tag:theconversation.com,2011:/fr/topics/enzyme-2518/articlesEnzyme – The Conversation2021-11-01T14:13:02Ztag:theconversation.com,2011:article/1706602021-11-01T14:13:02Z2021-11-01T14:13:02ZDroughts create fertile ground for cholera. Plans are needed to face more dry periods<figure><img src="https://images.theconversation.com/files/429133/original/file-20211028-21-59ensr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/dried-out-dam-is-pictured-on-a-farm-in-piket-bo-berg-news-photo/932983846?adppopup=true">Wikus De Wet/AFP via Getty Images</a></span></figcaption></figure><p>Africa has a disproportionately <a href="https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003832">high burden</a> of cholera. The World Health Organization reports that between <a href="https://www.who.int/cholera/publications/global-roadmap.pdf?ua=1">40 million and 80 million</a> people in Africa live in cholera hotspots. Globally, disease outbreaks have more than tripled since 1980, with 1,307 epidemic events between 2011 and 2017. Cholera was the <a href="https://www.who.int/emergencies/diseases/managing-epidemics-interactive.pdf">biggest contributor</a> to this with 308 events. </p>
<p>This is particularly concerning, considering cholera is an under reported disease. </p>
<p>Cholera tracks with areas of high poverty and low access to safe drinking water, sanitation and hygiene. More than a third of people still don’t have access to water in central and west Africa and less than 40% have adequate sanitation, <a href="https://www.unicef.org/wca/what-we-do/wash">according to UNICEF</a>. </p>
<p>Children and women are facing particularly serious consequences to this inaction. This is because cholera is a major component to child mortality. In addition, young girls and women are primarily responsible for water collection, reducing the time available for work or education and exposing them to the risk of sexual violence.<br>
In a <a href="https://www.tandfonline.com/doi/full/10.1080/20477724.2021.1981716">recent paper</a> I looked at drought-related cholera outbreaks in Africa and the implications of an increase in dry periods as a result of climate change. <a href="https://www.imperial.ac.uk/people/g.charnley19">My research</a> is focused on infectious diseases, including cholera, which have several links and relationships to droughts. </p>
<p>I focused on the subject because droughts are generally an understudied natural hazard. This is perhaps due to their complexity involving meteorological, hydrological, agricultural and societal changes. I sought to collate historically reported risk factors and understand which regions had reported these drought-related outbreaks. I found a lack of literature on the subject but there were several inequities that were repeated and that must be addressed to support drought affected communities better, including food and water assistance. </p>
<h2>Climate change and cholera</h2>
<p>One consequence of a warming world is prolonged dry spells and periods of drought. And a known consequence of droughts and their associated risk factors are infectious disease outbreaks, which are worsened by malnutrition, poor access to water, sanitation and hygiene and population displacement. </p>
<p>These are perfect conditions for a rise in outbreaks of cholera.</p>
<p>It’s hard to predict where future droughts will happen. But available evidence <a href="https://www.sciencedirect.com/science/article/abs/pii/S0048969718324987?via%3Dihub">suggests</a> that some areas of Africa are likely to see more intense and longer droughts. How long and how intense, will likely rely on how countries adapt and respond, including the management of water. </p>
<p>Suggested mechanisms through which droughts may exacerbate the transmission of cholera include elevated concentrations of the pathogen, multi-use drinking water, reduced fuel for cooking and using alternative foods and water. </p>
<p>Cholera has known environmental and climatic links. But some <a href="https://www.medrxiv.org/content/10.1101/2021.07.16.21260629v1">research </a> has suggested these may only be important up to a certain threshold, then socio-economic conditions are needed to make the human-environment link. </p>
<p><a href="https://www.nature.com/articles/s41598-021-85146-0">Evidence</a> for this is clear in the areas which suffer from cholera outbreaks following climatological events. For example, Europe and North America have a long history of drought and dry spells but cholera outbreaks do not follow. This is because there is widespread access to safe drinking water and sanitation. </p>
<p>Drought and cholera outbreaks can also result in displacement, a risk factor commonly cited as causing infectious disease outbreaks. Displacement can help to spread cholera to new areas. For example, during the <a href="https://www.fao.org/3/X5558E/X5558e01.htm">Mozambican drought</a> in 1991-1992, over one million people were forced to seek refuge elsewhere. This resulted in an influx of refugees to Zimbabwe, which <a href="https://academic.oup.com/trstmh/article-abstract/90/4/378/1864864?redirectedFrom=fulltext">subsequently suffered</a> a fast-moving cholera outbreak. </p>
<p>Other population groups that suffer particularly badly in times of drought are nomadic communities and poorer rural communities. This is due to their reliance on agriculture, inability to afford alternative water sources and isolation from society.</p>
<h2>Mitigation</h2>
<p>I conclude in my paper that disasters don’t cause outbreaks. Rather its societal response, or the lack thereof.</p>
<p>Arguably the most fundamental way to reduce the impacts of drought and resultant cholera outbreaks is to alleviate population vulnerabilities before the hazard occurs. Such steps include:</p>
<ul>
<li><p>expanding access to water and sanitation, </p></li>
<li><p>alleviating poverty, and </p></li>
<li><p>reducing the marginalisation of groups. </p></li>
</ul>
<p>This would enable people to adapt better to a changing climate.</p>
<p>In addition multi-country drought response plans and water agreements are needed. How one country manages a water source can have a knock-on effect and drought rarely affects one country in isolation. </p>
<p>When cholera outbreaks do occur, the response needs to be rapid, due to its short incubation period - less than two hours to five days. </p>
<p>Oral cholera vaccines are an essential tool in controlling outbreaks, along with providing chlorinated water. </p>
<p>More awareness of the implications of drought on health are needed including enhanced research, technology, surveillance and forecasting to assess health under an interdisciplinary lens. Better drought diplomacy, which involves using drought-related activities to create <a href="https://onlinelibrary.wiley.com/doi/10.1002/9781118885154.dipl0086">fresh diplomatic opportunities</a> and not conflicts, is needed at all levels to improve the capacity to cope and offer effective solutions. </p>
<p>Communities also need to be consulted and encouraged in climate adaptation talks and negotiations.</p>
<p>The current <a href="https://pubmed.ncbi.nlm.nih.gov/29123067/">cholera pandemic</a> shows no signs of waning and remain unlikely while so many people live in conditions that allow its transmission. These issues will only be worsened as climate change progresses. A greater call to action is needed to provide the basic human right of water and sanitation.</p><img src="https://counter.theconversation.com/content/170660/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gina Charnley receives funding from the Natural Environmental Research Council (NERC). </span></em></p>A consequence of a warming world is prolonged dry spells and periods of drought that can lead to infectious diseases like cholera.Gina Charnley, Research Postgraduate, Imperial College LondonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1185682019-07-31T11:48:23Z2019-07-31T11:48:23ZTOR: an enzyme that could hold the secret to longevity and healthy ageing<figure><img src="https://images.theconversation.com/files/285308/original/file-20190723-110154-g9e3ov.jpg?ixlib=rb-1.1.0&rect=166%2C2%2C832%2C663&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Protein-rich foods.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/684710068?src=wU-meNy0P_90U0NTr6OwDA-1-0&studio=1&size=medium_jpg">Syda Productions/Shutterstock</a></span></figcaption></figure><p>Calorie-restricted diets have been shown to increase the lifespan and healthspan of everything from <a href="https://www.ncbi.nlm.nih.gov/pubmed/19539741/">yeast</a> to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988801/">monkeys</a> – as long as there is no malnutrition. And while no long-term studies have proven the benefits of calorie restriction on human lifespan, <a href="https://link.springer.com/article/10.1007%2Fs11892-017-0951-7">shorter-term studies</a> suggest that it does improve health. Here’s how it might work.</p>
<p>Our bodies monitor and sense the amount of nutrients available through specific molecules in our cells. Depending on the amount of food we eat, these molecules tweak our metabolism to regulate how we use the available nutrients. One of these molecules is an enzyme called TOR. </p>
<p>When there is a lot of food, the TOR enzyme instructs cells in the body to grow. If there is less food, TOR instructs the body to be on alert - a state that scientists refer to as a “mild stress response”. </p>
<p>Many <a href="https://www.ncbi.nlm.nih.gov/pubmed/29190625">experiments</a> have shown that when animals eat a lot of food, especially for prolonged periods, TOR senses this and their lifespan becomes shorter. But do all foods have this effect on TOR?</p>
<p>TOR enzyme is <a href="https://www.ncbi.nlm.nih.gov/pubmed/28768171">especially activated</a> when cells sense large amounts of amino acids (the building blocks of protein) or protein. A protein-restricted diet, without malnutrition, can have the same effects on the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254277">metabolism and lifespan</a> of lab animals as a calorie-restricted diet.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/285481/original/file-20190724-110154-nv0go8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Rapamycin was discovered on Rapa Nui (Easter Island).</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/552775792?src=Dm0YyT3jj-dt7ni1EYZ41g-1-6&studio=1&size=medium_jpg">Olga Danylenko/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Age-related disease</h2>
<p>Age-related diseases are known to be caused by genetic mutations, but could there be a connection between TOR, nutrition and diseases of old age? We know that nutrition is associated with cancer and heart disease, and overactive TOR is <a href="https://www.ncbi.nlm.nih.gov/pubmed/28770023">known to be involved</a> in these diseases, but recent <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765916/">studies</a> show that TOR is also directly related to neurodegenerative diseases. For example, the activity of the TOR enzyme in the brains of people with Alzheimer’s is much higher compared with healthy brains. Also, simulating these diseases in mice and other lab animals has shown that removing excess TOR <a href="https://www.ncbi.nlm.nih.gov/pubmed/20376313/">stops brain cells dying</a>. </p>
<p>So there may be a link between what we eat, how it is sensed by our body and the risk of neurodegenerative disease. Scientists are exploring different possibilities to prevent neurodegeneration. If more protein means more active TOR, we could either modify our diet, safely, or develop a drug that tricks our body into thinking it is getting less protein. </p>
<p>Work in many labs, including ours, have shown that <a href="https://link.springer.com/article/10.1186/2046-2395-1-9">caffeine</a> and a drug called <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798131/">rapamycin</a> do exactly that. While cells have abundant protein, their metabolism and lifespan are similar to protein-restricted cells. We are currently investigating this in human neurons and the first results point in the same direction.</p>
<h2>Not that simple</h2>
<p>Does that mean that we should change our diets and protein intake? What about other nutrients such as sugars? Unfortunately, as expected, things are not that simple. Many other molecules within our bodies are involved in sensing nutrients including carbohydrates, which affect longevity and age-related disease.</p>
<p>This is why we need to be very cautious. First, everyone has different needs for nutrients depending on their developmental stage and age, gender or activity levels – to name only a few important factors. Also, while evidence from the lab using human cells and tissues is piling up, we need large population studies that can record specific diets, including protein, fat and carbohydrate intakes, with parallel analyses of the relevant health or molecular markers. Such studies need decades to generate solid data and valid conclusions.</p>
<p>Still, with the development of new technologies and scientific approaches, we are taking steps towards understanding the underlying causes of ageing and age-related disease. Coupled with targeted clinical trials and population studies, perhaps one day soon we’ll be able to achieve healthy ageing and longer lifespans.</p><img src="https://counter.theconversation.com/content/118568/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Charalampos (Babis) Rallis is affiliated with University of East London, University College London and Birkbeck College, University of London. </span></em></p>An enzyme called TOR could hold the secret to a longer, healthier life.Charalampos (Babis) Rallis, Senior Lecturer in Biochemistry, University of East LondonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1043692018-10-04T10:29:04Z2018-10-04T10:29:04Z2018 Nobel Prize for chemistry goes to scientists who learned to ‘hack’ evolution in the lab<figure><img src="https://images.theconversation.com/files/239191/original/file-20181003-52666-1qu4ycq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Scientists are now using evolution to create designer proteins for therapies and industrial processes.</span> <span class="attribution"><span class="source">Johan Jarnestad / The Royal Academy of Sciences</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>The three 2018 Nobel Prize winners for chemistry were recognized for inventing fast and reliable methods for “hacking” evolution – techniques that have transformed scientific research and have already led to better drug treatments, greener and more efficient chemical manufacturing processes, and more economical biofuels. </p>
<p>Thanks to these inventions, what nature takes millennia to do, can now be performed by chemists in weeks or less. What’s more, these prize-winning methods form what I regard as a final proof for the molecular basis for Charles Darwin’s theory of evolution.</p>
<p>The Nobel Prize in chemistry was split between Frances H. Arnold and George P. Smith and Sir Gregory P. Winter; the latter two received the
other half. I will admit my bias toward Frances H. Arnold whose technology the Nobel Committee recognized – on the directed evolution of enzymes, which are proteins that catalyze chemical reactions – because much of my own work has been built on it. Smith and Winter also used evolution to fast-track the development of proteins and antibodies with desirable properties. They harnessed the power of viruses to exponentially increase the scale of directed evolution envisioned by Arnold and expanded it to the development of protein-based therapeutics like Humira for chronic pain. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=453&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=453&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=453&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=569&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=569&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239232/original/file-20181003-52691-ehvmyd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=569&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A stamp printed by Congo, shows an early ancestors of the modern elephant.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/congo-circa-1994-stamp-printed-by-87988546?src=eIqV0Co7cKfgpgfVqvUpjA-1-7">rook76/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>To explain it simply, both methods generate a broad variety of proteins in the lab and then use un-natural selection – that is, selecting the protein with the most desirable qualities – and then mutating this new protein in the lab to make it better and better. In that way, it’s a molecular version of evolution. Darwinian evolution created the modern elephant’s trunk from a stubby nose by the repeated processes of natural genetic mutation and survival of the fittest; directed evolution creates new enzymes from natural occurring ones by iterative cycles of mutation and selection.</p>
<h2>Survival of the fittest - molecules</h2>
<p>In high school biology, we learn about the “lock-and-key” concept of enzymes. In this model, enzymes, which are nature’s biocatalysts that speed up chemical reactions, are the “locks” evolved to connect with a natural target molecules – the “keys” – to complete a specific chemical reaction.</p>
<p>If you want an enzyme to do something new, something unnatural, like selectively insert an oxygen atom into a molecule to manufacture a valuable drug, you are unlikely to find that enzyme in nature. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=245&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=245&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=245&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=309&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=309&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239230/original/file-20181003-52660-2kcxg0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=309&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 lock (red) and key (blue-orange) model of an enzyme. In nature, enzymes that fit only one key take millions of years to evolve. Arnold figured out how to speed up the evolution of the enzymes to perfectly match the target she was trying to alter.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/245391454?size=huge_jpg">joshya/shutterstock.com</a></span>
</figcaption>
</figure>
<p>Arnold’s approach is to take an enzyme from nature and then transform it – through laboratory evolution – into one that performs the reactions that interest her. She does this by taking the gene that encodes the enzyme and putting it through the biological equivalent of an error-prone Xerox copier, which then duplicates the gene millions of times but inserts mutations randomly throughout.</p>
<p>Arnold then took these millions of poorly copied genes and inserted each one into a different bacterium. This collection of bacteria is called a gene library. Because each of the genes is mutated in a different way, the enzyme each bacterium produces when it is fed and grows will be slightly different. The challenge is to find the bacterium that carries the enzyme with the most desirable qualities.</p>
<p>For example, say you have an industrial process that requires an enzyme that works at high temperatures, but the natural enzyme falls apart under these extreme conditions. You would make thousands of random copy mutants, test them each to see if they perform at a high temperature, pick the winners and repeat the process with the winner. That’s an iterative process of mutation and selection, just like natural evolution. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=200&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=200&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=200&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=251&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=251&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239225/original/file-20181003-52695-1npt1zu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=251&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Frances Arnold, George Smith and Gregory Winter won the 2018 Nobel Prize for chemistry.</span>
<span class="attribution"><span class="source">Caltech | MU News Bureau | LMB News</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>It is not unlike what it took to breed wolves into miniature dachshunds over the last tens of thousands of years. In this case, sexual reproduction is used by breeders to create gene variations and then selected traits they wanted, over many generations to arrive at the various dog breeds. Arnold figured out how to do that on a single-enzyme scale. In this way, the enzyme lock ends up changed to fit a new molecular key.</p>
<p>One of the first examples Arnold demonstrated as proof of concept was a little scary. She started with an enzyme responsible for drug resistance that chews up penicillin drugs and forced it to evolve to chew up a newer generation of penicillins, in this case, a more advanced antibiotic. </p>
<p>In this way she sped up the evolutionary clock for antibiotic resistance in a test tube. Since then, the same principle of directed evolution has been adopted to create enzymes with many useful new functions, for instance to evolve enzymes to make biofuels and drugs. Drugs now made using enzymes generated by directed evolution include the blockbuster cholesterol lowering drug atorvastatin (lipitor) and the diabetes drug sitagliptin (Januvia).</p>
<h2>Evolution with help from viruses</h2>
<p>Arnold shares the Nobel Prize with Smith and Winter, who invented ways to attach or “display” proteins and antibodies of interest on the surface of special virus particles, called bacteriophage. Using viruses rather than bacteria, as Arnold had done, was a different approach for identifying a gene that encoded a protein with particularly valuable qualities. This method is particularly useful for finding proteins that bind to a target protein, such as the target of a drug.</p>
<p>Each virus in a phage library displays a different protein on its surface. The viruses expressing the most desirable proteins are identified through several complex steps. The “winning” viruses then go through multiple cycles of mutation and testing and selection to yield proteins that fit and bind perfectly to their target.</p>
<p>The advantage of using viruses to display the proteins with the desired properties miniaturizes the selection process and allows you to process millions of mutated genes to find the one that best fits the job, as compared to only thousands of mutated genes using bacteria. </p>
<p>This technology has had the greatest impact on antibody therapies. Antibodies are molecules our immune system uses to bind and kill pathogens and naturally clear dying cells. But scientists are increasingly using them to bind to drug targets to treat various diseases. Adalimumab (Humira) is an example of a therapeutic antibody used in treatment of rheumatoid arthritis.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=181&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=181&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=181&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=227&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=227&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239227/original/file-20181003-52660-18bjpz0.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=227&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">With each subsequent generation, the antibodies evolve and and better fit their target protein. With each generation, the fit between antibody and target grows stronger and more specific.</span>
<span class="attribution"><a class="source" href="https://www.nobelprize.org/uploads/2018/10/press-fig4-antibodyEvolution.pdf">Johan Jarnestad/The Royal Swedish Academy of Sciences</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>From single enzymes to evolving concerts of enzymes</h2>
<p>I started off my own career in chemical synthesis, which is developing ways to make chemicals atom by atom in a round-bottomed flask. This is challenging work and I came to realize that organisms makes complex chemicals seemingly effortlessly as they grow, so I wanted to learn how to adapt nature’s enzyme catalysts – the tools that life uses to do chemistry – to synthesize useful unnatural molecules. </p>
<p>Around the mid-1990s, Arnold’s research showed me that we could ultimately use this nature-inspired method of directed evolution to improve the function of single enzymes to get them to perform chemistry they could not do naturally, millions of times faster, and get them to perform chemistry we could not do by any means. </p>
<p>I wondered: If doing a single biotransformation, converting A to B, is a powerful thing, could we find a way to generate pathways to connect three, four or even five or more steps, converting steps A to E and beyond in a single test tube? If one biocatalyst is a good thing, how about a molecular assembly line inside of cells for a non-natural molecule such as an AIDS drug. We called our pathway directed evolution technique bioretrosynthesis, because we start with the last step and work to the first. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239229/original/file-20181003-52681-15tegea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">By.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/make-things-better-motivational-quote-written-296051639?src=HlKb--kfAgEc1x3_hTEv_w-2-89">Emil Durov/Shutterstock.com</a></span>
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</figure>
<p>In a paper published in <a href="https://www.nature.com/articles/nchembio.1494">Nature Chemical Biology</a>, we described how we reverse engineered a five-step molecular production line to synthesize the AIDS drug Didanosine using Arnold’s bacterial method. </p>
<p>Currently this drug is made using chemical processes and is very expensive. Our proof of principle showed the cost could be lessened by using a starting material that is 30-fold less expensive and using enzymes created through directed evolution to do the hard work.</p>
<p>One of the most exciting things to me about this Nobel breakthrough is that it provides a direct proof of Darwin’s theory of evolution, at the molecular scale, from gene to physical trait. This theory, supported by the observations of gradual changes in the fossil record over geological timescales, can now be witnessed in the lab over the course of just a few weeks to make incredibly useful tools that benefit humanity.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/lSrPOWgtkh4?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Frances Arnold, after she received the news learning she won the Nobel Prize for chemistry, explains how she mimics nature and began using evolution to design powerful proteins.</span></figcaption>
</figure><img src="https://counter.theconversation.com/content/104369/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Brian Bachmann 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>Nature doesn’t always make the things we need so three Nobel Prize winners figured out how to fast-track evolution in the lab to create medicines, biofuels and industrial chemicals for modern life.Brian Bachmann, Professor of Chemistry, Vanderbilt UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/952332018-04-18T15:42:01Z2018-04-18T15:42:01ZHow plastic-eating bacteria actually work – a chemist explains<figure><img src="https://images.theconversation.com/files/215385/original/file-20180418-163971-zln6cu.jpg?ixlib=rb-1.1.0&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/biofilm-antibiotic-resistant-bacteria-closeup-view-369173630?src=3xFxdldNMRmnbo-KiyY3wA-1-81">Shutterstock</a></span></figcaption></figure><p>The plastic bottles we throw away today will be around for <a href="http://rstb.royalsocietypublishing.org/content/364/1526/2115.long">hundreds of years</a>. It’s one of the key reasons why the mounting plastic pollution problem, which is having a <a href="https://theconversation.com/in-the-ocean-the-most-harmful-plastic-is-too-small-to-see-35336">deadly effect on marine life</a>, is so serious. </p>
<p>But scientists <a href="https://theconversation.com/new-plastic-munching-bacteria-could-fuel-a-recycling-revolution-55961">recently discovered</a> a strain of bacteria that can literally eat the plastic used to make bottles, and have now <a href="http://www.pnas.org/content/early/2018/04/16/1718804115">improved it</a> to make it work faster. The effects are modest – it’s not a complete solution to plastic pollution – but it does show how bacteria could help create more environmentally friendly recycling.</p>
<p>Plastics are complex polymers, meaning they are long, repeating chains of molecules that don’t dissolve in water. The strength of these chains makes plastic very durable and means it takes a very long time to decompose naturally. If they could be broken down into their smaller, soluble chemical units, then these building blocks could be harvested and recycled to form new plastics in a closed-loop system.</p>
<p>In 2016, <a href="http://science.sciencemag.org/content/351/6278/1196.full">scientists from Japan</a> tested different bacteria from a bottle recycling plant and found that <em>Ideonella sakaiensis</em> 201-F6 could digest the plastic used to make single-use drinks bottles, polyethylene terephthalate (PET). It works by secreting an enzyme (a type of protein that can speed up chemical reactions) known as PETase. This splits certain chemical bonds (esters) in PET, leaving smaller molecules that the bacteria can absorb, using the carbon in them as a food source. </p>
<p>Although <a href="https://pubs.acs.org/doi/full/10.1021/ma9005318">other bacterial enzymes</a> were already known to slowly digest PET, the new enzyme had apparently evolved specifically for this job. This suggests it might be faster and more efficient and so have the potential for use in bio-recycling. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/215395/original/file-20180418-163982-191d2hd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Plastic crisis.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/amsterdam-netherlands-march-27-2017-plastic-619321145?src=hYHxmUUwluTCGV1ZtDTetA-1-1">Shutterstock</a></span>
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<p>As a result, several teams have been trying to understand exactly how PETase works by studying its structure. In the past 12 months, groups from <a href="https://www.nature.com/articles/s41467-018-02881-1">Korea</a>, <a href="https://www.nature.com/articles/s41467-017-02255-z">China</a> and the <a href="http://www.pnas.org/content/early/2018/04/16/1718804115">UK, US and Brazil</a> have all published work showing the structure of the enzyme at high resolution and analysing its mechanisms.</p>
<p>These papers show that the part of the PETase protein that performs the chemical digestion is physically tailored to bind to PET surfaces and works at 30°C, making it suitable for recycling in bio-reactors. Two of the teams also showed that by subtly changing the enzyme’s chemical properties so it interacted with PET differently made it work more quickly than the natural PETase. </p>
<p>Using enzymes from bacteria in bio-reactors to break down plastic for recycling is still easier said than done. The physical properties of plastics make them <a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/1751-7915.12710">very difficult</a> for enzymes to interact with.</p>
<p>The PET used in drinks bottles has a semi-crystalline structure, which means the plastic molecules are tightly packed and difficult for the enzyme to get to. The <a href="http://www.pnas.org/content/early/2018/04/16/1718804115">latest study</a> shows that the enhanced enzyme probably worked well because the part of the molecule that is involved in the reaction is very accessible, making it easy for the enzyme to attack even the buried PET molecules. </p>
<h2>Modest improvements</h2>
<p>The improvements to the PETase activity were not dramatic, and we are nowhere near a solution to our plastic crisis. But this research helps us understand how this promising enzyme breaks down PET and hints at how we could make it work faster by manipulating its active parts.</p>
<p>It is relatively unusual to be able to engineer enzymes to work better than they have evolved through nature. Perhaps this achievement reflects the fact that the bacteria that use PETase are only recently evolved to survive on this man-made plastic. This could give scientists an exciting opportunity to overtake evolution by engineering optimised forms of PETase.</p>
<p>There is one worry, though. While any modified bacteria used in bioreactors are likely to be highly controlled, the fact that it evolved to degrade and consume plastic in the first place suggests this material we rely on so heavily may not be as durable as we thought.</p>
<p>If more bacteria began eating plastic in the wild then products and structures designed to last many years could come under threat. The plastics industry would face the serious challenge of preventing its products becoming contaminated with hungry micro-organisms.</p>
<p>Lessons from antibiotics teach us we are <a href="https://theconversation.com/bacterias-secret-weapons-in-defeating-antibiotics-discovered-87272">slow to outwit bacteria</a>. But perhaps studies such as these will give us a head start.</p><img src="https://counter.theconversation.com/content/95233/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Emily Flashman receives funding from the B.B.S.R.C.</span></em></p>New research has found a way to speed up enzymes that break down the PET plastic in bottles.Emily Flashman, Research Fellow in Enzymology, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/887672017-12-27T20:46:51Z2017-12-27T20:46:51ZWhy do people with East Asian heritage get flushed after drinking alcohol?<figure><img src="https://images.theconversation.com/files/199666/original/file-20171218-27547-1e1t79l.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">More than one in three people with Chinese, Japanese and Korean heritage flush when drinking alcohol.</span> <span class="attribution"><span class="source">Marcella Cheng/The Conversation</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>If your face goes red when drinking alcohol, you’re not alone. More than one in three people with East Asian heritage (Chinese, Japanese and Korean) <a href="http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000050">experience facial flushing</a> when drinking beer, wine or spirits. </p>
<p>In Asian populations, it is due to an inherited deficiency in one of the enzymes involved in the breakdown of alcohol: aldehyde dehydrogenase. This type of reaction is very rare, but not unknown, in other ethnic groups. </p>
<p>But there is more to this deficiency than just an embarrassing reddening of the face. There are positive and negative health implications. And it provided a lightbulb moment, helping us understand how a common treatment for alcoholism works.</p>
<h2>How you digest alcohol</h2>
<p>Alcohol is broken down in your liver in two steps. In the first step, the enzyme alcohol dehydrogenase converts alcohol into a rather nasty chemical called acetaldehyde. A build up of this toxic chemical is one of the reasons you feel sick when hungover. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/got-a-hangover-heres-whats-happening-in-your-body-51027">Got a hangover? Here's what's happening in your body</a>
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<p>Then a second enzyme, aldehyde dehydrogenase, converts the acetaldehyde into acetic acid (the harmless acidic component of vinegar). </p>
<p>Aldehyde dehydrogenase deficiency is common among Chinese, Korean and Japanese people. Some inherit two copies of the defective gene for this enzyme; one from each parent. Their liver makes a faulty version of the enzyme. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=384&fit=crop&dpr=1 600w, https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=384&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=384&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=482&fit=crop&dpr=1 754w, https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=482&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/199375/original/file-20171215-17884-5w81qn.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=482&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Facial flushing in a 22-year-old before (left) and after (right) drinking alcohol.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Alcohol_flush_reaction#/media/File:The_Alcohol_Flushing_Response.png">Brooks PJ, Enoch M-A, Goldman D, Li T-K, Yokoyama A - Brooks PJ, Enoch M-A, Goldman D, Li T-K, Yokoyama A 2009. The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption. PLoS Med</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
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<p>Others inherit the defective gene from just one parent and they produce both normal and faulty enzyme. However, this partial deficiency results in only 1% of full enzyme activity, rather than the 50% you might expect. This is because <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507646/">the faulty version is less stable</a> and multiple copies of the enzyme need to work together as a unit.</p>
<p>If you inherit full or partial deficiency in aldehyde dehydrogenase, you will experience prolonged high levels of acetaldehyde very soon after drinking alcohol – and all the unpleasant sensations that go with that. Think of it as an instant hangover: nausea, sweating, headache, racing heart, dizziness, along with facial flushing. </p>
<h2>What does it mean?</h2>
<p>The good news is that because of aldehyde dehydrogenase deficiency, alcoholism and alcohol-related cancers are <a href="https://link.springer.com/article/10.1186/s12929-017-0327-y">much less prevalent in East Asian populations</a>. This is because people feel so bad after drinking alcohol, they tend to drink very little, if at all. </p>
<p>Now for the bad news. If you do have aldehyde dehydrogenase deficiency, but still drink, you are at a <a href="http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000050">higher risk of alcohol-related cancers</a>, such as cancer of the oesophagus (the tube between your mouth and your stomach). </p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/alcohol-increases-cancer-risk-but-dont-trust-the-booze-industry-to-give-you-the-facts-straight-83632">Alcohol increases cancer risk, but don't trust the booze industry to give you the facts straight</a>
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<p>The risk is highest for those with partial deficiency. This is because their low residual enzyme activity allows them to develop some tolerance to the unpleasant effects of drinking, but they are still exposed to high levels of acetaldehyde.</p>
<p>It may come as a surprise that anyone with aldehyde dehydrogenase deficiency would drink. But the reasons why we like alcohol are complex. Some of it is metabolic, some is brain chemistry and some is social. </p>
<p>Certain people feel <a href="https://www.niaaa.nih.gov/news-events/news-releases/receptor-variant-influences-dopamine-response-alcohol">more intense pleasure than others</a> when drinking alcohol and this can contribute to addiction. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714821/">Studies of the drinking habits of Asian-American university students</a> have shown that social influences, such as exposure to drinking culture, peer pressure and family attitudes to alcohol can help override the unpleasant physical effects that come with aldehyde dehydrogenase deficiency.</p>
<h2>What can you do about it?</h2>
<p>It is regularly reported in the <a href="https://news.usc.edu/112489/antihistamines-prevent-asian-flush-the-red-face-some-people-get-from-alcohol-but-with-huge-risks/">media</a> and <a href="http://flush.blog/pepcid/">online</a> that “antihistamines” prevent “Asian flush”. </p>
<p>There are drugs that can reduce facial flushing, but they are not the classical antihistamines, such as you take for hay fever. Certain drugs used to treat gastric acid reflux (such as Zantac and Tagamet) have the side effect of reducing alcohol-induced facial flushing. We don’t normally think of these drugs as antihistamines, but technically they are, because they block the <a href="https://www.drugs.com/drug-class/h2-antagonists.html">histamine H2 receptors</a> in the stomach, which are associated with the release of stomach acid. </p>
<p>The drugs we commonly call antihistamines (Zyrtec, Telfast and Claratyne) target the <a href="https://en.wikipedia.org/wiki/H1_antagonist">histamine H1 receptor</a> and they have no effect on alcohol-induced facial flushing.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/199377/original/file-20171215-17845-t4uw0x.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">H2 blockers are no magic bullet.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/8x_fFNrmeDk">Luca Bravo</a></span>
</figcaption>
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<p>H2 blockers have few side effects and are relatively safe drugs. But while they mask the symptoms, they won’t reduce the toxic effects of acetaldehyde. Popping a pill and drinking to excess can lead to acetaldehyde tolerance and increase the risk of cancer. </p>
<p>So, if you have aldehyde dehydrogenase deficiency, it’s better to avoid alcohol altogether. But if you do drink, just drink a little and let the flush happen. </p>
<p>It doesn’t matter what form the alcohol comes in, it is metabolised the same way. But how much alcohol a drink contains and how fast you drink it will affect the concentration of acetaldehyde in your body.</p>
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<em>
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Read more:
<a href="https://theconversation.com/do-different-drinks-make-you-different-drunk-88247">Do different drinks make you different drunk?</a>
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<h2>How this helps treat addiction</h2>
<p>The rareness of alcoholism in Asian populations has a surprising parallel with a treatment for this addiction. </p>
<p>It had long been noted that workers in rubber factories suffered similar symptoms when they drank alcohol. In the 1930s, the offending chemical, <a href="https://en.wikipedia.org/wiki/Disulfiram">Disulfiram</a>, was identified and by the 1950s it was marketed as the drug Antabuse. In the 1980s experts realised <a href="https://www.ncbi.nlm.nih.gov/pubmed/7135154">Antabuse blocks the activity of aldehyde dehydrogenase</a>. </p>
<p>So, taking Antabuse creates temporary aldehyde dehydrogenase deficiency and one drink is enough to bring on the same unpleasant symptoms felt by those that inherit the deficiency. </p>
<p>But it isn’t a silver bullet and doesn’t work for everyone. Just as some people with inherited aldehyde dehydrogenase deficiency still drink to excess and develop alcoholism, an instant hangover is not enough to drive some people with alcohol problems away from the “demon drink”.</p><img src="https://counter.theconversation.com/content/88767/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Terry Mulhern 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>Facial flushing when drinking alcohol is caused by an inherited deficiency in one of the enzymes involved in the breakdown of alcohol.Terry Mulhern, Senior Lecturer in Biochemistry and Molecular Biology, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/786382017-05-31T16:08:09Z2017-05-31T16:08:09ZCRISPR controversy raises questions about gene-editing technique<figure><img src="https://images.theconversation.com/files/171655/original/file-20170531-23531-1sfeuqi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Laboratory mice are among the first animals to have their diseases treated by CRISPR</span> <span class="attribution"><a class="source" href="https://pixabay.com/en/animal-mouse-experiment-laboratory-1554745/">tiburi via Pixabay.com</a></span></figcaption></figure><p><em>Editor’s note: On March 30, 2018, journal Nature Methods <a href="https://retractionwatch.com/2018/03/30/nature-journal-retracts-controversial-crispr-paper-after-authors-admit-results-may-be-wrong/">retracted</a> the original research paper that reported high levels of off-target DNA edits produced by a CRISPR-based gene editing therapy. According to the journal, “<a href="https://doi.org/10.1038/nmeth.4293">it is not certain that the variants reported are due to CRISPR treatment</a>.”</em></p>
<p>A new research paper is stirring up controversy among scientists interested in using DNA editing to treat disease.</p>
<p>In a two-page article published in the journal Nature Methods on May 30, a group of six scientists <a href="https://doi.org/10.1038/nmeth.4293">report an alarming number of so-called “off-target mutations”</a> in mice that underwent an experimental gene repair therapy.</p>
<p>CRISPR, the hot new gene-editing technique that’s taken biology by storm, is <a href="https://theconversation.com/beyond-just-promise-crispr-is-delivering-in-the-lab-today-77596">no stranger to headlines</a>. What is unusual, however, is a scientific article so clearly describing a potentially fatal shortcoming of this promising technology.</p>
<p>The research community is digesting this news – with many experts suggesting flaws with the experiment, not the revolutionary technique.</p>
<h2>Unwanted DNA changes</h2>
<p>The research team sought to repair a genetic mutation known to cause a form of blindness in mice. This could be accomplished, <a href="https://doi.org/10.1038/mt.2016.107">they showed</a>, by changing just one DNA letter in the mouse genome.</p>
<p>They were able to successfully correct the targeted mutation in each of the two mice they treated. But they also observed an alarming number of additional DNA changes — more than 1,600 per mouse — in areas of the genome they did not intend to modify.</p>
<p>The authors attribute these unintended mutations to the experimental CRISPR-based gene editing therapy they used.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=587&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=587&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=587&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=738&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=738&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=738&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Cas9, the CRISPR enzyme that snips DNA, in contact with its target.</span>
<span class="attribution"><span class="source">rcsb.org | PDB: 5FW2 | doi:10.2210/pdb5fw2/pdb</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>A central promise of CRISPR-based gene editing is its ability to pinpoint particular genes. But if this technology produces dangerous side effects by creating unexpected and unwanted mutations across the genome, that could hamper or even derail many of its applications.</p>
<p>Several previous research articles <a href="https://doi.org/10.1038/nmeth.3408">have reported off-target effects of CRISPR</a>, but far fewer than this group found.</p>
<h2>Reaction is skeptical</h2>
<p>The publicly traded biotech companies seeking to commercialize CRISPR-based gene therapies – <a href="http://www.editasmedicine.com">Editas Medicine</a>, <a href="http://www.intelliatx.com">Intellia Therapeutics</a> and <a href="http://www.crisprtx.com">Crispr Therapeutics</a> – <a href="https://www.statnews.com/2017/05/30/crispr-stocks-off-target/">all took immediate stock market hits</a> based on the news.</p>
<p>Experts in the field quickly responded.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"869742617839448064"}"></div></p>
<p>“Either the enzyme is acting at near optimal efficiency or something fishy is going on here,” <a href="https://twitter.com/JMTali/status/869742617839448064">tweeted</a> Matthew Taliaferro, a postdoctoral fellow at MIT who <a href="http://genes.mit.edu/burgelab/index.html">studies gene expression and genetic disease</a>.</p>
<p>The Cas9 enzyme in the CRISPR system is what actually cuts DNA, leading to genetic changes. Unusually high levels of enzyme activity could account for the observed off-target mutations – more cutting equals more chances for the cell to mutate its DNA. Different labs use slightly different methods to try to ensure the right amount of cuts happen only where intended.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"869705549453119489"}"></div></p>
<p>“Unusual methods were used,” <a href="https://twitter.com/LluisMontoliu/status/869705549453119489https://twitter.com/LluisMontoliu/status/869705549453119489">tweeted</a> Lluis Montoliu, who runs a lab at the Spanish National Centre for Biotechnology that specializes in <a href="http://wwwuser.cnb.csic.es/%7Emontoliu/indexe.html">editing mice genes using CRISPR</a>. He believes the authors used suboptimal molecular components in their injected CRISPR therapies – specifically a plasmid that causes cells to produce too much Cas9 enzyme – likely leading to the off-target effects they observed. </p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"869676177094393856"}"></div></p>
<p><a href="http://jcsmr.anu.edu.au/groups/groups/burgio-group">Gaétan Burgio</a>, whose laboratory at the Australian National University is working to understand the role that cellular context plays on CRISPR efficiency, believes the paper’s central claim that CRISPR caused such an alarming number of off-target mutations is “<a href="https://twitter.com/GaetanBurgio/status/869676177094393856">not substantiated</a>.”</p>
<p>Burgio says there could be a range of reasons for seeing so many unexpected changes in the mice, including problems with accurately detecting DNA variation, the extremely small number of mice used, random events happening after Cas9 acted or, he concedes, problems with CRISPR itself.</p>
<p>Burgio has been editing the DNA of mice using CRISPR since 2014 and has never seen a comparable level of off-target mutation. He says he’s confident that additional research will refute these recent findings.</p>
<h2>Continuing CRISPR work</h2>
<p>Although the news of this two-mouse experiment fired up the science-focused parts of the Twittersphere, the issue it raises is not new to the field.</p>
<p>Researchers have known for a few years now that off-target mutations are likely given certain CRISPR protocols. More precise variants of the Cas9 enzyme <a href="https://doi.org/10.1038/nature16526">have been shown to improve targeting</a> in human tissue the lab.</p>
<p>Researchers have also focused on developing <a href="https://doi.org/10.1101/gr.162339.113">methods to more efficiently locate off-target mutations</a> in the animals they study.</p>
<p>As scientists continue to hone the gene-editing technique, we recognize there’s still a way to go before CRISPR will be ready for safe and effective gene therapy in humans.</p><img src="https://counter.theconversation.com/content/78638/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Haydon 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>A new research paper reports dangerous side effects in CRISPR-edited mice. Some scientists are pushing back, placing blame for the unwanted mutations on the experiment, not the technique.Ian Haydon, Doctoral Student in Biochemistry, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/759862017-04-11T01:52:07Z2017-04-11T01:52:07ZEnzymes versus nerve agents: Designing antidotes for chemical weapons<figure><img src="https://images.theconversation.com/files/164543/original/image-20170408-7394-159yw03.png?ixlib=rb-1.1.0&rect=134%2C0%2C1547%2C871&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Enzymes, the catalysts of biology, can engulf and break down hundreds of nerve agent molecules per second.</span> <span class="attribution"><span class="source">Image: Pymol. PDB 4E3T rcsb.org</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>A chemical weapons attack that killed <a href="http://www.bbc.com/news/world-middle-east-39500947">more than 80 people</a>, <a href="https://www.nytimes.com/2017/04/04/world/middleeast/syria-gas-attack.html">including children</a>, triggered the Trump administration’s <a href="https://www.nytimes.com/2017/04/07/world/middleeast/syria-attack-trump.html?_r=0">recent missile strikes</a> against the Syrian government. The use of illegal nerve agents – apparently by the Assad regime – violated <a href="https://ihl-databases.icrc.org/customary-ihl/eng/docs/v1_rul_rule74">international law</a>; President Trump said he was <a href="https://www.whitehouse.gov/the-press-office/2017/04/06/statement-president-trump-syria">moved to act by images</a> of the victims’ horrible deaths.</p>
<p>But there’s another path to mitigate the danger of chemical weapons. This route lies within the domains of science – the very same science that produced chemical weapons in the first place. Researchers in the U.S. and around the world, including here at the University of Washington’s <a href="http://www.ipd.uw.edu">Institute for Protein Design</a>, are developing the tools needed to quickly and safely destroy nerve agents – both in storage facilities and in the human body.</p>
<p>Nerve agents, a class of synthetic phosphorous-containing compounds, are <a href="https://doi.org/10.1093/jat/28.5.372">among the most toxic substances known</a>. Brief exposure to the most potent variants can lead to death within minutes. Once nerve agents enter the body, they irreversibly inhibit a vitally important enzyme called acetylcholinesterase. Its normal job within the nervous system is to help brain and muscle communicate. When a nerve agent shuts down this enzyme, classes of neurons throughout the central and peripheral nervous systems quickly get overstimulated, leading to <a href="https://www.opcw.org/about-chemical-weapons/types-of-chemical-agent/nerve-agents/#c4118">profuse sweating, convulsions and an excruciating death by asphyxiation</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164556/original/image-20170408-29390-75dm34.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">U.S. Marine Corps specialists performing decontamination procedures.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:U.S._Marine_Corps_chemical,_biological,_radiological_and_nuclear_(CBRN)_defense_specialists_with_Marine_Wing_Headquarters_Squadron_(MWHS)_3,_3rd_Marine_Aircraft_Wing,_perform_decontamination_procedures_during_130430-M-EF955-271.jpg">Sgt. Keonaona Paulo</a></span>
</figcaption>
</figure>
<p>Chemical weapons are often associated with wars of the previous century – mustard gas in WWI, Zyklon B in WWII. But the worst variety, nerve agents, were <a href="http://cen.acs.org/articles/94/i41/Nazi-origins-deadly-nerve-gases.html">never deployed in the world wars</a>, though Nazi scientists developed the first generation of these compounds. Gerhard Schrader, the so-called <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2710.2008.00972.x/full">father of nerve agents</a>, didn’t begin life as a Nazi scientist – he was developing new pesticides to combat world hunger when he accidentally synthesized the first organophosphorus nerve agent. Later, he led the research team that produced sarin, or GB, the most toxic of the all the so-called G-series nerve agents. The U.S. government stated with <a href="https://www.whitehouse.gov/the-press-office/2017/04/06/press-briefing-secretary-state-rex-tillerson-and-national-security">“very high confidence” that sarin was used</a> in the recent attack near Idlib, Syria.</p>
<p>Beginning in 2013, teams from the Organization for the Prohibition of Chemical Weapons went to Syria and, with help from the Danish, Norwegian, Russian, Chinese and <a href="https://www.defense.gov/News/Article/Article/602835">U.S. government</a>, <a href="https://www.opcw.org/news/article/destruction-of-syrian-chemical-weapons-completed/">destroyed all declared stockpiles</a> of Syrian chemical weapons. It seems that either not all of Assad’s stockpiles were in fact <a href="https://www.nytimes.com/2017/04/07/world/middleeast/werent-syrias-chemical-weapons-destroyed-its-complicated.html?_r=0">declared and destroyed, or that new nerve agents arrived</a> in Syria – either via the black market or chemical synthesis – in the intervening years. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164553/original/image-20170408-7394-1opyv30.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>
<figcaption>
<span class="caption">Empty sarin containers at Pine Bluff Arsenal.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Empty_sarin_containers_at_Pine_Bluff_Arsenal.jpg">U.S. Army</a></span>
</figcaption>
</figure>
<h2>Clearing chemical weapons</h2>
<p>Twenty-first-century chemists, biochemists and computer scientists are working right now to sap chemical weapons of their horrifying power by designing counter agents that safely and efficiently destroy them. </p>
<p>Sarin sitting in a container – as opposed to in a human body – is relatively easy to destroy. The simplest method is to add a soluble base and heat the mixture to near-boiling temperatures. After several hours, the vast majority – more than 99.9 percent – of the deadly compound can be broken apart by a process called hydrolysis. This is how <a href="https://www.hdiac.org/node/1936">trained specialists</a> dispose of chemical weapons like sarin. </p>
<p>Nerve agents that make their way inside the body are a different story. For starters, you clearly cannot add a near-boiling base to a person. And because nerve agents kill so quickly, any treatment that takes hours to work is a nonstarter.</p>
<p>There are chemical interventions for warding off death after exposure to certain chemical weapons. Unfortunately, these interventions are costly, difficult to dose properly and <a href="https://doi.org/10.1111/j.1742-7843.2011.00678.x">are themselves quite toxic</a>. The chemical antidotes pralidoxime and the cheaper atropine <a href="http://www.chicagotribune.com/news/opinion/editorials/ct-syria-gas-attack-assad-sarin-chlorine-edit-0405-jm-20170404-story.html">were deployed</a> after recent attacks in Syria, but <a href="http://time.com/4727073/idlib-chemical-attack-sarin-gas-pralidoxime/">doctors in the area worry</a> their dwindling supplies offer little protection against possible future attacks. </p>
<p>For a medical intervention to work after nerve gas exposure, it has to work fast. If a first responder administers a sarin-destroying molecule, each therapeutic molecule must be capable of breaking down through hydrolysis <a href="https://dx.doi.org/10.3109/10242429709003196">hundreds of nerve agent molecules per second</a>, one after another. </p>
<p>Enzymes, the genetically encoded catalysts of biology, are up for such a task. Famous enzymes include lactase, which breaks down milk sugars in those who are lactose tolerant. Another known as RuBisCO is vital to the process of carbon fixation in plants. The most efficient enzymes in your body can perform <a href="http://www.vivo.colostate.edu/hbooks/molecules/carbonic_anhydrase.html">a million reactions per second</a>, and do so under chemically mild conditions. </p>
<p>Aside from their astonishing speed, enzymes often display an equally impressive selectivity. That is, they react with only a small number of structurally similar compounds and leave all other compounds alone. Selectivity is useful in the context of the chemical soup that is the cell but problematic when it comes to xenobiotics: those compounds which are foreign to one’s biology. Man-made organophosphates such as sarin are xenobiotics. There are no enzymes that hydrolyze them well – or so we thought.</p>
<p>When farmers spray pesticides, much of it ends up on the ground. Soil bacteria living nearby are challenged by high doses of these potent foreign chemicals. It turns out that <a href="https://doi.org/10.1111/j.1752-4571.2010.00175.x">efficient detoxifying enzymes have recently evolved</a> inside some of these microbes as a result.</p>
<p>Scientists have identified and isolated a small number of these enzymes and tested them on a range of nasty compounds, including nerve agents, which are structurally similar to some pesticides. A select few did indeed show hydrolytic activity.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=480&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=480&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=480&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=603&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=603&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164558/original/image-20170408-29399-hwdml4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=603&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Scientists are using computers to design a new generation of proteins to solve 21st-century problems.</span>
<span class="attribution"><span class="source">UW Institute for Protein Design</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Improving on the discovery</h2>
<p>Researchers have taken these naturally occurring enzymes as raw material. Then, using <a href="http://pubs.acs.org/doi/abs/10.1021/cb4004892">computer modeling and controlled evolution in the lab</a>, we’ve bolstered the efficiency of the originally found anti-nerve agent enzymes. Enzymes that initially showed only modest activity have been turned into potential therapeutics against VX – a chemical cousin of sarin and the most toxic nerve agent of all.</p>
<p>In a proof-of-concept study conducted jointly by researchers in Germany and Israel in late 2014, guinea pigs under anesthesia were exposed to lethal doses of VX, followed by optimized VX-destroying proteins. Low doses of the protein drug, even after a 15-minute delay, resulted in <a href="https://doi.org/10.1016/j.toxlet.2014.09.003">survival of all animals</a> and only moderate toxicity.</p>
<p>Despite these promising advances, no enzyme yet exists which is efficient enough for lifesaving use in people. Scientists are <a href="https://doi.org/10.1038/nchembio.777">refining these microscopic machines</a>, and <a href="https://doi.org/10.1038/nature19946">new paradigms in computer-aided protein engineering</a> are unlocking the door to this and other applications of biomolecular design. We may be only a few years away from developing the kind of therapeutics that would make chemical weapons a worry of the past. </p>
<p>As the world grieves over the latest attacks in Syria, it is worth keeping in mind the awesome and often complex power of science. In trying to combat hunger, one might accidentally invent liquid death. In studying soil microbes, one might discover a tool to prevent atrocities.</p><img src="https://counter.theconversation.com/content/75986/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Haydon works at the Institute for Protein Design and receives funding from the National Science Foundation.</span></em></p>Scientists invented chemical weapons; some are now working to destroy them. New biomolecular design techniques let researchers design proteins that can destroy nerve agents in bodies.Ian Haydon, Doctoral Student in Biochemistry, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/647582016-09-05T14:06:22Z2016-09-05T14:06:22ZTo avoid antibiotic apocalypse, we need to diagnose infections faster<figure><img src="https://images.theconversation.com/files/136594/original/image-20160905-4765-9j2299.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chop, chop. </span> <span class="attribution"><a class="source" href="https://www.google.co.uk/search?hl=en&authuser=0&site=imghp&tbm=isch&source=hp&biw=1440&bih=762&q=studying+microbes+in+the+lab&oq=studying+microbes+in+the+lab&gs_l=img.3...1139.7736.0.8023.30.14.1.14.14.0.170.1413.9j5.14.0....0...1ac.1.64.img..1.16.1417...0j0i24k1j0i10i24k1j0i30k1j0i8i30k1.LPaj_b0hpfI#q=studying+microbes+in+the+lab&hl=en&authuser=0&tbm=isch&tbs=sur:fc&imgrc=oHwxzFGE-Tg4DM%3A">USFDA</a></span></figcaption></figure><p>You will have heard of the “antibiotic apocalypse” – the nightmare scenario in which we run out of treatments for bacterial infections because too many bacteria have acquired antibiotic resistance. </p>
<p>It has been the subject of a <a href="http://www.resistancethefilm.com">major documentary</a> and endless books and articles. David Cameron, when prime minister of the UK, commissioned a <a href="http://amr-review.org">major review</a> on the subject, led by the distinguished economist Lord Jim O'Neill. England’s chief medical officer, Dame Sally Davies, <a href="https://www.theguardian.com/society/2016/may/19/englands-chief-medical-officer-warns-of-antibiotic-apocalypse">warned</a> that the apocalypse may already be upon us. I <a href="http://codi.beltanenetwork.org/event/codi-2016-the-antibiotic-apocalypse-threatens-us-all/">discussed it</a> at the Edinburgh Fringe recently as part of the Cabaret of Dangerous Ideas.</p>
<p>Being able to diagnose bacterial infections more quickly is seen as a key to the problem, as highlighted in the ten-point plan in O'Neill’s <a href="http://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf">final report</a> in May. At the moment, diagnoses take a number of days. If we could do them in minutes, it would reduce the need for “just in case” antibiotics and ensure that the correct antibiotic is given for the infection. It would also mean we stopped using them to treat infections caused by viruses. </p>
<p>Use fewer antibiotics and it would reduce the pressure on bacteria that results in them developing resistance. This would help our already limited range of antibiotics remain effective for longer. To incentivise the research community, the UK government set up the £10m <a href="https://longitudeprize.org">Longitude Prize</a> a couple of years ago. So how are we getting on?</p>
<h2>Diagnosing <em>Salmonella</em></h2>
<p>To give a sense of the challenge, take <em>Salmonella</em>. This bacteria can frequently cause gastroenteritis (food poisoning) from people eating contaminated meat, eggs and chicken, among other things. </p>
<p>In some countries, different types of <em>Salmonella</em> can cause more serious infections such as <a href="http://www.nhs.uk/Conditions/Typhoid-fever/Pages/Introduction.aspx">Typhoid fever</a>. This can be life-threatening to the elderly, newborns and those with defective immune systems – another reason why rapid diagnosis is important. </p>
<p>In the UK, clinical laboratories identify bacteria that cause infections according to the <a href="https://www.gov.uk/government/collections/standards-for-microbiology-investigations-smi">Standards for Microbiology Investigations (SMI)</a>. For <em>Salmonella</em>, the <a href="https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/443443/ID_24i3.pdf">standard practice</a> is to do four tests. </p>
<p>You start by growing a bacterial culture from a sample of blood or another bodily product in a petri dish – this scales up the bacteria and makes it easier to identify. Next the technician has to first analyse the bacterial cells under a microscope; then mix <em>Salmonella</em>-specific antibodies with a blood sample to look for signs of clumps forming (agglutination); then carry out biochemical tests that identify bacteria by revealing what kind of enzymes they possess. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=503&fit=crop&dpr=1 600w, https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=503&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=503&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=632&fit=crop&dpr=1 754w, https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=632&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/136595/original/image-20160905-4758-eew4bk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=632&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Your friendly neighbourhood Salmonella.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Salmonella_NIH.jpg">Wikimedia</a></span>
</figcaption>
</figure>
<p>Before any of this can begin, a patient needs to present at the clinic or hospital and provide a suitable sample. This may be a number of hours after the onset of infection. Growing a culture can take at least 24 hours. The microscope study and the agglutination only take minutes, but the enzyme testing will take another 24 hours. </p>
<p>Sometimes another prior step is necessary to make the bacteria easier to identify. In a blood sample, for example, bacteria might be present in low numbers which can affect test sensitivity. Or where it’s a faecal sample, there will be other bacteria present which could affect the sensitivity of any tests done. </p>
<p>This extra step can involve various ways of enriching the bacteria – for instance subjecting the sample to conditions that will favour the bacteria in question to the detriment of others. This will normally add another 24 hours. Put everything together and you’re talking about between two and five days from infection to diagnosis. </p>
<p>Other more rapid tests that have become possible in recent years. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943139/">Nucleic acid amplification tests</a> (NAATs) can identify bacteria based on the presence of their specific DNA within hours; and <a href="http://www.jove.com/video/50635/matrix-assisted-laser-desorptionionization-time-flight-maldi-tof-mass">MALDI-TOF mass spectometry</a> can identify bacteria in minutes from the protein components of their cells. Yet these require specialist equipment that is too expensive for many laboratories. Both still require a cultured sample, which again adds 24 hours. And NAATs in particular have limitations which can produce false results and inaccuracies.</p>
<h2>The way forward</h2>
<p>So where do we go from here? The Holy Grail is something analogous to a pregnancy test in terms of simplicity and speed. Such a test could be administered by a doctor or nurse at the point of first consultation and provide a diagnosis before your appointment is finished. </p>
<p>There is precedent for rapid disease diagnosis with the release of a <a href="http://hivselftest.co.uk/">self-test for HIV</a>, where you can obtain a result in about 15 minutes. Producing an equivalent test for bacterial infection is more complex, however. Where the HIV self-test works by detecting HIV antibodies, with bacterial infection it can take time for antibodies to be produced while the onset of symptoms can be rapid. Some bacteria are also covered in molecules which can fool the immune system so that no antibodies are produced. </p>
<p>Another hurdle that would need to be overcome is that any test would need to be able to distinguish the bacteria causing the infection from the <a href="http://www.gutmicrobiotaforhealth.com/en/glossary/commensal-bacteria/">harmless bacteria</a> we normally find in the body.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=367&fit=crop&dpr=1 600w, https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=367&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=367&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=461&fit=crop&dpr=1 754w, https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=461&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/136597/original/image-20160905-4760-1klsgu3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=461&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">‘I told you I’d be quick’.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Midwife#/media/File:US_Navy_midwife_checks_on_a_mom.jpg">Wikimedia</a></span>
</figcaption>
</figure>
<p>In short, the development of a new rapid method of diagnostics is by no means an easy task. I think it unlikely that either MALDI-TOF mass spectrometry or NAATs are the answer. In my laboratory we are trying to use our knowledge of bacterial physiology to think beyond these methods to design microbial sensors that can detect the harmful bacteria, but without the need for culture. I am aware that others are exploring developing a diagnostic that can sense whether an infection is present by identifying specific molecules produced by the body in response to infection. </p>
<p>Either way, I am optimistic that we will find a solution within the next five to ten years, and that it will come from a multidisciplinary approach from scientists, engineers and industry working in partnership. With £10m Longitude Prize on offer too, it’s a great incentive. For most working towards this, however, the real reward will be contributing to averting one of the most serious threats that humanity currently faces.</p><img src="https://counter.theconversation.com/content/64758/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Clare is General Secretary of the Society for Applied Microbiology.</span></em></p>How slow diagnosis of bacterial infections is exacerbating our antibiotics problem.Clare Taylor, Senior Lecturer in Medical Microbiology, Edinburgh Napier UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/559612016-03-10T19:06:05Z2016-03-10T19:06:05ZNew plastic-munching bacteria could fuel a recycling revolution<figure><img src="https://images.theconversation.com/files/114627/original/image-20160310-26271-1mmzp17.jpg?ixlib=rb-1.1.0&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>We manufacture over <a href="http://www.statista.com/statistics/282732/global-production-of-plastics-since-1950/">300m tonnes</a> of plastics each year for use in everything from packaging to clothing. Their resilience is great when you want a product to last. But once discarded, plastics linger in the environment, littering streets, fields <a href="https://theconversation.com/in-the-ocean-the-most-harmful-plastic-is-too-small-to-see-35336">and oceans alike</a>. Every corner of our planet <a href="https://theconversation.com/plastic-pollution-is-a-problem-we-still-know-too-little-about-22407">has been blighted</a> by our addiction to plastic. But now we may have some help to clean up the mess in the form of bacteria that have been found slowly munching away on discarded bottles in the sludge of a recycling centre.</p>
<p><a href="http://www.chem1.com/acad/webtext/states/polymers.html">Plastics are polymers</a>, long thin molecules made of repeating (monomer) building blocks. These are cross-linked to one another to build a durable, malleable mesh. Most plastics are made from carbon-based monomers, so in theory they are a good source of food for microorganisms.</p>
<p>But unlike natural polymers (such as cellulose in plants) <a href="http://www.livescience.com/33085-petroleum-derived-plastic-non-biodegradable.html">plastics aren’t generally biodegradable</a>. Bacteria and fungi co-evolved with natural materials, all the while coming up with new biochemical methods to harness the resources from dead matter. But plastics have only been around for about 70 years. So microorganisms simply haven’t had much time to evolve the necessary biochemical tool kit to latch onto the plastic fibres, break them up into the constituent parts and then utilise the resulting chemicals as a source of energy and carbon that they need to grow.</p>
<h2>Enzyme innovation</h2>
<p>Now a team at Kyoto University have, by rummaging around in piles of waste, found a <a href="http://science.sciencemag.org/cgi/doi/10.1126/science.aad6359">plastic munching microbe</a>. After five years of searching through 250 samples, they isolated a bacteria that could live on <a href="http://www.napcor.com/PET/whatispet.html">poly(ethylene terephthalate) (PET)</a>, a common plastic used in bottles and clothing. They named the new species of bacteria <em>Ideonella sakaiensis</em>.</p>
<p>You may think this is the rerun of an old story, as plastic-eating microbes have already been touted as <a href="http://www.natureworldnews.com/articles/8922/20140908/plastic-eating-fungus-may-solve-worlds-waste-problems.htm">saviours of the planet</a>. But there are several important differences here. First, previous reports were of tricky-to-cultivate fungi, where in this case the microbe is easily grown. The researchers more or less left the PET in a warm jar with the bacterial culture and some other nutrients, and a few weeks later all the plastic was gone. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=441&fit=crop&dpr=1 600w, https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=441&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=441&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=554&fit=crop&dpr=1 754w, https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=554&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/114623/original/image-20160310-26261-87xcj8.jpg?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">
<figcaption>
<span class="caption">Bottle breakdown.</span>
<span class="attribution"><a class="source" href="http://science.sciencemag.org/cgi/doi/10.1126/science.aaf2853">Illustration: P. Huey. Reprinted with permission from U.T. Bornscheuer, Science 351:1154 (2016).</a></span>
</figcaption>
</figure>
<p>Second - and the real innovation - is that the team have identified the enzymes that <em>Ideonella sakaiensis</em> uses to breakdown the PET. All living things <a href="http://www.rsc.org/Education/Teachers/Resources/cfb/enzymes.htm">contain enzymes</a> that they use to speed up necessary chemical reactions. Some enzymes help digest our food, dismantling it into useful building blocks. Without the necessary enzymes the body can’t access certain sources of food. </p>
<p>For example, people who are lactose intolerant don’t have the enzyme that breaks down the lactose sugar found in dairy produce. And no human can digest cellulose, while some microbes can. <em>Ideonella sakaiensis</em> seems to have evolved an efficient enzyme that the bacteria produces when it is in an environment that is rich in PET.</p>
<p>The Kyoto researchers identified the gene in the bacteria’s DNA that is responsible for the PET-digesting enzyme. They then were able to manufacture more of the enzyme and then demonstrate that PET could be broken down with the enzyme alone.</p>
<h2>First real recycling</h2>
<p>This opens a whole new approach to plastic recycling and decontamination. At present, most plastic bottles are not truly recycled. Instead they are melted and reformed into other hard plastic products. Packaging companies <a href="http://www.ciwm-journal.co.uk/coca-cola-commits-to-decreasing-virgin-plastics-in-packaging/">typically prefer</a> freshly made “virgin” plastics that are created from chemical starting materials that are usually derived from oil.</p>
<p>The PET-digesting enzymes offer a way to truly recycle plastic. They could be added to vats of waste, breaking all the bottles or other plastic items down into into easy-to-handle chemicals. These could then be used to make fresh plastics, producing a true recycling system.</p>
<p>Manufactured enzymes are already used to great effect in a wide range of everyday items. <a href="http://www.rsc.org/images/TM0313%20Trade%20secrets%20-%20bio%20or%20non-bio%20washing%20powder_tcm18-230874.pdf">Biological washing powders</a> contain enzymes that digest fatty stains. The enzymes known as rennet that are used to harden cheese once came from calfs’ intestines but are now manufactured using <a href="http://blogs.scientificamerican.com/food-matters/do-gmo-opponents-have-a-problem-with-cheese/">genetically engineered bacteria</a>. Maybe we can now use a similar manufacturing method to clean up our mess.</p><img src="https://counter.theconversation.com/content/55961/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Lorch is member of the Royal Society of Chemistry.</span></em></p>Scientists have discovered the first easy-to-grow bacteria that can break down plastics.Mark Lorch, Senior Lecturer in Biological Chemistry, Associate Dean for Engagement, University of HullLicensed as Creative Commons – attribution, no derivatives.