physiological state and potentially alter its function.</p>
<p>So to examine the structure of E1E2, we needed a way to extract and purify, stabilize and trap the entire shape-shifting protein into one configuration.</p>
<h2>How to take a picture of protein</h2>
<p><a href="https://doi.org/10.1038/d41586-020-01658-1">Cryo-EM, or cryo-electron microscopy</a>, is a type of imaging technique that views specimens at cryogenic temperatures, in this case the boiling point of nitrogen: minus 320.8 degrees Fahrenheit (minus 196 Celsius). With temperatures that cold, ice freezes so quickly that it doesn’t have time to crystallize. That creates a beautiful glasslike frame around the protein of interest, allowing an unhindered view of every structural detail. Cryo-EM also requires very little protein to work, reducing the amount of material we would need to purify. </p>
<p>Winner of the <a href="https://www.nobelprize.org/prizes/chemistry/2017/press-release/">2017 Nobel Prize in chemistry</a> and <a href="https://doi.org/10.1038/nmeth.3730">Nature magazine’s 2015 “Method of the Year</a>” award, cryo-EM is superb for imaging biological macromolecules in their native, or natural, state in the aqueous environment of human blood. Cryo-EM was also pivotal for characterizing the <a href="https://doi.org/10.1038/nature17200">structure of the COVID-19 virus</a> and its variants.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Qq8DO-4BnIY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cryo-EM has allowed researchers to see complex proteins they weren’t able to before.</span></figcaption>
</figure>
<p>So how do you take a picture of a protein? </p>
<p>First, we embedded the genetic code to make E1E2 in human cells in a petri dish so we would have sufficient amounts of protein to study. After purifying the protein, we <a href="https://caic.bio.cam.ac.uk/electron-microscopy/SpecimenPrep/PlungeFreezing">plunged it into liquid ethane</a> followed by liquid nitrogen. Liquid ethane is used to freeze the protein because it has a higher boiling point than liquid nitrogen. This means it is able to capture more heat before turning to a gas, allowing the protein to freeze much more quickly than it would in liquid nitrogen and avoid structural damage. </p>
<p>Once the protein was vitrified, or in a glasslike ice state, we were able not just to see its overall structure, but also to capture multiple individual configurations of the protein that it takes when it shape-shifts, including its less stable forms.</p>
<p>At this point, our protein was ready for its close-up. We employed a microscope that <a href="https://www.ccber.ucsb.edu/ucsb-natural-history-collections-botanical-plant-anatomy/transmission-electron-microscope">uses a beam of focused, high energy electrons</a> and a very fancy camera that detects how the elections bounce off the protein’s surface. This created a 2D image that we then mathematically transformed into a 3D model. And that was how we got the coveted “close-up” of HCV’s surface protein. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/jgEQ6A2-liU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">This video shows the newly identified 3D structure of the E1E2 protein on the surface of the hepatitis C virus. The two main subunits of the protein are colored in pink and blue. Sugar molecules are colored in green.</span></figcaption>
</figure>
<p>Our next step was then to assess the location of each amino acid, or building block of the protein, in 3D space. Because every amino acid has a unique shape, we used a computer program that could identify each one in our 3D map. This allowed us to manually reconstruct a high-resolution model of the protein, one building block at a time.</p>
<h2>A new tool to design an HCV vaccine</h2>
<p>Our 3D map and model of the HCV E1E2 protein supports previous research describing its structure while providing new insights into features that will help pave the way for a long-sought vaccine design against this virus. </p>
<p>For example, our structure reveals that the interface between the two main parts of the protein is stabilized by sugars and hydrophobic patches, or areas that push out water molecules. This creates sticky binding hubs along the protein and keeps it from falling apart – a potential site for protective antibodies and new drugs to target. </p>
<p>Researchers now have the tools to design antiviral drugs and vaccines against HCV infection.</p><img src="https://counter.theconversation.com/content/193705/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lisa Eshun-Wilson receives funding from the National Science Foundation. </span></em></p><p class="fine-print"><em><span>Alba Torrents de la Peña receives funding from Netherlands Organization for Scientific Research (NWO) Rubicon Grant 45219118. </span></em></p>Using a Nobel Prize-winning technique called cryo-EM, researchers were able to identify potential areas on the hepatitis C virus that a vaccine could target.Lisa Eshun-Wilson, Postdoctoral Scholar in Molecular and Cell Biology, The Scripps Research InstituteAlba Torrents de la Peña, Postdoctoral Fellow in Integrative Structural and Computational Biology, The Scripps Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1927102022-11-02T12:29:28Z2022-11-02T12:29:28ZWater was both essential and a barrier to early life on Earth – microdroplets are one potential solution to this paradox<figure><img src="https://images.theconversation.com/files/492830/original/file-20221101-26-hkb6tg.png?ixlib=rb-1.1.0&rect=5%2C0%2C1724%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Water microdroplets provide a unique interface that can significantly speed up chemical reactions.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/macro-abstract-of-water-drops-on-a-mid-blue-royalty-free-image/1356063821">Marianna Armata/Moment via Getty Images</a></span></figcaption></figure><p>It’s a <a href="https://doi.org/10.1021/acs.jpca.1c02864">paradox</a>: Life needs water to survive, but a world full of water can’t generate the biomolecules that would have been essential for early life. Or so researchers thought.</p>
<p>Water is everywhere. <a href="https://www.usgs.gov/special-topics/water-science-school/science/water-you-water-and-human-body">Most of the human body</a> is made of it, <a href="https://www.usgs.gov/special-topics/water-science-school/science/how-much-water-there-earth">much of planet Earth</a> is covered by it and humans can’t survive more than a <a href="https://www.jstor.org/stable/45016189">couple of days without drinking it</a>. Water molecules have <a href="https://sitn.hms.harvard.edu/uncategorized/2019/biological-roles-of-water-why-is-water-necessary-for-life/">unique characteristics</a> that allow them to dissolve and transport compounds through your body, provide structure to your cells and regulate your temperature. In fact, the basic chemical reactions that enable life as we know it require water, <a href="https://education.nationalgeographic.org/resource/photosynthesis">photosynthesis</a> being one example.</p>
<p>However, when the first biomolecules like proteins and DNA started coming together in the early stages of planet Earth, water was actually a barrier to life.</p>
<p>The reason why is surprisingly simple: The presence of water prevents chemical compounds from losing water. Take, for example, proteins, which are one of the main classes of biological molecules that make up your body. Proteins are, in essence, chains of amino acids linked together by chemical bonds. These bonds are formed through a <a href="https://chem.libretexts.org/Bookshelves/Introductory_Chemistry/Introductory_Chemistry_(CK-12)/25%3A_Organic_Chemistry/25.18%3A_Condensation_Reactions">condensation reaction</a> that results in the loss of a molecule of water. Essentially, the amino acids need to get “dry” in order to form a protein.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of condensation reaction joining two amino acids with a peptide bond" src="https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=382&fit=crop&dpr=1 600w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=382&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=382&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=480&fit=crop&dpr=1 754w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=480&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=480&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Condensation reactions join amino acids by losing a molecule of water.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:CNX_Chem_20_04_peptide.png">OpenStax/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Considering that Earth before life was <a href="https://doi.org/10.1126/science.abh4289">covered in water</a>, this was a <a href="https://doi.org/10.1073/pnas.1210029109">big problem</a> for making the proteins essential to life. Like trying to get dry inside of a swimming pool, two amino acids would have had a hard time losing water to come together in the <a href="https://doi.org/10.1007/978-3-662-44185-5_1275">primordial soup</a> of early Earth. And it wasn’t only proteins that faced this problem in the presence of water: Other biomolecules essential to life, including DNA and complex sugars, also rely on condensation reactions and losing water to form.</p>
<p>Over the years, researchers have proposed many solutions to this “water paradox.” Most of them rely on very specific scenarios on early Earth that could have allowed water removal. These include <a href="https://doi.org/10.1002/anie.201503792">drying puddles</a>, <a href="https://doi.org/10.1038/s41467-017-02248-y">mineral surfaces</a>, <a href="https://doi.org/10.1089/ast.2019.2045">hot springs</a> and <a href="https://doi.org/10.1126/science.283.5403.831">hydrothermal vents</a>, among others. These solutions, while plausible, require particular geological and chemical conditions that might not have been commonplace.</p>
<p>In our <a href="https://doi.org/10.1073/pnas.2212642119">recent study</a>, <a href="https://aston.chem.purdue.edu/index.html">my colleagues</a> <a href="https://scholar.google.com/citations?user=aC4GqPMAAAAJ&hl=en">and I</a> found a simpler and more general solution to the water paradox. Quite ironically, it might be water itself – or to be more precise, very small water droplets – that allowed early biomolecules to form.</p>
<h2>Why microdroplets?</h2>
<p>Water droplets are everywhere, both in the modern world and especially during prebiotic (or pre-life) Earth. In a planet covered by crashing waves and raging tides, the small water droplets in <a href="https://doi.org/10.1021/ar300027q">sea spray and other aerosols</a> would have plausibly provided a simple and abundant place for the <a href="https://doi.org/10.1073/pnas.200366897">first biomolecules to assemble</a>.</p>
<p>Water microdroplets – typically very small droplets with diameters <a href="https://doi.org/10.1007/s13361-019-02264-w">around a millionth of a meter</a>, far smaller than the <a href="http://scienceline.ucsb.edu/getkey.php?key=6105">diameter of spider silk</a> – might not seem to solve the water paradox at first, until you consider the very particular chemical environments they create.</p>
<p>Microdroplets have a substantial surface area-to-volume ratio that <a href="https://doi.org/10.1002/jms.4585">gets larger the smaller the droplet is</a>. This means there is a significant space where the solvent they are made of (in this case, water) and the medium they are surrounded by (in this case, air) meet.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/fxlMABxU7zU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The chemical properties of water are what make it so important to life.</span></figcaption>
</figure>
<p>Over the years, researchers have shown that the air-water interface is a unique chemical environment. The chemistry of these microdroplet interfaces is dominated by <a href="https://doi.org/10.1038/s41467-021-27941-x">large electric fields</a>, <a href="https://doi.org/10.1002/cplu.202100373">partial solvation</a> where molecules are partially surrounded by water, <a href="https://doi.org/10.1073/pnas.1911883116">highly reactive molecules</a> and <a href="https://doi.org/10.1039/D0SC02467H">very high acidity</a>. All these factors allow microdroplets to accelerate the chemical reactions that occur in them.</p>
<p><a href="https://aston.chem.purdue.edu/">Our lab</a> has been studying microdroplets for a <a href="https://doi.org/10.1039/C0SC00416B">decade</a>, and our previous work has shown how the rate of common chemical reactions can be sped up to a <a href="https://doi.org/10.1146/annurev-physchem-121319-110654">million times</a> faster in microdroplets. Reactions that would have taken a full day could now be complete in just a fraction of a second using these small droplets.</p>
<p>In <a href="https://doi.org/10.1073/pnas.2212642119">our recent work</a>, we proposed that microdroplets could be a solution to the water paradox because their air-water interface not only accelerates reactions but also acts as a “drying surface” that facilitates the reactions needed to create biomolecules despite the presence of water.</p>
<p>We tested this theory by spraying amino acids dissolved in microdroplets of water toward a <a href="https://www.broadinstitute.org/technology-areas/what-mass-spectrometry">mass spectrometer</a>, an instrument that can be used to analyze the products of a chemical reaction. We found that two amino acids can successfully join together in the presence of water via microdroplets. When we added more amino acids and collided two sprays of this mixture together, mimicking crashing waves in the prebiotic world, we found that this can form short peptide chains of up to six amino acids. </p>
<p>Our findings suggest that water microdroplets in settings like sea spray or atmospheric aerosols were fundamental microreactors in early Earth. In other words, microdroplets may have provided a chemical medium that allowed the basic molecules of life to form from the simple, small compounds dissolved in the vast primordial ocean that covered the planet.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Close-up of water droplets against clear background" src="https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.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">Water microdroplets may have provided the chemical environment necessary for life.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/water-drops-on-a-clear-white-background-royalty-free-image/1356063793">Marianna Armata/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>Microdroplets past and future</h2>
<p>The chemistry of microdroplets might be helpful in tackling current challenges across many scientific fields. </p>
<p>Drug discovery, for example, requires synthesizing and testing hundreds of thousands of compounds to find a potential new drug. The power of microdroplet reactions can be integrated with automation and new tools to speed up synthesis rates to <a href="https://doi.org/10.1177/24726303211047839">more than one reaction per second</a> as well as <a href="https://doi.org/10.1002/anie.202009598">biological analysis</a> to less than a second per sample.</p>
<p>In this way, the same phenomenon that might have aided the origin of the building blocks of life billions of years ago can now help scientists develop new medicines and materials faster and more efficiently.</p>
<p>Perhaps <a href="https://www.worldcat.org/title/1328130044">J.R.R. Tolkien</a> was right when he wrote: “Such is oft the course of deeds that move the wheels of the world: small hands do them because they must, while the eyes of the great are elsewhere.”</p>
<p>I believe the importance of these small droplets is far bigger than their tiny size.</p><img src="https://counter.theconversation.com/content/192710/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nicolás M. Morato received funding from Eastman Chemical Company through a Summer Fellowship in Analytical Chemistry (Jun - Aug 2021) and from the Division of Analytical Chemistry of the American Chemical Society through a Graduate Fellowship sponsored by Agilent Technologies (Sep 2021 - May 2022). </span></em></p>The chemical reaction that forms essential biomolecules like proteins and DNA normally doesn’t occur in the presence of water. Microdroplets provide a unique environment that make it possible.Nicolás M. Morato, PhD Candidate in Chemistry, Purdue UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1906902022-10-03T14:59:29Z2022-10-03T14:59:29ZSome coronaviruses kill, while others cause a common cold. We are getting closer to knowing why<figure><img src="https://images.theconversation.com/files/487040/original/file-20220928-20-v0xkqd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some human coronaviruses cause seasonal colds or other mild symptoms. Others can be severe and even fatal.</span> <span class="attribution"><span class="source">Jdidi wassim/SOPA Images/LightRocket via Getty Images</span></span></figcaption></figure><p>It’s hard to imagine a time when “coronavirus” wasn’t a household word. But for a long time, this family of viruses had merited very little attention. Believed to be ubiquitous among <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543176/">animals and avian species</a>, the <a href="https://pubmed.ncbi.nlm.nih.gov/4158999/">first coronavirus to infect and cause disease in humans</a> was only isolated and identified in the 1960s. </p>
<p>Seven human coronaviruses <a href="https://www.nature.com/articles/s41579-020-00468-6">have been identified</a> since then.</p>
<p>Most cause only relatively minor health concerns: the common cold and seasonal respiratory infections that come around every year. But the 2003 outbreak in China and other parts of Asia of <a href="https://www.cdc.gov/sars/about/fs-sars.html">severe acute respiratory syndrome</a> (SARS), caused by SARS-CoV (now renamed as SARS-CoV-1), propelled the virus onto the global stage. Coronaviruses gained further infamy when, in 2012, cases of the much more severe <a href="https://www.mayoclinic.org/diseases-conditions/sars/expert-answers/what-is-mers-cov/faq-20094747nk">Middle East respiratory syndrome</a> (MERS) were identified in Saudi Arabia. </p>
<p>Both outbreaks were relatively contained. Not surprisingly, the concern over coronavirus diseases largely faded from the minds of ordinary people. The same was true for virologists, who focused their time and funding on more pressing viruses. Then in late 2019 came SARS-CoV-2, the causative agent of COVID-19. </p>
<p>Fortunately, some researchers had retained an interest in coronaviruses. After all, viruses can mutate and reappear, causing new outbreaks. One such cohort, ourselves among them, works at the University of the Western Cape in South Africa. Our laboratory had, among other things, been studying some of the structural proteins that are the building blocks of coronaviruses. These proteins - named spike, nucleocapsid, membrane, and envelope proteins - have different roles, but are essential to how coronaviruses reproduce, spread and cause disease.</p>
<p>In our <a href="https://www.mdpi.com/1999-4915/14/8/1707">most recent paper</a>, we examined what possibly sets the human coronaviruses that cause SARS, MERS and COVID-19 apart from the other human coronaviruses that cause milder diseases like seasonal colds. The answer, we argue, lies with the envelope protein.</p>
<h2>Shedding light on the E protein</h2>
<p>The envelope protein is possibly the most enigmatic and least-studied in the coronavirus-suite, owing to its small size and the difficulty of studying it in laboratory settings. In May 2019, two of us published a <a href="https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0">review paper</a> on what was known about the envelope protein at the time.</p>
<p>The paper has racked up nearly 2,000 citations, most coming after the outbreak of COVID-19 – a testament less to our foresight than to the critical and previously understated role the envelope protein plays in human coronaviruses.</p>
<p>Even before the COVID-19 outbreak, based on what we had learnt from the SARS and MERS outbreaks, we were convinced that this protein – once written off as a “<a href="https://pubmed.ncbi.nlm.nih.gov/17530462/">minor component</a>” of the virus – was key to the development of disease. It is critical, for instance, in the final assembly of the virus, forming the envelope or wrapping that covers it when all its constituent components come together. </p>
<p>It also plays a role in the virus’s budding, when it exits from the host cell; and in the process known as pathogenesis, or the development and progression of the infection. </p>
<p>And it may hold a clue to either the <a href="https://doi.org/10.1371/journal.ppat.1004320">severity</a> or <a href="https://www.nature.com/articles/s41422-021-00519-4">relative mildness</a> of the disease. </p>
<p>Our <a href="https://www.frontiersin.org/articles/10.3389/fmicb.2020.02086/full">ongoing</a> <a href="https://www.mdpi.com/1999-4915/13/8/1457">research</a> is beginning to suggest that the structure of the envelope protein may determine the severity of a coronavirus disease, or the difference between a blocked nose on the one hand, and collapsed lungs on the other. </p>
<h2>The sting in the protein’s “tail”</h2>
<p>This led us to our <a href="https://www.mdpi.com/1999-4915/14/8/1707">most recent paper</a>. We collaborated with structural bioinformatics expert Ruben Cloete, of the <a href="https://www.sanbi.ac.za/">South African National Bioinformatics Institute</a> at the University of the Western Cape, to develop full-length, 3D models of the envelope proteins of five human coronaviruses: SARS-CoV-1 and -2, and MERS-CoV (responsible for the severe SARS, COVID-19 and MERS diseases); and HCoV-229E and HCoV-NL63, responsible for milder diseases. For this work, we relied on a modelling program known as <a href="https://salilab.org/modeller/">MODELLER</a>, allowing us to explore the proteins in some detail.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=495&fit=crop&dpr=1 600w, https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=495&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=495&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=622&fit=crop&dpr=1 754w, https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=622&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/487472/original/file-20220930-19-6msqnn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=622&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">3D models of the envelope (E) protein for the human coronaviruses that cause SARS (SARS-CoV-1), COVID-19 (SARS-CoV-2), MERS (MERS-CoV), and the more seasonal common colds (HCoV-229E and HCoV-NL63).</span>
<span class="attribution"><span class="source">Authors supplied</span></span>
</figcaption>
</figure>
<p>We then used a web server, HADDOCK2.4, <a href="https://wenmr.science.uu.nl/haddock2.4/">to simulate</a> how the envelope protein interacts with the human PALS-1 protein – an interaction already shown to be critical with <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982091/">SARS-CoV-1</a>. Each of the envelope proteins could bind to the PALS-1 protein, but the coronaviruses causing SARS, MERS and COVID-19 appeared to bind more stably to PALS-1. </p>
<p>The answers, we believe, may lie in the conformation or shape of what’s known as the PDZ-binding motif, or PBM, which sits at the tail-end of the envelope protein. This PBM - essentially a distinctive sequence on a protein - acts like a one-of-a-kind key to a very specific lock (known as the PDZ domain) on a host cell protein. This ‘key’ allows the viral protein to interact with the host protein, making the disease worse.</p>
<p>We found that the more flexible, extended coil of the PBM of the coronaviruses behind SARS, MERS and COVID-19 viruses may well be what differentiates them from the more rigid PBM of the coronaviruses that cause milder diseases.</p>
<h2>Inner workings</h2>
<p>It is yet too early to draw definitive conclusions, as these findings will have to be confirmed with more studies – in the laboratory and in living organisms. </p>
<p>But it does shine some light on the inner workings of these coronaviruses and the still-enigmatic envelope protein. In so doing it could offer opportunities for the development of essential life-saving treatments and vaccines.</p><img src="https://counter.theconversation.com/content/190690/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dewald Schoeman received funding from National Research Foundation and the Poliomyelitis Research Foundation. </span></em></p><p class="fine-print"><em><span>Burtram C. Fielding receives funding from the National Research Foundation. </span></em></p><p class="fine-print"><em><span>Ruben Cloete receives funding from the Department of Higher Education and Training. </span></em></p>The enigmatic envelope protein seems to hold the key to understanding why some human coronaviruses cause more severe disease than others.Dewald Schoeman, PhD Candidate, Molecular Biology and Virology, University of the Western CapeBurtram C. Fielding, Dean Faculty of Natural Sciences and Professor, University of the Western CapeRuben Cloete, Lecturer in Bioinformatics, University of the Western CapeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1875152022-08-01T12:27:02Z2022-08-01T12:27:02ZHelping cells become better protein factories could improve gene therapies and other treatments – a new technique shows how<figure><img src="https://images.theconversation.com/files/476727/original/file-20220729-13650-l4tehb.jpg?ixlib=rb-1.1.0&rect=5%2C0%2C1991%2C1500&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Your genetic material instructs your cells to produce the proteins encoded in it.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/protein-synthesis-illustration-royalty-free-illustration/1296294290">Juan Gaertner/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The cells in your body are <a href="https://www.ncbi.nlm.nih.gov/books/NBK26885/">not all the same</a>. Each of your organs has cells with very different functions. For example, liver cells are top-notch secretors, as their job requires them to make and export many of the proteins in your blood. By contrast, muscle cells are tasked with facilitating the contractions that allow you to move. </p>
<p>The fact that cells are so specialized has implications for <a href="https://medlineplus.gov/genetics/understanding/therapy/procedures/">gene therapy</a>, a way to treat genetic diseases by correcting the source of the error in a patient’s DNA. Health providers use a harmless <a href="https://patienteducation.asgct.org/gene-therapy-101/vectors-101">viral or bacterial vector</a> to carry a corrective gene into a patient’s cells, where the gene then directs the cell to produce the proteins necessary to treat the disease. Muscle cells are a common target because gene therapies <a href="https://medlineplus.gov/genetics/understanding/therapy/procedures/">injected into the muscle</a> are more accessible than introduction into the body by other routes. But muscle cells may not produce the desired protein as efficiently as needed if the job the gene instructs it to do is very different from the one it specializes in.</p>
<p>We are <a href="https://scholar.google.com/citations?user=SPyKrnIAAAAJ&hl=en">cell biologists</a> and <a href="https://scholar.google.com/citations?user=PL6N9eoAAAAJ&hl=en">biophysicists</a> who study how healthy proteins are produced and maintained in cells. This field is called <a href="https://doi.org/10.1093%2Fgerona%2Fgln071">protein homeostasis, also known as proteostasis</a>. Our <a href="https://dx.doi.org/10.1073/pnas.2206103119">recently published study</a> details a way to make muscle cells behave more like liver cells by changing protein regulation networks, enhancing their ability to respond to gene therapy and treat genetic diseases.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/BxEoX6TkitY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Gene therapy involves replacing a defective gene with a functioning one that can direct cells to produce missing or dysfunctional proteins.</span></figcaption>
</figure>
<h2>Boosting protein factories</h2>
<p>One disease for which gene therapy has great potential is <a href="http://doi.org/10.1056/NEJMra1910234">alpha-1 antitrypsin (AAT) deficiency</a>, a condition in which liver cells are unable to make adequate amounts of the protein AAT. It results in a breakdown of lung tissue that can cause <a href="https://www.uncoveralpha1.com/what-is-alpha-1">serious respiratory problems</a>, including the development of severe lung diseases such as chronic obstructive pulmonary disease (COPD) or emphysema. </p>
<p>Patients are usually treated by <a href="https://www.nhlbi.nih.gov/health/alpha-1-antitrypsin-deficiency">receiving AAT via infusion</a>. But this requires patients to either make regular trips to the hospital or keep expensive equipment at home for the rest of their lives. Replacing the faulty gene that caused their AAT shortage in the first place could be a boon for patients. Current gene therapies inject the AAT-producing gene into muscle. One of our colleagues, <a href="https://scholar.google.com/citations?user=Sd6B6-UAAAAJ&hl=en">Terence Flotte</a>, developed a way to use a harmless version of an adeno-associated virus as a vehicle to deliver AAT gene therapies into the body via injection, allowing for <a href="https://doi.org/10.1016/j.ymthe.2017.03.029">sustained release of the protein</a> over several years.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of panlobular emphysema" src="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=404&fit=crop&dpr=1 600w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=404&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=404&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=507&fit=crop&dpr=1 754w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=507&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=507&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Lung damage from alpha-1 antitrypsin deficiency can lead to emphysema.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/8TqvpQ">Atlas of Pulmonary Pathology/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>But muscle cells aren’t very good at producing the AAT proteins the gene instructs them to make. Flotte and his team found that AAT levels one to five years after gene therapy were <a href="https://doi.org/10.1016/j.ymthe.2017.03.029">only 2% to 2.5%</a> of the optimal concentration for therapeutic effect.</p>
<p>We wanted to find a way to turn muscle cells into better protein factories, like liver cells. We tested a number of different molecules on mice muscle cells to determine if they would boost AAT secretion. We found that adding a molecule called <a href="https://doi.org/10.1074/jbc.M112.404707">suberoylanilide hydroxamic acid, or SAHA</a>, helps muscle cells make AAT at a production level more like that of liver cells. It works because SAHA is a <a href="https://doi.org/10.7554%2FeLife.15550">proteostasis regulator</a> with the ability to boost the cell’s protein output.</p>
<p>Down the road, we believe that adding SAHA or similar proteostasis regulators to gene therapies could help increase the effectiveness of these treatments for many genetic diseases.</p>
<h2>Beyond gene therapy</h2>
<p>Our findings have implications beyond just gene therapies. The effectiveness of <a href="https://doi.org/10.1038/s41573-021-00283-5">mRNA vaccines</a>, for example, is also affected by how well each cell produces a particular type of protein. Because most mRNA vaccines are given through an injection to the muscle, they may also face the same limitations as gene therapies and produce a lower-than-desirable immune response. Increasing the protein production of muscle cells could potentially improve vaccine immunity.</p>
<p>Additionally, many drugs created by the biotech industry called <a href="https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers">biologics</a> that are derived from natural sources rely heavily on a given cell’s <a href="https://doi.org/10.3389/fbioe.2019.00420">protein production capabilities</a>. But many of these drugs use <a href="https://weekly.biotechprimer.com/biomanufacturing-how-biologics-are-made/">cells that aren’t specialized to make large amounts of protein</a>. Adding a protein homeostasis enhancer to the cell could optimize protein yield and increase the effectiveness of the drug.</p>
<p>Protein homeostasis is a burgeoning field that goes beyond drug development. Many <a href="https://doi.org/10.1038/s41580-019-0101-y">neurodegenerative diseases</a> like Alzheimer’s and Parkinson’s are linked to abnormal protein regulation. The deterioration of a cell’s ability to manage protein production and use over time may contribute to age-related diseases. Further research on ways to improve the cellular machinery behind protein homeostasis could help delay aging and open many new doors for treating a wide range of diseases.</p><img src="https://counter.theconversation.com/content/187515/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Daniel N. Hebert receives funding from Alpha One Foundation and NIH/NIGMS. </span></em></p><p class="fine-print"><em><span>Lila Gierasch receives funding from NIH/NIGMS and the Alpha1 Foundation.</span></em></p>Gene therapies and vaccines are often injected into muscle cells that are inefficient at producing desired proteins. Making them work more like liver cells could lead to better treatment outcomes.Daniel N. Hebert, Professor of Biochemistry and Molecular Biology, UMass AmherstLila Gierasch, Distinguished Professor of Biochemistry and Molecular Biology, UMass AmherstLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1852572022-07-07T15:18:34Z2022-07-07T15:18:34ZHow the cell’s waste management systems might be targeted to treat cancer<figure><img src="https://images.theconversation.com/files/472399/original/file-20220704-17-lg7mjs.jpg?ixlib=rb-1.1.0&rect=0%2C97%2C7167%2C3944&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The proteasome is a cellular machine that chews up misfolded and unwanted proteins, and can promote cell death, making it an interesting target for cancer treatment. </span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Human organs and tissues are made up of millions of microscopic living units called cells. Over their lifespans, these cells accumulate waste products that include unwanted, misfolded and surplus proteins. </p>
<p>Waste management within these cells is a complex and critically important process that is essential for the proper functioning of organs within any given system. </p>
<p>The faulty functioning of cellular waste management machinery can lead to <a href="https://www.nature.com/articles/nrm1552">cancer and neurodegenerative diseases</a>. As researchers in immunology and oncology at the Université de Montréal, we want to explain how this process allows cells to adapt to adverse situations. </p>
<h2>Proteins are essential</h2>
<p>Every cell, tissue or organ contains thousands of different genes. Like a barcode, the genetic information in our DNA is read and translated, enabling the production of thousands of different proteins. Each protein has a precise 3D structure, a specific location and role within a cell type.</p>
<p>Proteins are functional units, similar to tiny machines, that carry out many processes within cells. These processes include the uptake of nutrients to ensure cell survival, cell respiration using oxygen to promote energy production, cell proliferation to replace dead cells and promote organ growth, and cell migration within tissue to place them in the right place at the right time. In short, proteins are responsible for the proper functioning of all cellular processes and allow cells to coexist in harmony within an organism.</p>
<p>Each of our cells has exactly the same set of genes, but each cell type has a unique protein profile. For example, one type of protein may be present and active in brain cells but absent in kidney or muscle cells. A protein might be essential for one organ but not for another, and their presence or absence within the cell is governed by a dynamic balance, orchestrated by mechanisms that regulate <a href="https://tbiomed.biomedcentral.com/articles/10.1186/1742-4682-7-25">protein production and elimination</a>.</p>
<h2>How cells decide which proteins to discard</h2>
<p>Over the past few decades, researchers have learned a great deal about how proteins are produced from genes via messenger RNA translation. This process involves a structure called the ribosome, the <a href="https://www.nature.com/collections/qmwjqzqcrb/">factory for protein production</a>. </p>
<p>Once produced, some proteins must be eliminated, either because of they are misfolded or because they have become redundant. Protein degradation is a highly co-ordinated and complex cellular process.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="figure" src="https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472806/original/file-20220706-17-lpo9ki.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Balance between protein synthesis by the ribosome and degradation by the proteasome.</span>
<span class="attribution"><span class="source">(El Bachir Affar, created on BioRender.com)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Our lab, among others, is interested in understanding how cells make the initial decision to eliminate proteins and then proceed to destroy them. To ensure their removal, cells set up a complex process of quality control and decision-making that <a href="https://www.nature.com/articles/nrm.2017.83">results in protein ubiquitination</a>. Ubiquitination is an essential process that consists of binding a small protein, called ubiquitin, to various unwanted protein targets. It occurs in all cells in the body.</p>
<p>The ubiquitination stamp allows the proteasome to recognize unwanted proteins and sort them for removal. The proteasome is a tiny cylindrical chamber made up of many specialized proteins, which act like molecular scissors to shred proteins. As an essential protein complex, there are multiple copies of the proteasome in all living cells. </p>
<p>The proteasome is responsible for the rapid and highly specific breakdown of unwanted, misfolded or surplus proteins. This process is extremely important for the proliferation and proper functioning of cells.</p>
<p>The aberrant or reduced degradation of cellular proteins can lead to a variety of diseases, including cancer and brain diseases. However, the exact mechanisms underlying the normal functions and pathological alterations associated with the proteasome are still poorly understood. </p>
<h2>Cells react to lack of nutrients</h2>
<p>We recently discovered that when the body is nutrient deprived, proteasomes assemble in the nucleus of cells to form <a href="https://www.nature.com/articles/s41467-021-27306-4">large structures called “bodies” or “foci.”</a> This aggregation of proteasomes can be observed in various cell types and is a general cellular response to nutrient deprivation. </p>
<p>Specifically, this phenomenon only occurs when cells are deprived of amino acids, the necessary building blocks of proteins. Consequently, there’s a tightly controlled balance between the supply of amino acids for protein synthesis and their break down by the proteasome.</p>
<p>The formation of proteasome foci amplifies this degradation process during periods of nutrient deprivation. Interestingly, our study also found that these foci promote cell death during severe nutrient stress, where the cell triggers molecular mechanisms that lead to its destruction, a form of cellular suicide. Although this cell death is detrimental to individual cells, the outcome could be beneficial for overall cell population that forms the tissues and organs.</p>
<p>In fact, the death of some cells in an organ, in response to nutrient deficiency, could initially decrease the competition between cells for limited resources. The release of cellular components, in particular nutrients, during cell death could help nearby cells survive. In addition, dying cells could send signals to summon specialized rescue cells to repair tissues.</p>
<p>We also found that some cells present in tumours have a reduced ability to form proteasome foci following nutrient deprivation, suggesting that these cells have acquired resistance to stress. The formation of these foci, in normal cells, could be a defence mechanism that promotes the death of cells that have undergone drastic changes caused by the absence of nutrients. </p>
<p>In this respect, inducing cellular suicide by forming proteasome foci in cells that have undergone changes that promote cancer development could be an interesting new approach to prevent cancer.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="figure" src="https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=704&fit=crop&dpr=1 600w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=704&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=704&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=884&fit=crop&dpr=1 754w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=884&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/472808/original/file-20220706-23-aorjb.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=884&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Proteasome foci and their involvement in cell death.</span>
<span class="attribution"><span class="source">(El Bachir Affar, created on BioRender.com)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Now that researchers have a better understanding of what affects proteasome function, they could target it for personalized cancer treatment, which requires the knowledge of all the molecular disruptors of cancer cells.</p>
<p>It is possible that cells that escaped death as a result of nutrient stress have nevertheless accumulated changes in their functioning that could make them vulnerable. We are currently working on this hypothesis. </p>
<p><em>Malik Affar co-authored this article and helped produce the graphics.</em></p><img src="https://counter.theconversation.com/content/185257/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>El Bachir Affar received funding from the Canadian Institutes of Health Research (CIHR).</span></em></p><p class="fine-print"><em><span>Clémence Messmer received funding from the Canadian Institutes of Health Research (CIHR).</span></em></p>Faulty cellular waste management machinery can lead to cancer and neurodegenerative diseases, but researchers are also targeting this machinery to treat these diseases.El Bachir Affar, Professeur en biochimie et oncologie moléculaire, Université de MontréalClémence Messmer, Etudiante au doctorat en biochimie, Université de MontréalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1820312022-06-16T18:39:25Z2022-06-16T18:39:25ZA celebrated AI has learned a new trick: How to do chemistry<figure><img src="https://images.theconversation.com/files/469287/original/file-20220616-12-dmwhkp.jpg?ixlib=rb-1.1.0&rect=2%2C0%2C1794%2C840&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Figuring out what makes some proteins glow requires an understanding of chemistry.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/128643624@N07/16652974221/">eLife - the journal</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Artificial intelligence has changed the way science is done by allowing researchers to analyze the massive amounts of data modern scientific instruments generate. It can find a needle in a million haystacks of information and, using <a href="https://www.techtarget.com/searchenterpriseai/definition/deep-learning-deep-neural-network">deep learning</a>, it can learn from the data itself. AI is accelerating advances in <a href="https://doi.org/10.1186/s13073-021-00965-0">gene hunting</a>, <a href="https://doi.org/10.1038/s41591-020-01197-2">medicine</a>, <a href="https://news.mit.edu/2021/drug-discovery-binding-affinity-0315">drug design</a> and <a href="https://doi.org/10.1038/nature25978">the creation of organic compounds</a>.</p>
<p>Deep learning uses algorithms, often neural networks that are trained on large amounts of data, to extract information from new data. It is very different from traditional computing with its step-by-step instructions. Rather, it learns from data. Deep learning is far less transparent than traditional computer programming, leaving important questions – what has the system learned, what does it know?</p>
<p>As a <a href="https://scholar.google.ca/citations?user=RpiSPiwAAAAJ&hl=en">chemistry professor</a> I like to design tests that have at least one difficult question that stretches the students’ knowledge to establish whether they can combine different ideas and synthesize new ideas and concepts. We have devised such a question for the poster child of AI advocates, AlphaFold, which has solved the <a href="https://doi.org/10.1146%2Fannurev.biophys.37.092707.153558">protein-folding problem</a>.</p>
<h2>Protein folding</h2>
<p>Proteins are present in all living organisms. They provide the cells with structure, catalyze reactions, transport small molecules, digest food and do much more. They are made up of long chains of amino acids like beads on a string. But for a protein to do its job in the cell, it must twist and bend into a complex three-dimensional structure, a process called protein folding. Misfolded proteins can lead to disease.</p>
<p>In his chemistry Nobel acceptance speech in 1972, <a href="https://www.nobelprize.org/prizes/chemistry/1972/anfinsen/biographical/">Christiaan Anfinsen</a> postulated that it should be possible to <a href="https://directorsblog.nih.gov/tag/christian-anfinsen/">calculate the three-dimensional structure of a protein from the sequence of its building blocks</a>, the amino acids. </p>
<p>Just as the order and spacing of the letters in this article give it sense and message, so the order of the amino acids determines the protein’s identity and shape, which results in its function. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="a graphic showing a thread-like line on the left and a coiled structure on the right" src="https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=266&fit=crop&dpr=1 600w, https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=266&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=266&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=334&fit=crop&dpr=1 754w, https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=334&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/462041/original/file-20220509-23-mkr8t2.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=334&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Within milliseconds of the exit of an amino acid chain (left) from the ribosome, it is folded into the lowest-energy 3D shape (right), which is required for the protein’s function.</span>
<span class="attribution"><span class="source">Marc Zimmer</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>Because of the inherent flexibility of the amino acid building blocks, a typical protein can adopt an estimated <a href="https://web.archive.org/web/20110523080407/http:/www-miller.ch.cam.ac.uk/levinthal/levinthal.html">10 to the power of 300 different forms</a>. This is a massive number, more than the <a href="https://educationblog.oup.com/secondary/maths/numbers-of-atoms-in-the-universe">number of atoms in the universe</a>. Yet within a millisecond every protein in an organism will fold into its very own specific shape – the lowest-energy arrangement of all the chemical bonds that make up the protein. Change just one amino acid in the hundreds of amino acids typically found in a protein and it may misfold and no longer work. </p>
<h2>AlphaFold</h2>
<p>For 50 years computer scientists have tried to solve the protein-folding problem – with little success. Then in 2016 <a href="https://www.deepmind.com/">DeepMind</a>, an AI subsidiary of Google parent Alphabet, initiated its <a href="https://www.deepmind.com/blog/alphafold-a-solution-to-a-50-year-old-grand-challenge-in-biology">AlphaFold</a> program. It used the <a href="https://www.rcsb.org/">protein databank</a> as its training set, which contains the experimentally determined structures of over 150,000 proteins. </p>
<p>In less than five years AlphaFold had <a href="https://www.deepmind.com/blog/alphafold-a-solution-to-a-50-year-old-grand-challenge-in-biology">the protein-folding problem beat</a> – at least the most useful part of it, namely, determining the protein structure from its amino acid sequence. AlphaFold does not explain how the proteins fold so quickly and accurately. It was a major win for AI, because it not only accrued huge scientific prestige, it also was a major scientific advance that could affect everyone’s lives.</p>
<p>Today, thanks to programs like <a href="https://www.deepmind.com/blog/alphafold-a-solution-to-a-50-year-old-grand-challenge-in-biology">AlphaFold2</a> and <a href="https://www.ipd.uw.edu/2021/07/rosettafold-accurate-protein-structure-prediction-accessible-to-all/">RoseTTAFold</a>, researchers like me can determine the three-dimensional structure of proteins from the sequence of amino acids that make up the protein – at no cost – in an hour or two. Before AlphaFold2 we had to crystallize the proteins and solve the structures using <a href="https://doi.org/10.1136%2Fmp.53.1.8">X-ray crystallography</a>, a process that took months and cost tens of thousands of dollars per structure. </p>
<p>We now also have access to the <a href="https://alphafold.ebi.ac.uk/">AlphaFold Protein Structure Database</a>, where Deepmind has deposited the 3D structures of nearly all the proteins found in humans, mice and more than 20 other species. To date they it has solved more than a million structures and plan to add another 100 million structures this year alone. Knowledge of proteins has skyrocketed. The structure of half of all known proteins is likely to be documented by the end of 2022, among them many new unique structures associated with new useful functions.</p>
<h2>Thinking like a chemist</h2>
<p>AlphaFold2 was not designed to predict how proteins would interact with one another, yet it has been able to model how individual proteins combine to <a href="https://www.nature.com/articles/d41586-022-00997-5">form large complex units composed of multiple proteins</a>. We had a challenging question for AlphaFold – had its structural training set taught it some chemistry? Could it tell whether amino acids would react with one another – a rare yet important occurrence?</p>
<p>I am a computational chemist interested in <a href="https://theconversation.com/fluorescent-proteins-light-up-science-by-making-the-invisible-visible-39272">fluorescent proteins</a>. These are proteins found in hundreds of marine organisms like jellyfish and coral. Their glow can be used <a href="https://theconversation.com/from-crispr-to-glowing-proteins-to-optogenetics-scientists-most-powerful-technologies-have-been-borrowed-from-nature-164459">to illuminate</a> and <a href="https://global.oup.com/academic/product/illuminating-disease-9780199362813?cc=us&lang=en&">study diseases</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="two multicolored blobs with bright lines inside them against a black background" src="https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=302&fit=crop&dpr=1 600w, https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=302&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=302&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=379&fit=crop&dpr=1 754w, https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=379&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/468852/original/file-20220614-12-84y9j5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=379&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Neurons expressing fluorescent proteins reveal the brain structures of two fruit fly larvae.</span>
<span class="attribution"><a class="source" href="https://images.nigms.nih.gov/pages/DetailPage.aspx?imageid2=6808">Wen Lu and Vladimir I. Gelfand, Feinberg School of Medicine, Northwestern University</a></span>
</figcaption>
</figure>
<p>There are 578 fluorescent proteins in the <a href="https://www.rcsb.org/search?request=%7B%22query%22%3A%7B%22type%22%3A%22group%22%2C%22nodes%22%3A%5B%7B%22type%22%3A%22group%22%2C%22nodes%22%3A%5B%7B%22type%22%3A%22group%22%2C%22nodes%22%3A%5B%7B%22type%22%3A%22terminal%22%2C%22service%22%3A%22text%22%2C%22parameters%22%3A%7B%22attribute%22%3A%22struct_keywords.pdbx_keywords%22%2C%22operator%22%3A%22contains_phrase%22%2C%22value%22%3A%22FLUORESCENT%20PROTEIN%22%7D%7D%5D%2C%22logical_operator%22%3A%22and%22%7D%5D%2C%22logical_operator%22%3A%22and%22%2C%22label%22%3A%22text%22%7D%5D%2C%22logical_operator%22%3A%22and%22%7D%2C%22return_type%22%3A%22entry%22%2C%22request_options%22%3A%7B%22paginate%22%3A%7B%22start%22%3A0%2C%22rows%22%3A25%7D%2C%22scoring_strategy%22%3A%22combined%22%2C%22sort%22%3A%5B%7B%22sort_by%22%3A%22score%22%2C%22direction%22%3A%22desc%22%7D%5D%7D%2C%22request_info%22%3A%7B%22query_id%22%3A%223e70236cf383b26f27688c5c79c6eb2b%22%7D%7D">protein databank</a>, of which 10 are “broken” and don’t fluoresce. Proteins rarely attack themselves, a process called autocatalytic posttranslation modification, and it is very difficult to predict which proteins will react with themselves and which ones won’t. </p>
<p>Only a chemist with a significant amount of fluorescent protein knowledge would be able to use the amino acid sequence to find the fluorescent proteins that have the right amino acid sequence to undergo the chemical transformations required to make them fluorescent. When we presented AlphaFold2 with the sequences of 44 fluorescent proteins that are not in the protein databank, <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267560">it folded the fixed fluorescent proteins differently from the broken ones</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="a diagram showing a light bulb on the left and the stem only of a light bulb on the right" src="https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=333&fit=crop&dpr=1 600w, https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=333&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=333&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=419&fit=crop&dpr=1 754w, https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=419&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/462050/original/file-20220509-12-fxhj9p.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=419&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">AlphaFold2 can take the amino acid sequence of fluorescent proteins (letters at the top) and predict their 3D barrel shapes (middle). This isn’t surprising. What is totally unexpected is that it can also predict which fluorescent proteins are ‘broken’ and can’t fluoresce.</span>
<span class="attribution"><span class="source">Marc Zimmer</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>The result stunned us: AlphaFold2 had learned some chemistry. It had figured out which amino acids in fluorescent proteins do the chemistry that makes them glow. We suspect that the protein databank training set and <a href="https://samfordubioinformatics.wordpress.com/bioinformatics-techniques/multiple-sequence-alignment/">multiple sequence alignments</a> enable AlphaFold2 to “think” like chemists and look for the amino acids required to react with one another to make the protein fluorescent. </p>
<p>A folding program learning some chemistry from its training set also has wider implications. By asking the right questions, what else can be gained from other deep learning algorithms? Could facial recognition algorithms find hidden markers for diseases? Could algorithms designed to predict spending patterns among consumers also find a propensity for minor theft or deception? And most important, is this capability – and <a href="https://www.technologyreview.com/2019/09/17/75427/open-ai-algorithms-learned-tool-use-and-cooperation-after-hide-and-seek-games/">similar leaps in ability</a> in other AI systems – desirable?</p><img src="https://counter.theconversation.com/content/182031/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marc Zimmer 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>The AI AlphaFold can figure out the three-dimensional protein structure any string of amino acids will become. It has now exceeded its training by figuring out what makes some proteins glow.Marc Zimmer, Professor of Chemistry, Connecticut CollegeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1830832022-05-17T18:59:18Z2022-05-17T18:59:18ZZinc is a metal essential to life – scientists have discovered a protein that helps keep cells alive when zinc levels are low<figure><img src="https://images.theconversation.com/files/463386/original/file-20220516-19-5mwuzq.jpg?ixlib=rb-1.1.0&rect=6%2C0%2C2111%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A protein called ZNG1 helps cells make use of zinc when stores of this essential nutrient are running low.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/zinc-mine-nugget-royalty-free-image/163263590">bagi1998/E+ via Getty Images</a></span></figcaption></figure><p>All living things, including people, need zinc in their diets. Getting too little of this <a href="https://www.ncbi.nlm.nih.gov/books/NBK493231/">essential metal</a> can impair growth and cause immune dysfunction, neurological disorders and cancer. Unfortunately, <a href="https://doi.org/10.1371/journal.pone.0050568">over 17% of the world’s population</a> is at risk for zinc deficiency. The World Health Organization considers this kind of <a href="https://www.who.int/news-room/fact-sheets/detail/malnutrition">micronutrient-related malnutrition</a> a leading contributor to disease and death.</p>
<p>After you eat a meal, zinc is taken up by the cells of your body. Inside each cell, zinc <a href="https://doi.org/10.1021/pr050361j">binds to proteins</a> to support their structure and function. Researchers estimate that up to 10% of all proteins need zinc to properly function. In this sense, a zinc protein without zinc is similar to a car without an engine or without screws holding it together: It either might not work or disassemble completely. </p>
<p>Despite zinc’s importance to human health, several aspects of how it supports cellular processes aren’t completely understood, including how it’s incorporated into the proteins essential for cell function in the first place. </p>
<p>As <a href="https://scholar.google.com/citations?user=aPlke6sAAAAJ&hl=en">researchers</a> <a href="https://scholar.google.com/citations?hl=en&user=Vc7LnewAAAAJ">who study</a> how metals work in biological systems such as the human body, we wanted to understand how zinc is distributed within a cell. Which proteins in the cell get zinc first, especially if there isn’t enough to go around? How does zinc get to these important proteins? </p>
<p>With our colleagues in the <a href="https://www.vumc.org/skaar-lab/laboratory-eric-skaar-phd-mph">Skaar Lab</a> at Vanderbilt University Medical Center and the <a href="https://giedroc.lab.indiana.edu/">Giedroc Lab</a> at Indiana University, we recently identified the <a href="http://dx.doi.org/10.1016/j.cell.2022.04.011">first known molecule</a> that delivers zinc to crucial proteins.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/NhSKyK2pYtk?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Zinc is a micronutrient you can’t live without.</span></figcaption>
</figure>
<h2>Delivering zinc to where it needs to go</h2>
<p>We started by investigating the molecules a cell produces when zinc levels are low. One family of proteins seemed particularly interesting because it looked as if it could be a potential <a href="https://doi.org/10.1016/s1074-5521(02)00156-4">metallochaperone</a>, a protein that selectively inserts metals, such as zinc and iron, into other proteins. We named this protein family ZNG1.</p>
<p>As it turns out, <a href="https://doi.org/10.1186/1471-2164-10-470">all vertebrates</a> have the gene that directs cells to produce ZNG1. While ZNG1 interacts with several proteins that bind zinc, one in particular, a protein called <a href="https://doi.org/10.1074/mcp.RA117.000360">METAP1</a>, caught our attention. METAP1 is known to activate many other essential proteins within the cell. Cells without functioning METAP proteins cannot survive. </p>
<p>We were intrigued by METAP1 because it interacts with ZNG1 proteins across species – among them zebrafish, mice and people. The finding suggests that the connection between these two proteins has been maintained for over 400 million years of evolution, meaning that the ZNG1’s supportive role in METAP1 function is important in all organisms that produce these proteins.</p>
<p>To study the role ZNG1 plays in animal health, we mutated the gene coding for ZNG1 in mice and zebrafish. When animals without ZNG1 were deprived of zinc, they either failed to grow or displayed developmental defects. Although the animals still have trace amounts of zinc available, they were unable to use the zinc correctly. This confirmed that ZNG1 helps METAP1 function properly, likely by helping it bind to or use zinc.</p>
<p>Using molecular imaging and other methods, we also observed that the energy-producing mitochondria of zinc-starved mouse cells without working ZNG1 proteins were not functioning correctly. This highlights ZNG1’s importance during periods of zinc deficiency by helping the cell allocate trace levels of this essential metal to the mitochondria and ultimately sustain cellular energy production.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Variety of zinc-rich foods laid out on a white table" src="https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/463692/original/file-20220517-15-ku0913.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Zinc-rich foods include a variety of meats, nuts and legumes, eggs and whole grains.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/foods-high-in-zinc-royalty-free-image/1189476693">bit245/iStock via Getty Images Plus</a></span>
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<h2>ZNG1 may hold the key to zinc deficiency</h2>
<p>We believe this research is just the first step to better understand how zinc metallochaperones maintain health and cellular function when zinc levels are low. </p>
<p>We hypothesize that ZNG1 supports the function of additional zinc-dependent proteins in the cell. In that way, ZNG1 would be the gatekeeper that distributes zinc to a network of essential proteins, ultimately allowing an organism to survive even if dietary zinc is limited.</p>
<p>This research paves the way to understanding how cells use zinc during periods of malnourishment or zinc deficiency. Further research on the proteins to which ZNG1 preferentially gives zinc when there isn’t enough available could help identify which cellular processes are most crucial to sustain life when zinc is limited. This in turn could help in the fight against the negative health consequences of zinc deficiency.</p><img src="https://counter.theconversation.com/content/183083/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andy Weiss receives funding from the American Heart Association Postdoctoral Fellowship and National Institutes of Health T32 and F32 fellowships.</span></em></p><p class="fine-print"><em><span>Caitlin Murdoch receives funding from National Institutes of Health T32 and F32 fellowships</span></em></p>While iron and calcium are the metals that get the most attention, zinc is also important for human health and function.Andy Weiss, Postdoctoral Fellow in Pathology, Microbiology and Immunology, Vanderbilt UniversityCaitlin Murdoch, Postdoctoral Researcher in Pathology, Microbiology and Immunology, Vanderbilt UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1808412022-04-11T16:12:30Z2022-04-11T16:12:30ZHow climate change stresses plants and alters their growth<figure><img src="https://images.theconversation.com/files/456690/original/file-20220406-18446-30zzt7.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4089%2C2035&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Climate change stresses plants, forcing them to turn off the cellular machinery that helps them grow.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Plants that inhabit the Earth have the incredible ability to grow continually for hundreds of years, and always towards the light of the sun, which provides them with the necessary energy to sprout. </p>
<p>At the source of this growth are changes in their environment, such as variations in light, temperature and humidity. But new stimuli from current climate changes are disrupting the normal growth of plants.</p>
<p>As a doctoral candidate in biochemistry at the University of Québec in Montréal, I am interested in the structure of plant proteins, and study the ways plants adapt to environmental stresses (drought, cold, deficiencies) at the molecular level in order to select more resilient variants for agriculture.</p>
<h2>The unmatched longevity of Pando</h2>
<p>The <a href="https://doi.org/10.1111/j.1365-294X.2008.03963.x">oldest forest on the planet</a>, called Pando, is 80,000 years old. Located in Utah it contains 40,000 genetically identical (clones) of quaking, or trembling, aspen trees. The colony communicates via a single root network.</p>
<p>Pando is considered to be the oldest living organism in the world. This colony originated <a href="https://www.science.org/doi/10.1126/sciadv.abj9496">30,000 years before the first <em>Homo sapiens</em> settled in Europe</a>. Pando, therefore, has borne witness to the totality of modern human life: <a href="https://bmcr.brynmawr.edu/2009/2009.04.66/">the empires of China and Rome</a>, <a href="https://www.canada.ca/en/department-national-defence/services/military-history/history-heritage/popular-books/aboriginal-people-canadian-military/world-wars.html">world wars</a> and also to humanity’s greatest feats.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/454832/original/file-20220328-15-281h9h.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">
<figcaption>
<span class="caption">Identical quaking aspen trees in Fishlake National Forest, Utah. At 80,000 years old, Pando is one of the oldest forests in the world.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>Nonetheless, the colony’s poplars have not grown nonstop for 80,000 years. On the one hand, their <a href="https://doi.org/10.1016/j.febslet.2011.03.051">development is orchestrated by the seasons</a>. On the other hand, they must control their developmental growth according to their needs and physical capacities to face external aggressions. By disrupting external environmental stimuli, the <a href="https://climate.nasa.gov/news/3124/global-climate-change-impact-on-crops-expected-within-10-years-nasa-study-finds/">current climate crisis directly</a> affects this normal growth regulation.</p>
<h2>The secret of plant growth is buried in the cell</h2>
<p>Plants form new organs such as leaves, <a href="https://doi.org/10.1016/S0070-2153(10)91002-8">flowers or roots, as needed to respond</a> to an external stimulus from the environment. For example, a change in the light exposure period during spring <a href="https://doi.org/10.1038/nature01636">triggers flowering</a>. </p>
<p>These stimuli target the DNA by activating specific genes for the development of each organ to form an adult plant. DNA is comparable to a dictionary of genes that contains the code for the physical peculiarities of the plant. These genes are the living words that must be read to express their meaning, and the <a href="https://doi.org/10.1146/annurev.arplant.49.1.127">information they contain</a>.</p>
<p>From seed germination to flower reproduction and the formation of stems, roots and leaves, all the stages of plant development and growth are due to a gene reading phenomenon. To read the genes, specific activators are needed for each of the words. If the environmental conditions change and are conducive to growth, then these activators position themselves at the front of the gene to read and express it, and lead to the <a href="https://doi.org/10.1038/nrg3291">specific growth of the organ encoded by the gene</a>.</p>
<figure class="align-center ">
<img alt="Diagram showing how growth activators can boost gene exptression." src="https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=254&fit=crop&dpr=1 600w, https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=254&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=254&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=319&fit=crop&dpr=1 754w, https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=319&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/457183/original/file-20220408-42486-hgjtw1.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=319&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Gene activation is linked to plant growth thanks to the actions of growth activators.</span>
<span class="attribution"><span class="source">(Souleïmen Jmii)</span></span>
</figcaption>
</figure>
<h2>DELLA proteins determine growth</h2>
<p>Plants cannot afford to grow indefinitely because of the <a href="https://doi.org/10.1016/S1672-6308(12)60045-6">energy costs of growth</a>. In addition, similar to animals that hibernate, plants stop growing during the winter, <a href="https://doi.org/10.1126/science.171.3966.29">becoming dormant</a> to survive the season. To do this, plants block the reading of genes thanks to safeguards called <a href="https://books.google.ca/books?hl=en&lr=&id=1u4eDAAAQBAJ">DELLA proteins</a>.</p>
<p>Found only in plants, these proteins have been constant throughout evolution. They are found particularly in <a href="https://doi.org/10.1111/j.1744-7909.2008.00703.x">mosses, ferns, conifers and flowering plants</a>. DELLAs are located in the cell nucleus, closest to DNA. They are produced continually and can block gene activators.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=320&fit=crop&dpr=1 600w, https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=320&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=320&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=402&fit=crop&dpr=1 754w, https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=402&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/457184/original/file-20220408-24-ozejr5.png?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">Growth blocking through the sequestration of activators, thanks to DELLA proteins.</span>
<span class="attribution"><span class="source">(Souleïmen Jmii)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>To mature, plants must destroy the DELLAs to release the activators. Plants have <a href="https://doi.org/10.1093/pcp/pcaa113">developed a system for labelling these proteins</a> to influence their destiny in the cell according to their needs. To degrade DELLAs, the cell adds a small protein, called ubiquitin, to its surface. Ubiquitin acts like a postage stamp that tells the cell to deliver the DELLAs to a new destination, a “cellular trash can,” where they will be degraded.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=168&fit=crop&dpr=1 600w, https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=168&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=168&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=211&fit=crop&dpr=1 754w, https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=211&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/457185/original/file-20220408-19484-8tprsb.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=211&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The degradation of DELLA proteins through ubiquitin labelling (Ub).</span>
<span class="attribution"><span class="source">(Souleïmen Jmii)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<h2>Climate stress blocks DELLA degradation</h2>
<p><a href="https://doi.org/10.1016/j.quaint.2006.11.004">Floods or droughts are increasing</a> all over the planet. Because of their immobility, <a href="https://books.google.ca/books?hl=en&lr=&id=sHH8DwAAQBAJ">plants cannot flee from these external attacks</a>. These new environmental parameters stress wild plants and agricultural crops by <a href="https://books.google.ca/books?hl=en&lr=&id=8ImiDwAAQBAJ">disrupting their growth</a>, meaning they must save their energy to survive rather than grow, and must not degrade the DELLA proteins. </p>
<p>This requires the DELLA proteins to be labelled in another way, through a cousin of ubiquitin, which scientists have named SUMO. SUMO replaces ubiquitin, and serves as a life buoy so that it does not get degraded.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=527&fit=crop&dpr=1 600w, https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=527&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=527&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=663&fit=crop&dpr=1 754w, https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=663&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/452022/original/file-20220314-131609-1iy1zlb.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=663&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Competition between ubiquitin (Ub) and SUMO at the same labelling site.</span>
<span class="attribution"><span class="source">(Souleïmen Jmii)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<p>In fact, SUMO labelling is done in the exact same place where ubiquitin should be added. The presence of SUMO no longer makes it possible to add ubiquitin, which allows plants to <a href="https://doi.org/10.3389/fpls.2019.01122">survive adverse climatic</a> events.</p>
<p>In the current climate crisis, it is important to investigate and understand this plant growth mechanism in the hope of maintaining sustainability in agricultural crops. Researchers are actively working to isolate or select plants capable of rapidly activating SUMO in order to grow under adverse environmental conditions.</p><img src="https://counter.theconversation.com/content/180841/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Souleïmen Jmii ne travaille pas, ne conseille pas, ne possède pas de parts, ne reçoit pas de fonds d'une organisation qui pourrait tirer profit de cet article, et n'a déclaré aucune autre affiliation que son organisme de recherche.</span></em></p>The climate crisis makes it important to investigate and understand the mechanisms of plant growth if we are to keep agricultural crops sustainable.Souleïmen Jmii, Ph.D Biologie structurale / Biochimie végétale, Université du Québec à Montréal (UQAM)Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1786842022-03-16T14:01:12Z2022-03-16T14:01:12ZWhy the cost of food is not yielding to Nigeria’s government policies<figure><img src="https://images.theconversation.com/files/451571/original/file-20220311-18-oa09dj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Threatened by insecurity, Nigerian farmers are increasingly abandoning their land, adding to food inflation</span> <span class="attribution"><span class="source">Photo by Kola Sulaimon/AFP via Getty Images</span></span></figcaption></figure><p>Nigeria has had a series of policies directed towards improving food supply at affordable prices. <a href="https://www.irglobal.com/article/impact-of-selected-agricultural-policies-and-intervention-programs-in-nigeria-1960-till-date/">Policies</a> have kept coming since the 1960s, including the <a href="https://www.sciencedirect.com/science/article/abs/pii/0309586X85900779">National Accelerated Food Production Programme of 1972</a> and the most recent – <a href="https://sciencenigeria.com/natip-policy-implementation-will-fast-track-agricultural-revolution-shehuri/">the National Agricultural Technology and Innovation Policy of 2021 to 2025</a>. </p>
<p>Essentially, these policies aimed at improving food production, through land reform, mass literacy, affordable funding, subsidised farm inputs, research, mechanisation, linkages and extension services. </p>
<p>Yet food prices have continued to rise. </p>
<p>I have previously <a href="https://theconversation.com/food-prices-in-nigeria-have-shot-through-the-roof-but-is-the-pandemic-to-blame-144028">written</a> about food price inflation in recent times, arguing that the COVID pandemic was not solely responsible. Other drivers included the dearth of capital, technology, infrastructural facilities and insurgency.</p>
<p>These factors still feature prominently as drivers of food inflation in Nigeria. They show that policies aimed at tackling food inflation have failed.</p>
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Read more:
<a href="https://theconversation.com/pandemic-underscores-flaws-in-nigerias-farming-and-food-supply-chains-156998">Pandemic underscores flaws in Nigeria's farming and food supply chains</a>
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<p>Well out of the COVID lockdown, <a href="https://www.statista.com/statistics/1118891/monthly-consumer-price-index-in-nigeria/">Nigeria’s consumer price index</a> has persistently increased. Between September 2020 and January 2021, there was an 8.13% increase, and a further rise of 8.07% by July 2021. By January 2022, the composite food index <a href="https://nairametrics.com/2022/02/25/fuel-scarcity-drives-food-prices-up-in-lagos-as-traders-lament-surge-in-transport-cost/">rose</a> by <a href="https://tradingeconomics.com/nigeria/food-inflation">17.13% year on year</a>, in spite of government efforts to stabilise food prices. </p>
<p>An example is the <a href="https://allafrica.com/stories/202201180515.html">rice pyramid initiative</a> by the federal government. In a bid to improve the local supply of rice and suppress prices, the government, through the Central Bank’s <a href="https://www.cbn.gov.ng/Out/2021/CCD/ABP%20Guidelines%20October%2013%202021%20-%20Final%20(002).pdf">Anchor Borrower’s fund</a>, supported local rice farmers to double their production capacity between 2015 and 2021. The output of that programme was stacked in pyramids displayed to the public in January 2022. Two months after this display of rice, the price of the staple food rose by 15%. </p>
<p>This is further evidence of some disconnection between policy and results. </p>
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<strong>
Read more:
<a href="https://theconversation.com/why-nigeria-should-first-support-rice-farmers-before-it-cuts-off-imports-108095">Why Nigeria should first support rice farmers before it cuts off imports</a>
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<p>The reason policies haven’t worked is that they lack substance and are not implemented appropriately. The danger is that food inflation will continue if these problems are not attended to. </p>
<p>The government needs to be more inclusive in formulating policies. From the start, it should involve those who will implement these policies. </p>
<h2>2022 food prices</h2>
<p>The price of a 50kg bag of rice rose by 17.58% from March 2021 to March 2022. A 100kg bag of beans became 5% more expensive in the same period. Tomatoes went up by <a href="https://www.statista.com/statistics/1121161/prices-of-selected-food-products-in-nigeria/">11.93%</a> for a 60kg basket and onions by 5.27%.</p>
<p>Most Nigerians can’t afford meat, a source of protein. The price of boneless beef rose 24.4%, frozen chicken prices 14.3%, and titus fish (mackerel) a whopping 34.5%. </p>
<p>Perhaps the most jarring are the <a href="https://nairametrics.com/2022/02/25/fuel-scarcity-drives-food-prices-up-in-lagos-as-traders-lament-surge-in-transport-cost/">45.5%</a> increase in the price of eggs and the 44.4% increase in the price of bread. The price of milk has increased by 50% and noodles by 24%. </p>
<p>Fruits are no longer within the reach of lower earners, as essential as they are for a balanced diet. Price increases have ranged from <a href="https://www.legit.ng/1401550-legitng-weekly-price-check-traders-reveal-top-seasonal-fruits-lagos-market.html">50% to 100%</a>.</p>
<p>The cost of <a href="https://punchng.com/transport-fares-jump-by-283-amid-rising-fuel-subsidy-nbs-report/">transport</a>, which is a key service required for food supply, increased by 283% between January 2017 and December 2021. This was without an official fuel pump price increase. </p>
<h2>What’s going wrong</h2>
<p>Obviously, the rate at which food prices have risen shows that they do not reflect the expected outcomes of government policies aimed at tackling the cost of food. </p>
<p>My <a href="https://theconversation.com/food-prices-in-nigeria-have-shot-through-the-roof-but-is-the-pandemic-to-blame-144028">previous research</a> highlighted some of the reasons, including inadequate financing, technological know-how and banditry.</p>
<p>A further factor is errors of policy. As I have found in my <a href="https://www.jstor.org/stable/10.5325/jafrideve.21.1.0096">research</a> that focused on the agribusiness value chain in sub-Saharan Africa, increased technology and land usage have not improved output. This indicated the possibility that digital technology introduced into the agriculture value chain was not being accessed by those who really needed them or would have used the technology. </p>
<p>Firstly, policy makers often lack the deep and intensive preliminary groundwork they need. Policies therefore lack substance. Policy formulation requires deeper work, broader scope, workability testing and the inclusion of those who will eventually implement the policy. These elements are often missing in the various policies Nigeria has designed to tackle rising food prices. </p>
<p>Secondly, policies are usually implemented in a way that is detached from the formulation process. This often flows from the fact that those who must implement the policy are not carried along in its formulation. Since they were not part of the formulation, what they require in implementation is often not taken into consideration. The policies become unworkable and unimplementable. </p>
<p>Another factor in food price inflation is Nigeria’s rate of population growth. Policies often fail to take adequate account of this. In 2022, the population <a href="https://www.macrotrends.net/countries/NGA/nigeria/population-growth-rate">growth rate</a> is expected to be 2.53%. </p>
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<strong>
Read more:
<a href="https://theconversation.com/nigerias-2022-census-is-overdue-but-preparation-is-in-doubt-177781">Nigeria's 2022 census is overdue but preparation is in doubt</a>
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<p>This explains the need to import enormous quantities to meet demand. For example, <a href="https://www.trade.gov/country-commercial-guides/nigeria-agriculture-sector">52%</a> of the rice demand was met from imports in 2018. For wheat, 99.7% of total demand is sourced from imports. About 70% of dairy products demand is imported. </p>
<p>This is why price volatility in the global commodity market directly affects domestic food prices in Nigeria. For instance, Russia’s war on Ukraine could destabilise international trade and the commodity market and this would have direct implications for food prices in Nigeria.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/how-russia-ukraine-conflict-could-influence-africas-food-supplies-177843">How Russia-Ukraine conflict could influence Africa's food supplies</a>
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<p>Though policies have acknowledged the need to produce more, the supply of food has not improved. One reason is these deficiencies in formulation and implementation of policy. </p>
<h2>How to get ahead</h2>
<p>The government needs to be more inclusive by incorporating its officials at state and local government levels as well as smallholder farmers and other key players in the agricultural value chain in the formulation of policies that they would later be expected to implement. </p>
<p>This improves understanding, enhances commitment and optimises the policy progress monitoring. </p>
<p>The country needs to import less food and produce more, sustainably. </p>
<p>Nigeria can achieve sufficient food supply at reasonable prices. It only requires policies that focus on relevant issues, and their sound execution.</p><img src="https://counter.theconversation.com/content/178684/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Folasade Bosede Adegboye 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>In spite of policies aimed at tackling food inflation, food prices in Nigeria have continued to rise.Folasade Bosede Adegboye, Senior Lecturer in Finance, Covenant UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1767232022-02-24T12:22:10Z2022-02-24T12:22:10ZBiofuel: how new microalgae technologies can hasten the end of our reliance on oil<figure><img src="https://images.theconversation.com/files/448064/original/file-20220223-25-1ev0gv8.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C6016%2C4016&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/photobioreactor-lab-algae-fuel-biofuel-industry-1427613143">Chokniti Khongchum/Shutterstock</a></span></figcaption></figure><p><a href="https://doi.org/10.1016/B978-0-12-800776-1.00002-9">Microalgae</a> have been used by the Chinese for <a href="https://doi.org/10.1016/B978-0-12-811405-6.00009-8">medicinal and nutritional</a> purposes for thousands of years in the belief they could cure almost any health condition. The idea that microalgae have extraordinary healing powers isn’t as far-fetched as some might think. Though the ancient Chinese believed the microalgae was responsible for health-improving benefits, we now know that it was in fact the biochemical compounds produced by these microscopic creatures that provided the “magic”.</p>
<p>There are approximately 100,000 species of microalgae, each with their own distinct set of properties. This diversity allows microalgae to flourish in almost every environment on Earth. Mostly they exist in aquatic habitats such as fresh or wastewater, but they have been found in moist soil – and even snowbanks too.</p>
<p>Microalgae are usually described as being green, and this is true for species such as <em>B. braunii</em> and <em>C. vulgaris</em>. But there are other species, such as <em>C. officinalis</em>, which is red or <em>F. spiralis</em>, which is brown. Each classification produces different types or quantities of biochemical compounds, making some more useful for certain applications than others.</p>
<p>Over the past few decades <a href="https://doi.org/10.1007/s11157-010-9214-7">research</a> has demonstrated the huge potential of microalgae, especially in the production of <a href="https://www.britannica.com/technology/biofuel">biofuel</a> – fuel that is created from plant material or animal waste. I wanted to <a href="https://www.sciencedirect.com/science/article/abs/pii/S0048969721061891">review this research</a> to provide a framework to establish the most suitable microalgae species for large-scale biofuel production that can ultimately rival oil and gas giants and reduce our reliance on fossil fuels.</p>
<h2>The magic of micoalgae</h2>
<p>Microalgae have a unique ability to convert sunlight and carbon dioxide into a wide range of biochemical compounds. Despite being classed as animals, they metabolise the same way as plants, producing oxygen to replenish what we humans consume. This cycle acts as a carbon capture system, whereby harmful CO₂ in the atmosphere is converted to useful oxygen. Microalgae also produce a wide range of other compounds found inside the cells, and these are what make microalgae so good at combating the effects of global warming.</p>
<p>Generally, the products from microalgae can be grouped into three classes: proteins, carbohydrates and lipids (fats). But <a href="https://fbscience.com/Scholar/articles/10.2741/S490">research</a> has found that there are several other high-value biochemical compounds that have significant applications in a wide range of different industries. For example, microalgae produce compounds known as carotenoids, more commonly known as dyes or pigments. These compounds are responsible for giving salmon its pink colour, as the food they eat contains high quantities of carotenoids.</p>
<p>Another high-value class of compounds are <a href="https://medlineplus.gov/ency/patientinstructions/000747.htm">polyunsaturated fatty acids</a> (PUFA). These compounds are part of the lipid family and play a vital role in supplying the cells with energy. Microalgae have been deemed one of the richest sources of these compounds, which help treat the <a href="https://pubs.acs.org/doi/10.1021/np050354%2B">effects of diabetes and arthritis</a>.</p>
<p>But how is it possible for these organisms to produce oil that can be used in cars? The petrol and diesel currently used is derived from crude oil that was formed millions of years ago from dead sea creatures. But modern biofuel is produced from living organisms on a real-time basis. </p>
<h2>How biofuel is produced</h2>
<p>Biofuel made from microalgae is currently one of the most promising fossil fuel alternatives to sustain the world’s energy demand. This is no easy task, especially having to compete with a highly profitable industry that has been established for more than a century. But unlike oil, which is non-renewable, biofuel is a renewable and sustainable source of fuel. Unfortunately, the economics of biofuel can’t yet compete with traditional fossil fuels. It all boils down to the bottom line, and currently the scale-up technology required isn’t here yet. </p>
<p>Microalgae don’t directly produce biofuel – they produce lipids (fats). To make biofuel these fats must be converted through a process known as <a href="https://doi.org/10.1016/B978-0-08-102728-8.00007-3">transesterification</a>. The process involves removing as much water as possible, known as dewatering, but this requires significant amounts of energy, resulting in high operating costs. As a result, the overall process becomes too expensive to compete with the oil and gas industry, despite its positive environmental impact.</p>
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<p>Economics aside, the future for microalgae cultivation and lipid extraction is extremely promising. The development of hybrid technologies will accelerate the global shift to reducing our reliance on fossil fuels. These include cell factories that use gold <a href="https://www.frontiersin.org/articles/10.3389/fbioe.2020.00990/full">nanoparticles</a> – subatomic particles similar to atoms that form the building blocks of physical matter – to increase production rates and increase efficiencies. </p>
<p>Another potential solution is a process known as “milking”. Traditional cultivation methods for microalgae mean they are destroyed after the cultivation period has ended, which limits the full potential of what each cell can offer. Just like milking a cow, the process can be repeated without killing the cow, and the same goes for microalgae. By repeatedly removing high-value compounds from the same culture of microalgae, the high production cost issues can be removed, resulting in a sustainable and scalable process for the future. </p>
<p>This would result in biofuel becoming cost competitive with current fossil fuels, helping to accelerate the shift towards alternative energy sources. Unfortunately, the prospect of competitive biofuel production has some way to go before it can rival fossil fuel prices and quantities. But these developing technologies have the potential to speed up the transition needed to help the world reach its 2050 emissions targets.</p><img src="https://counter.theconversation.com/content/176723/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Callum Russell 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>New developments in microalgae cultivation are helping to propel the potential of renewable biofuels to combat climate change.Callum Russell, Chemical Engineering PhD, University of the West of ScotlandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1726162022-02-18T03:17:49Z2022-02-18T03:17:49ZSunny side up: can you really fry an egg on the footpath on a hot day?<figure><img src="https://images.theconversation.com/files/436864/original/file-20211210-159504-1hfdr6i.jpg?ixlib=rb-1.1.0&rect=10%2C0%2C2385%2C1598&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Aahh, the Australian summer. When the temperatures top 40°C and only the bravest or most foolhardy would venture outside in bare feet, there’s a cherished old saying: “it’s so hot outside you could fry an egg on the footpath!” </p>
<p>But what does the science say? Does this claim stack up, or it half-baked?</p>
<p>To answer this question, we need to understand the chemicals inside an egg, what happens to them during the cooking process, and whether the footpath really gets hot enough to drive these chemical changes.</p>
<p>The first and most obvious point is that the egg’s yolk and white are <a href="https://www.compoundchem.com/2016/03/26/eggs/">chemically very different</a>. The white, which makes up about two-thirds of an egg’s mass, is roughly nine parts water and one part protein. The key here is that the protein’s structure changes if you heat it above a certain temperature.</p>
<p>About half the yolk’s mass is water, about a quarter is “fat”, about one-sixth is protein, and less than 5% is carbohydrates. The protein in the yolk is a completely different type of protein, but much like with the egg white, it’s how the protein responds to heat that gives us the texture of fried, scrambled, poached or hard-boiled eggs.</p>
<h2>Ok, so how does this work?</h2>
<p>We can think of proteins as being long chains of molecules called amino acids. In a raw egg, the protein is suspended in the watery mixture. The chain is curled up in a very particular way, held in shape by weak chemical bonds between different parts of the chain as it folds over on itself (the animation below shows the folded structure of ovalbumin, the main protein in egg white). This keeps it stable, and able to mix with the water. </p>
<p><img src="https://cdn.theconversation.com/static_files/files/1895/protein_animation.gif?1639369721" width="100%"></p>
<p>But once it’s heated up, the heat energy starts to break these weak chemical bonds and the chain begins to uncurl, rearrange itself and stick together again in a completely different way.</p>
<p>Suddenly, these reconfigured clumps of protein molecules are no longer water-soluble, and so they solidify. This is why eggs get harder if you cook them for longer.</p>
<p>This process is called <em>denaturation</em>, and it can happen to any type of protein. Denaturation is what turns milk into curds and whey, and changes the texture of meat as it cooks.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/kitchen-science-the-chemistry-behind-amazing-meringue-and-perfect-cappuccino-64670">Kitchen Science: the chemistry behind amazing meringue and perfect cappuccino</a>
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<p>For eggs, denaturation begins at around 60°C, but this is likely to only slightly cook the egg whites, and the yolk will <a href="https://blogs.unimelb.edu.au/sciencecommunication/2014/08/18/the-perfect-egg/">not turn solid at all</a>.</p>
<p>As you slowly go from 60°C to 70°C, however, there is more heat energy available and all of the egg’s proteins now begin to denature. The egg white begins to turn gel-like and eventually rubbery, and the yolk begins to solidify into a viscous goo, before eventually becoming solid or even slightly powdery in texture.</p>
<p>Get the temperature right and this process unfolds nice and gradually, which means with a bit of practice you can get your eggs to turn out exactly how you like them.</p>
<h2>Righto, so is a footpath hot enough for this?</h2>
<p>That leaves us with the crucial question: how hot does pavement get on a scorching summer day? Does it reach the almost 70°C you would need for a footpath fry-up?</p>
<p>This depends on a lot of factors, including the air temperature, direct sunlight, the footpath material and even its colour. Black-painted concrete, for example, absorbs more heat than white or unpainted concrete. </p>
<p>All in all, at the peak of these conditions, on a boiling summer day, a footpath can potentially just about reach the right temperature. But sadly, that’s still not enough to sizzle an egg.</p>
<p>First, concrete is a poor conductor, so it will transfer heat to the egg much more slowly than a metal frying pan. Second, after cracking the egg onto the footpath, the footpath’s temperature will drop slightly.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/why-you-cant-fry-eggs-or-testicles-with-a-cellphone-70636">Why you can’t fry eggs (or testicles) with a cellphone</a>
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</em>
</p>
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<p>So if you were hoping for a cheap way to cook your sunny-side-up eggs on the footpath this summer, you might be disappointed. It’s much wiser to head back indoors to the kitchen. Your egg will be hotter, and you’ll be much cooler.</p><img src="https://counter.theconversation.com/content/172616/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Chris Thompson 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>It’s too hot for bare feet, but that doesn’t mean you can cook a fry-up on the path outside your house. A frying pan is a much better tool for the job, because it conducts heat far more efficiently.Chris Thompson, Associate Dean (Education) - Science, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1707722022-01-24T13:31:35Z2022-01-24T13:31:35ZHow mRNA and DNA vaccines could soon treat cancers, HIV, autoimmune disorders and genetic diseases<figure><img src="https://images.theconversation.com/files/441838/original/file-20220120-9603-u5kjhi.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3840%2C2160&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Nucleic acid vaccines use mRNA to give cells instructions on how to produce a desired protein.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/messenger-rna-or-mrna-strand-3d-rendering-royalty-free-image/1295693748?adppopup=true">Libre de Droit/iStock via Getty Images</a></span></figcaption></figure><p><em>The two most successful coronavirus vaccines developed in the U.S. – the Pfizer and Moderna vaccines – are both mRNA vaccines. The idea of using genetic material to produce an immune response has opened up a world of research and potential medical uses far out of reach of traditional vaccines. <a href="https://scholar.google.com/citations?user=eNprtJEAAAAJ&hl=en&oi=ao">Deborah Fuller is a microbiologist</a> at the University of Washington who has been studying genetic vaccines for more than 20 years. We spoke to her about the <a href="https://theconversation.com/mrna-vaccines-asteroid-missions-and-collaborative-robots-what-to-watch-in-science-in-2022-podcast-174413">future of mRNA vaccines for The Conversation Weekly podcast</a>.</em> </p>
<p><em>Below are excerpts from that conversation which have been edited for length and clarity.</em> </p>
<h2>How long have gene-based vaccines been in development?</h2>
<p>This type of vaccine has been in the works for <a href="https://doi.org/10.1038/356152a0">about 30 years</a>. Nucleic acid vaccines are based on the idea that DNA makes RNA and then RNA makes proteins. For any given protein, once we know the genetic sequence or code, we can design an mRNA or DNA molecule that prompts a person’s cells to start making it. </p>
<p>When we first thought about this idea of putting a genetic code into somebody’s cells, we were studying both DNA and RNA. The mRNA vaccines did not work very well at first. They <a href="https://www.nature.com/articles/nrd.2017.243">were unstable</a> and they caused pretty strong immune responses that were <a href="https://doi.org/10.1038/nrd.2017.243">not necessarily desirable</a>. For a very long time DNA vaccines took the front seat, and the very <a href="https://dx.doi.org/10.1038%2Fnrg2432">first clinical trials were with a DNA vaccine</a>.</p>
<p>But about seven or eight years ago, mRNA vaccines started to take the lead. Researchers solved a lot of the problems – notably the <a href="https://doi.org/10.1038/mt.2008.200">instability</a> – and discovered <a href="https://doi.org/10.1073/pnas.1209367109">new technologies to deliver mRNA</a> into cells and ways of modifying the coding sequence to <a href="https://doi.org/10.1038/nrd.2017.243">make the vaccines a lot more safe to use in humans</a>.</p>
<p>Once those problems were solved, the technology was really poised to become a revolutionary tool for medicine. This was just when COVID-19 hit. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A scanning electron microscope image of blue lumpy sphere of a T cell." src="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.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>
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<span class="caption">DNA and mRNA vaccines are much better at producing T cells than are normal vaccines.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/niaid/5950870236/in/photolist-2mEvEdt-a4RLoY-2mEn5zV-bo51Vz-MSuhWU-bo5rrZ-2kLN4tU-2kLN4uF-SjQFf7-2ewYf1r-rx2LVN-su1wdR-2j4icVg-2iKmbjG-2mfURRa-a7RGBX-xvJ8TV-2hVm2XZ-2hVhUoD-2iKjyJj-51svu9-51ojDi-51sByA-ni2rkv-2iKgNob-Fwbp7g-EpF3rg-HKERqY-51sBff-51ojop-2mfSkUp-2mfMhmB-2mfLV8V-2mfQZZp-2mfLTAG-2mfVWsD-2mfRRSs-2mfQJMF-2mfUQ1m-2mfSjPU">NIAID/NIH via Flickr</a></span>
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<h2>What makes nucleic acid vaccines different from traditional vaccines?</h2>
<p>Most vaccines induce antibody responses. Antibodies are the primary immune mechanism that blocks infections. As we began to study nucleic acid vaccines, we discovered that because these vaccines are expressed within our cells, they were also <a href="https://www.gavi.org/vaccineswork/what-are-nucleic-acid-vaccines-and-how-could-they-be-used-against-covid-19#:%7E:text=Nucleic%20acid%20vaccines%20use%20genetic,immune%20response%20against%20it">very effective at inducing a T cell response</a>. This discovery really prompted additional thinking about how researchers could use nucleic acid vaccines not just for infectious diseases, but also for immunotherapy to treat cancers and chronic infectious diseases – like HIV, hepatitis B and herpes – as well as autoimmune disorders and even for gene therapy.</p>
<h2>How can a vaccine treat cancers or chronic infectious diseases?</h2>
<p>T cell responses are very important for identifying cells infected with chronic diseases and aberrant cancer cells. They also play a big role in eliminating these cells from the body.</p>
<p>When a cell becomes cancerous, it <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neoantigen">starts producing neoantigens</a>. In normal cases, the immune system detects these neoantigens, recognizes that something’s wrong with the cell and eliminates it. The reason some people get tumors is that their immune system isn’t quite capable of eliminating the tumor cells, so the cells propagate.</p>
<p>With an mRNA or DNA vaccine, the goal is to make your body better able to recognize the very specific neoantigens the cancer cell has produced. If your immune system can recognize and see those better, it will <a href="https://doi.org/10.1038/d41586-019-03072-8">attack the cancer cells and eliminate them from the body</a>. </p>
<p>This same strategy can be applied to the <a href="https://www.genengnews.com/insights/immunotherapy-targets-emerging-infectious-diseases/">elimination of chronic infections</a> like HIV, hepatitis B and herpes. These viruses infect the human body and stay in the body forever unless the immune system eliminates them. Similar to the way nucleic acid vaccines can train the immune system to eliminate cancer cells, they can be used to train our immune cells to recognize and eliminate chronically infected cells. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A syringe inserted into a vaccine vial." src="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&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">There are dozens of ongoing trials testing the efficacy of mRNA or DNA vaccines to treat cancers or chronic diseases.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/syringe-and-coronavirus-vaccine-royalty-free-image/1287271384?adppopup=true">Stefan Cristian Cioata/Moment via Getty Images</a></span>
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<h2>What is the status of these vaccines?</h2>
<p>Some of the very first clinical trials of nucleic acid vaccines happened in the 1990s and <a href="https://doi.org/10.1073/pnas.90.23.11307">were for cancer</a>, particularly for <a href="https://doi.org/10.1038/nrg2432">melanoma</a>.</p>
<p>Today, there are a <a href="https://www.cancernetwork.com/view/messenger-rna-vaccines-beckoning-of-a-new-era-in-cancer-immunotherapy">number of ongoing mRNA clinical trials</a> for the treatment of melanoma, prostate cancer, ovarian cancer, breast cancer, leukemia, glioblastoma and others, and there have been some promising outcomes. Moderna recently announced promising results with its phase 1 trial using mRNA to <a href="https://www.businesswire.com/news/home/20211112005897/en/Moderna-Announces-Presentation-of-Interim-Data-from-Phase-1-Study-of-mRNA-Triplet-Program-at-2021-SITC-Annual-Meeting">treat solid tumors and lymphoma</a></p>
<p>There are also a lot of ongoing trials looking at cancer DNA vaccines, because DNA vaccines are <a href="https://doi.org/10.1186/s13046-019-1154-7">particularly effective in inducing T cell responses</a>. A company called Inovio recently demonstrated a significant impact on cervical cancer caused by human papilloma virus in women <a href="https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Highlights-Key-Updates-on-Phase-3-Program-for-VGX-3100-its-DNA-based-Immunotherapy-for-the-Treatment-of-Cervical-HSIL-Caused-by-HPV-16-andor-HPV-18/default.aspx">using a DNA vaccine</a>.</p>
<h2>Can nucleic acid vaccines treat autoimmune disorders?</h2>
<p>Autoimmune disorders occur when a person’s immune cells are actually attacking a part of the person’s own body. An example of this is multiple sclerosis. If you have multiple sclerosis, your <a href="https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269">own immune cells are attacking myelin</a>, a protein that coats the nerve cells in your muscles.</p>
<p>The way to eliminate an autoimmune disorder is to modulate your immune cells to prevent them from attacking your own proteins. In contrast to vaccines, whose goal is to stimulate the immune system to better recognize something, treatment for autoimmune diseases seeks to dampen the immune system so that it stops attacking something it shouldn’t. Recently, researchers created an mRNA vaccine encoding a myelin protein with slightly tweaked genetic instructions to prevent it from stimulating immune responses. Instead of activating normal T cells that increase immune responses, the vaccine caused the body to <a href="https://doi.org/10.1126/science.aay3638">produce T regulatory cells</a> that specifically suppressed only the T cells that were attacking myelin.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram showing DNA turning into mRNA which turns into proteins." src="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=618&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=618&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=618&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=776&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=776&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=776&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many diseases result when people have mutations or are missing certain genes, and nucleic acid vaccines could act as temporary replacements for the missing genes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/mrna-and-protein-synthesis-difference-royalty-free-illustration/1323350905?adppopup=true">ttsz/iStock via Getty Images</a></span>
</figcaption>
</figure>
<h2>Any other applications of the new vaccine technology?</h2>
<p>The last application is actually one of the very first things that researchers thought about using DNA and mRNA vaccines for: gene therapy. Some people are born missing certain genes. The goal with gene therapy is to supply cells with the missing instructions they need to produce an important protein. </p>
<p>[<em>Over 140,000 readers rely on The Conversation’s newsletters to understand the world.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140ksignup">Sign up today</a>.]</p>
<p>A great example of this is cystic fibrosis, a genetic disease caused by mutations in a single gene. Using DNA or an mRNA vaccine, researchers are investigating the feasibility of essentially replacing the missing gene and allowing someone’s body to <a href="https://www.cff.org/gene-therapy-cystic-fibrosis#rna-therapy">transiently produce the missing protein</a>. Once the protein is present, the symptoms could disappear, at least temporarily. The mRNA would not persist very long in the human body, nor would it integrate into people’s genomes or change the genome in any way. So additional doses would be needed as the effect wore off.</p>
<p>Research has shown that this concept is feasible, but it still needs some work.</p><img src="https://counter.theconversation.com/content/170772/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Deborah Fuller is co-founder of Orlance, Inc, a biotechnology company developing a needle free technology to deliver RNA and DNA vaccines. She also serves as a scientific advisor for HDT Bio, a biotechnology company developing RNA vaccines for COVID19 and other infectious diseases; scientific advisor for Abacus, Inc., a biotechnology company developing cancer vaccines and scientific advisor for SQZ Biotech, a biotechnology company developing cell-based therapies for cancer and infectious diseases. She is also serving as a vaccine expert for Wilmerhale on legal matters. She receives funding supporting basic and translational research in RNA and DNA vaccines from the National Institutes of Health.</span></em></p>DNA and mRNA vaccines produce a different kind of immune response than traditional vaccines, allowing researchers to tackle some previously unsolvable problems in medicine.Deborah Fuller, Professor of Microbiology, School of Medicine, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1714282022-01-05T17:51:37Z2022-01-05T17:51:37ZFive chemistry research projects that you can get involved in<figure><img src="https://images.theconversation.com/files/432723/original/file-20211118-19-15kkq9z.jpg?ixlib=rb-1.1.0&rect=360%2C36%2C5637%2C3953&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The RiverDip experiment is one of many citizen science projects out there.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/gloved-hand-takes-water-into-test-2032008299">Natallia Boroda/Shutterstock</a></span></figcaption></figure><p>Sometimes the most powerful tool in research is people spending a few minutes to record their observations while going about their daily lives. An early example of this sort of “citizen science” is the <a href="https://www.rspb.org.uk/our-work/rspb-news/news/stories/11-big-garden-birdwatch-fascinating-facts/">annual garden bird watch</a> in the UK, which has been running since 1978 and is organised by the nature conservation charity, <a href="https://www.rspb.org.uk/">RSBP</a>. All you need do to take part is spending an hour watching the wildlife in you garden or local park.</p>
<p>Today, citizen science projects are increasingly popular, with people surveying and monitoring everything from <a href="https://www.cocorahs.org/">weather events</a>, <a href="https://easin.jrc.ec.europa.eu/easin/CitizenScience/Projects">invasive plant species</a> and <a href="https://www.coleoptera.org.uk/coccinellidae/home">ladybirds</a> to <a href="https://exoplanets.nasa.gov/citizen-science/">planets</a> orbiting stars other than our Sun. </p>
<p>As the citizen science field has developed, boundaries have blurred and scientists have begun involving citizens as more active researchers – carrying out important experiments, collecting environmental measurements and generating data.</p>
<p>Here are five just such projects with a distinctly chemical theme. </p>
<h2>RiverDip</h2>
<p>Our new paper, <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260102">published in PLOS One</a>, presents the results of such a project, <a href="https://riverdip.com/">RiverDip</a>, which enables and encourages citizens to monitor the chemical health of their local waterways. </p>
<p>This involves monitoring phosphates and nitrates – essential nutrients, making up the basis of agricultural fertilisers. But if they run off fields and into waterways they cause significant problems. </p>
<p>The fertilisers encourage rapid growth of algae and weeds, which form dense green mats on the surface of waterways. These block out the light to other plants. What’s more, later, when they rot they use up some of the dissolved oxygen in the water, resulting in deoxygenation that harms other aquatic plants and animals.</p>
<figure class="align-center ">
<img alt="Schematic picture showing the steps of the RiverDip experiment." src="https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=296&fit=crop&dpr=1 600w, https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=296&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=296&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=372&fit=crop&dpr=1 754w, https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=372&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/431245/original/file-20211110-27-uowlfb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=372&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The steps of the RiverDip experiment.</span>
</figcaption>
</figure>
<p>RiverDip was developed as part of the EU-funded <a href="https://northsearegion.eu/sullied-sediments/">Sullied Sediments</a> project as a means to allow citizens to monitor the phosphate levels in waterways. We provided interested folk with paper-based sensors that change colour in the presence of phosphates. The measurement takes just three minutes. After it’s done, volunteers upload their results via a bespoke mobile app. </p>
<p>Together we have collected hundreds of measurements and begun to <a href="https://riverdip.com/map">map phosphate levels</a> across the Europe’s North Sea Region, consisting of countries including the Scandinavian nations, England, the Netherlands and Germany. Having lots of measurements from different seasons will help us to understand how nutrient levels change over time, and we are currently looking for interested volunteer groups to continue this project. </p>
<h2>The Big Compost experiment</h2>
<p>If you like rummaging in the garden, this one is for you. Lots of packaging is now labelled as biodegradable or compostable, but what does this really mean and do these products really break down in a domestic compost bin? <a href="https://www.bigcompostexperiment.org.uk/">The Big Compost experiment</a> investigates new ways of reducing plastic waste, asking participants to check how well biodegradable and compostable packaging breaks down.</p>
<iframe width="100%" height="315" src="https://www.youtube.com/embed/7KnessNvHrE" title="YouTube video player" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture" allowfullscreen=""></iframe>
<p>You can help answer these questions by simply bagging up materials that claim to be compostable (such as some tea bags, carrier bags and disposable cups), placing them in your compost heap and then observing what happens. You can record your results <a href="https://www.bigcompostexperiment.org.uk/">via the experiment’s home page</a>.</p>
<h2>Fold-at-home</h2>
<p>If you fancy something easier and less messy, there are some great projects which you can contribute to from the comfort of your sofa.</p>
<p>Proteins are the molecular machines that govern all the chemical processes and interactions that make up a living organism. And like any machine (be it a proteins or a motor car), they help to understand how all the parts fit together when designing modifications and upgrades. So understanding proteins’ incredibly complex structures, how they interact with each other and potential drugs provides pharmaceutical developers with critical information that allows them to design more effective therapeutics. But modelling this requires vast amounts of computing power. One approach would therefore be to use vast amounts of money to build a computer dedicated to solving this problem. </p>
<p>But scientists have realised that, alternatively, you could ask people to contribute spare computing power of their home PCs to form a giant global supercomputer. All you need do is install the <a href="https://foldingathome.org/">Fold-at-home</a> software on your computer and when you nip off to make a cup of tea or plug into the television, your computer gets to work on folding proteins, which could lead to the development of COVID drugs or cancer therapies.</p>
<h2>Fold-It</h2>
<p>If puzzles and computer games are more your cup of tea, you may enjoy <a href="https://fold.it/">Fold-it</a>. This project attempts to predict the structure of a protein, but this time it needs a bit more human input. It takes advantage of people’s puzzle-solving intuitions when playing games competitively and challenges them to fold the best proteins. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Screen shot from the Fold-It game." src="https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=461&fit=crop&dpr=1 600w, https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=461&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=461&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=580&fit=crop&dpr=1 754w, https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=580&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/430840/original/file-20211108-15-tizbtw.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=580&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Screen shot from the Fold-It project.</span>
<span class="attribution"><span class="source">Animation Research Labs, University of Washington</span></span>
</figcaption>
</figure>
<p>This information helps researchers understand if human pattern recognition and puzzle solving abilities are better than current computer programs. Such information could be used to develop new computer strategies to predict protein structures even faster. This is really helpful as understanding how proteins fold and interact enables scientists to develop new proteins to help combat diseases such as Alzheimer’s and HIV/AIDS. </p>
<h2>Sensor community</h2>
<p>The <a href="https://sensor.community/en/">sensor community</a> project aims to build a network of small sensors to collect and openly share environmental data such as the <a href="https://sensor.community/en/campaign/no2/">nitrogen dioxide air pollution</a> generated by internal combustion engines and burning of fossil fuels. </p>
<p>Currently, the community has constructed and deployed nearly 14,000 active sensors in 69 countries, all of which are returning data in real time. To take part in this project, you build sensors using kits developed by the researchers and place them somewhere. The project has different communities that focus on different aspects of environmental pollution (including noise).</p>
<p>Getting involved in these kind of citizen sciences projects can be a great way to have a positive impact on the world, collecting large volumes of data that enable us to understand our impact on the planet.</p><img src="https://counter.theconversation.com/content/171428/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Lorch receives funding from European Regional Development Fund through the Interreg VB North Sea Region Programme</span></em></p><p class="fine-print"><em><span><a href="mailto:samantha.richardson-2016@hull.ac.uk">samantha.richardson-2016@hull.ac.uk</a> receives funding from European Regional Development Fund through the Interreg VB North Sea Region Programme. </span></em></p>Getting involved in citizen science projects can be a great way to have a positive impact on the world.Mark Lorch, Professor of Science Communication and Chemistry, University of HullSamantha Richardson, Lecturer of Analytical Chemistry, University of HullLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1732092022-01-05T13:47:58Z2022-01-05T13:47:58ZWhen researchers don’t have the proteins they need, they can get AI to ‘hallucinate’ new structures<figure><img src="https://images.theconversation.com/files/438742/original/file-20211221-129369-1f6d9kk.jpg?ixlib=rb-1.1.0&rect=600%2C104%2C869%2C650&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">De novo protein design with deep learning can open new doors for medicine and many other fields.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/human-ace2-receptor-molecule-royalty-free-illustration/1227506538"> Kateryna Kon/Science Photo Library via Getty Images</a></span></figcaption></figure><p>All living organisms use proteins, which encompass a vast number of complex molecules. They perform a wide array of functions, from allowing plants to <a href="https://www.energy.gov/science/articles/photosynthesis-gathering-sunshine-world-s-smallest-antennas">use solar energy for oxygen production</a> to helping your <a href="https://www.livescience.com/antibodies.html">immune system</a> fight against pathogens to letting your <a href="https://www.britannica.com/science/protein/The-muscle-proteins">muscles</a> perform physical work. <a href="https://doi.org/10.1007/978-1-61779-921-1_1">Many drugs</a> are also based on proteins.</p>
<p>For many areas of biomedical research and drug development, however, there are no natural proteins that can serve as suitable starting points to build new proteins. Researchers designing new drugs to <a href="https://www.doi.org/10.1126/science.abd9909">prevent COVID-19 infection</a>, or developing proteins that can <a href="https://doi.org/10.1038/s41586-019-1432-8">turn genes on or off</a> or <a href="https://www.doi.org/10.1126/science.aay2790">turn cells into computers</a>, had to create new proteins from scratch.</p>
<p>This process of <a href="https://doi.org/10.1038/nature19946">de novo protein design</a> can be difficult to get right. <a href="https://scholar.google.com/citations?user=Hp8zwAgAAAAJ&hl=ru">Protein engineers like me</a> have been trying to figure out ways to more efficiently and accurately design new proteins with the properties we need.</p>
<p>Luckily, a form of artificial intelligence called <a href="https://www.techtarget.com/searchenterpriseai/definition/deep-learning-deep-neural-network">deep learning</a> may provide an elegant way to create proteins that did not exist previously – <a href="https://doi.org/10.1038/s41586-021-04184-w">hallucination</a>.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/PJLT0cAPNfs?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">New proteins created from scratch can be deployed to tackle a wide range of environmental and medical challenges.</span></figcaption>
</figure>
<h2>Designing proteins from scratch</h2>
<p>Proteins are made up of hundreds to thousands of smaller building blocks called <a href="https://www.britannica.com/science/amino-acid">amino acids</a>. These amino acids are connected to one another in long chains that fold up to form a <a href="https://www.britannica.com/science/protein">protein</a>. The order in which these amino acids are connected to one another determines each protein’s unique structure and function.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of the four levels of protein structure." src="https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1046&fit=crop&dpr=1 600w, https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1046&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1046&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1315&fit=crop&dpr=1 754w, https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1315&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/423442/original/file-20210927-27-3uc4g3.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1315&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Proteins are composed of amino acid chains that fold into a protein.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Main_protein_structure_levels_en.svg">LadyofHats/Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>The biggest challenge protein engineers face when designing new proteins is coming up with a protein structure that will perform a desired function. To get around this problem, researchers typically create design templates based on naturally occurring proteins with a similar function. These templates have instructions on how to create the unique folds of each particular protein. However, because a template must be created for each individual fold, this strategy is time-consuming, labor-intensive and limited by what proteins are available in nature.</p>
<p>Over the past few years, various research groups, <a href="https://doi.org/10.1073/pnas.1914677117">including</a> the <a href="https://www.bakerlab.org/">lab I work in</a>, have developed a number of dedicated <a href="https://towardsdatascience.com/a-laymans-guide-to-deep-neural-networks-ddcea24847fb">deep neural networks</a> – computer programs that use multiple processing layers to “learn” from input data to make predictions about a desired output.</p>
<p>When the desired output is a new protein, millions of parameters describing different facets of a protein are put into the network. What’s predicted is a randomly chosen sequence of amino acids mapped onto the most probable 3D structure that sequence would take.</p>
<p>Network predictions for a random amino acid sequence are blurry, meaning the final structure of the protein is not very clear-cut, while both naturally occurring proteins and proteins built from scratch produce much more well-defined protein structures.</p>
<h2>Hallucinating new proteins</h2>
<p>These observations hint at one way that new proteins can be generated from scratch – by tweaking random inputs to the network until predictions yield a well-defined structure.</p>
<p>The <a href="https://doi.org/10.1038/s41586-021-04184-w">protein generation method</a> <a href="https://www.ipd.uw.edu/">my colleagues</a> and I developed is conceptually similar to <a href="https://towardsdatascience.com/everything-you-ever-wanted-to-know-about-computer-vision-heres-a-look-why-it-s-so-awesome-e8a58dfb641e">computer vision</a> methods such as <a href="https://ai.googleblog.com/2015/06/inceptionism-going-deeper-into-neural.html">Google’s DeepDream</a>, which finds and enhances patterns in images. </p>
<p>These methods work by taking networks trained to recognize human faces or other patterns in images, like the shape of an animal or an object, and inverting them so that they learn to recognize these patterns where they don’t exist. In DeepDream, for example, the network is given arbitrary input images that are adjusted until the network can recognize a face or some other shape in the image. While the final image doesn’t look much like a face to a person looking at it, it would to the neural network.</p>
<p>The products of this technique are often referred to as <a href="https://www.americanscientist.org/article/computer-vision-and-computer-hallucinations">hallucinations</a>, and this is what we call our designed proteins, too.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/hnT-P3aALVE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Deep neural networks can also learn how to hallucinate images from words.</span></figcaption>
</figure>
<p><a href="https://doi.org/10.1038/s41586-021-04184-w">Our method</a> starts by passing a random amino acid sequence through a deep neural network. The resulting predictions are initially blurry, with unclear structures, as expected for random sequences. Next, we introduce a mutation that changes one amino acid in the chain into a different one and pass this new sequence through the network again. If this change gives the protein a more defined structure, then we keep the amino acid and we introduce another mutation into the sequence.</p>
<p>With each repetition of this process, the proteins get closer and closer to the real shape they would take if they were produced in nature. Thousands of repetitions are required to create a brand-new protein. </p>
<p>Using this process, we generated 2,000 new protein sequences predicted to fold into well-defined structures. Of these, we selected over 100 that were the most distinct in shape to physically recreate in the lab. Finally, we chose three of the top candidates for detailed analysis and confirmed that they were close matches to the shapes predicted by our hallucinated models.</p>
<h2>Why hallucinate new proteins?</h2>
<p>Our hallucination approach greatly simplifies the protein design pipeline. By eliminating the need for templates, researchers can directly focus on creating a protein based on desired functions and let the network take care of figuring out the structure for them.</p>
<p>Our work opens up multiple avenues for researchers to explore. Our lab is <a href="https://doi.org/10.1101/2021.11.10.468128">currently investigating</a> how to best use this hallucination approach to generate even more specificity in the function of designed proteins. Our approach can also be readily extended to design new proteins using <a href="https://www.ipd.uw.edu/2021/07/rosettafold-accurate-protein-structure-prediction-accessible-to-all/">other</a> <a href="https://deepmind.com/blog/article/alphafold-a-solution-to-a-50-year-old-grand-challenge-in-biology">recently developed</a> deep neural networks.</p>
<p>The potential applications of de novo proteins are vast. With deep neural networks, researchers will be able to create even more proteins that can <a href="https://doi.org/10.1038/s41586-020-2149-4">break down plastics</a> to reduce environmental pollution, <a href="https://doi.org/10.1038/s41586-021-03258-z">identify and respond</a> to unhealthy cells and <a href="https://doi.org/10.1126/science.aay5051">improve vaccines</a> against existing and new pathogens – just to name a few.</p>
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<p class="fine-print"><em><span>Ivan Anishchenko receives funding from NSF (grant DBI 1937533) and NIAID (Federal Contract HHSN272201700059C). </span></em></p>Using a form of artificial intelligence called deep neural networks, researchers can generate new proteins from scratch without having to consult nature.Ivan Anishchenko, Acting instructor in Computational Biology, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.