tag:theconversation.com,2011:/africa/topics/protein-synthesis-3731/articlesProtein synthesis – The Conversation2022-11-02T12:29:28Ztag:theconversation.com,2011:article/1927102022-11-02T12:29:28Z2022-11-02T12:29:28ZWater was both essential and a barrier to early life on Earth – microdroplets are one potential solution to this paradox<figure><img src="https://images.theconversation.com/files/492830/original/file-20221101-26-hkb6tg.png?ixlib=rb-1.1.0&rect=5%2C0%2C1724%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Water microdroplets provide a unique interface that can significantly speed up chemical reactions.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/macro-abstract-of-water-drops-on-a-mid-blue-royalty-free-image/1356063821">Marianna Armata/Moment via Getty Images</a></span></figcaption></figure><p>It’s a <a href="https://doi.org/10.1021/acs.jpca.1c02864">paradox</a>: Life needs water to survive, but a world full of water can’t generate the biomolecules that would have been essential for early life. Or so researchers thought.</p>
<p>Water is everywhere. <a href="https://www.usgs.gov/special-topics/water-science-school/science/water-you-water-and-human-body">Most of the human body</a> is made of it, <a href="https://www.usgs.gov/special-topics/water-science-school/science/how-much-water-there-earth">much of planet Earth</a> is covered by it and humans can’t survive more than a <a href="https://www.jstor.org/stable/45016189">couple of days without drinking it</a>. Water molecules have <a href="https://sitn.hms.harvard.edu/uncategorized/2019/biological-roles-of-water-why-is-water-necessary-for-life/">unique characteristics</a> that allow them to dissolve and transport compounds through your body, provide structure to your cells and regulate your temperature. In fact, the basic chemical reactions that enable life as we know it require water, <a href="https://education.nationalgeographic.org/resource/photosynthesis">photosynthesis</a> being one example.</p>
<p>However, when the first biomolecules like proteins and DNA started coming together in the early stages of planet Earth, water was actually a barrier to life.</p>
<p>The reason why is surprisingly simple: The presence of water prevents chemical compounds from losing water. Take, for example, proteins, which are one of the main classes of biological molecules that make up your body. Proteins are, in essence, chains of amino acids linked together by chemical bonds. These bonds are formed through a <a href="https://chem.libretexts.org/Bookshelves/Introductory_Chemistry/Introductory_Chemistry_(CK-12)/25%3A_Organic_Chemistry/25.18%3A_Condensation_Reactions">condensation reaction</a> that results in the loss of a molecule of water. Essentially, the amino acids need to get “dry” in order to form a protein.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of condensation reaction joining two amino acids with a peptide bond" src="https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=382&fit=crop&dpr=1 600w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=382&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=382&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=480&fit=crop&dpr=1 754w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=480&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/492807/original/file-20221101-19-oovg5j.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=480&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Condensation reactions join amino acids by losing a molecule of water.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:CNX_Chem_20_04_peptide.png">OpenStax/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Considering that Earth before life was <a href="https://doi.org/10.1126/science.abh4289">covered in water</a>, this was a <a href="https://doi.org/10.1073/pnas.1210029109">big problem</a> for making the proteins essential to life. Like trying to get dry inside of a swimming pool, two amino acids would have had a hard time losing water to come together in the <a href="https://doi.org/10.1007/978-3-662-44185-5_1275">primordial soup</a> of early Earth. And it wasn’t only proteins that faced this problem in the presence of water: Other biomolecules essential to life, including DNA and complex sugars, also rely on condensation reactions and losing water to form.</p>
<p>Over the years, researchers have proposed many solutions to this “water paradox.” Most of them rely on very specific scenarios on early Earth that could have allowed water removal. These include <a href="https://doi.org/10.1002/anie.201503792">drying puddles</a>, <a href="https://doi.org/10.1038/s41467-017-02248-y">mineral surfaces</a>, <a href="https://doi.org/10.1089/ast.2019.2045">hot springs</a> and <a href="https://doi.org/10.1126/science.283.5403.831">hydrothermal vents</a>, among others. These solutions, while plausible, require particular geological and chemical conditions that might not have been commonplace.</p>
<p>In our <a href="https://doi.org/10.1073/pnas.2212642119">recent study</a>, <a href="https://aston.chem.purdue.edu/index.html">my colleagues</a> <a href="https://scholar.google.com/citations?user=aC4GqPMAAAAJ&hl=en">and I</a> found a simpler and more general solution to the water paradox. Quite ironically, it might be water itself – or to be more precise, very small water droplets – that allowed early biomolecules to form.</p>
<h2>Why microdroplets?</h2>
<p>Water droplets are everywhere, both in the modern world and especially during prebiotic (or pre-life) Earth. In a planet covered by crashing waves and raging tides, the small water droplets in <a href="https://doi.org/10.1021/ar300027q">sea spray and other aerosols</a> would have plausibly provided a simple and abundant place for the <a href="https://doi.org/10.1073/pnas.200366897">first biomolecules to assemble</a>.</p>
<p>Water microdroplets – typically very small droplets with diameters <a href="https://doi.org/10.1007/s13361-019-02264-w">around a millionth of a meter</a>, far smaller than the <a href="http://scienceline.ucsb.edu/getkey.php?key=6105">diameter of spider silk</a> – might not seem to solve the water paradox at first, until you consider the very particular chemical environments they create.</p>
<p>Microdroplets have a substantial surface area-to-volume ratio that <a href="https://doi.org/10.1002/jms.4585">gets larger the smaller the droplet is</a>. This means there is a significant space where the solvent they are made of (in this case, water) and the medium they are surrounded by (in this case, air) meet.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/fxlMABxU7zU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The chemical properties of water are what make it so important to life.</span></figcaption>
</figure>
<p>Over the years, researchers have shown that the air-water interface is a unique chemical environment. The chemistry of these microdroplet interfaces is dominated by <a href="https://doi.org/10.1038/s41467-021-27941-x">large electric fields</a>, <a href="https://doi.org/10.1002/cplu.202100373">partial solvation</a> where molecules are partially surrounded by water, <a href="https://doi.org/10.1073/pnas.1911883116">highly reactive molecules</a> and <a href="https://doi.org/10.1039/D0SC02467H">very high acidity</a>. All these factors allow microdroplets to accelerate the chemical reactions that occur in them.</p>
<p><a href="https://aston.chem.purdue.edu/">Our lab</a> has been studying microdroplets for a <a href="https://doi.org/10.1039/C0SC00416B">decade</a>, and our previous work has shown how the rate of common chemical reactions can be sped up to a <a href="https://doi.org/10.1146/annurev-physchem-121319-110654">million times</a> faster in microdroplets. Reactions that would have taken a full day could now be complete in just a fraction of a second using these small droplets.</p>
<p>In <a href="https://doi.org/10.1073/pnas.2212642119">our recent work</a>, we proposed that microdroplets could be a solution to the water paradox because their air-water interface not only accelerates reactions but also acts as a “drying surface” that facilitates the reactions needed to create biomolecules despite the presence of water.</p>
<p>We tested this theory by spraying amino acids dissolved in microdroplets of water toward a <a href="https://www.broadinstitute.org/technology-areas/what-mass-spectrometry">mass spectrometer</a>, an instrument that can be used to analyze the products of a chemical reaction. We found that two amino acids can successfully join together in the presence of water via microdroplets. When we added more amino acids and collided two sprays of this mixture together, mimicking crashing waves in the prebiotic world, we found that this can form short peptide chains of up to six amino acids. </p>
<p>Our findings suggest that water microdroplets in settings like sea spray or atmospheric aerosols were fundamental microreactors in early Earth. In other words, microdroplets may have provided a chemical medium that allowed the basic molecules of life to form from the simple, small compounds dissolved in the vast primordial ocean that covered the planet.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Close-up of water droplets against clear background" src="https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/492828/original/file-20221101-28600-be0m5m.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Water microdroplets may have provided the chemical environment necessary for life.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/water-drops-on-a-clear-white-background-royalty-free-image/1356063793">Marianna Armata/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>Microdroplets past and future</h2>
<p>The chemistry of microdroplets might be helpful in tackling current challenges across many scientific fields. </p>
<p>Drug discovery, for example, requires synthesizing and testing hundreds of thousands of compounds to find a potential new drug. The power of microdroplet reactions can be integrated with automation and new tools to speed up synthesis rates to <a href="https://doi.org/10.1177/24726303211047839">more than one reaction per second</a> as well as <a href="https://doi.org/10.1002/anie.202009598">biological analysis</a> to less than a second per sample.</p>
<p>In this way, the same phenomenon that might have aided the origin of the building blocks of life billions of years ago can now help scientists develop new medicines and materials faster and more efficiently.</p>
<p>Perhaps <a href="https://www.worldcat.org/title/1328130044">J.R.R. Tolkien</a> was right when he wrote: “Such is oft the course of deeds that move the wheels of the world: small hands do them because they must, while the eyes of the great are elsewhere.”</p>
<p>I believe the importance of these small droplets is far bigger than their tiny size.</p><img src="https://counter.theconversation.com/content/192710/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nicolás M. Morato received funding from Eastman Chemical Company through a Summer Fellowship in Analytical Chemistry (Jun - Aug 2021) and from the Division of Analytical Chemistry of the American Chemical Society through a Graduate Fellowship sponsored by Agilent Technologies (Sep 2021 - May 2022). </span></em></p>The chemical reaction that forms essential biomolecules like proteins and DNA normally doesn’t occur in the presence of water. Microdroplets provide a unique environment that make it possible.Nicolás M. Morato, PhD Candidate in Chemistry, Purdue UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1875152022-08-01T12:27:02Z2022-08-01T12:27:02ZHelping cells become better protein factories could improve gene therapies and other treatments – a new technique shows how<figure><img src="https://images.theconversation.com/files/476727/original/file-20220729-13650-l4tehb.jpg?ixlib=rb-1.1.0&rect=5%2C0%2C1991%2C1500&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Your genetic material instructs your cells to produce the proteins encoded in it.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/protein-synthesis-illustration-royalty-free-illustration/1296294290">Juan Gaertner/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The cells in your body are <a href="https://www.ncbi.nlm.nih.gov/books/NBK26885/">not all the same</a>. Each of your organs has cells with very different functions. For example, liver cells are top-notch secretors, as their job requires them to make and export many of the proteins in your blood. By contrast, muscle cells are tasked with facilitating the contractions that allow you to move. </p>
<p>The fact that cells are so specialized has implications for <a href="https://medlineplus.gov/genetics/understanding/therapy/procedures/">gene therapy</a>, a way to treat genetic diseases by correcting the source of the error in a patient’s DNA. Health providers use a harmless <a href="https://patienteducation.asgct.org/gene-therapy-101/vectors-101">viral or bacterial vector</a> to carry a corrective gene into a patient’s cells, where the gene then directs the cell to produce the proteins necessary to treat the disease. Muscle cells are a common target because gene therapies <a href="https://medlineplus.gov/genetics/understanding/therapy/procedures/">injected into the muscle</a> are more accessible than introduction into the body by other routes. But muscle cells may not produce the desired protein as efficiently as needed if the job the gene instructs it to do is very different from the one it specializes in.</p>
<p>We are <a href="https://scholar.google.com/citations?user=SPyKrnIAAAAJ&hl=en">cell biologists</a> and <a href="https://scholar.google.com/citations?user=PL6N9eoAAAAJ&hl=en">biophysicists</a> who study how healthy proteins are produced and maintained in cells. This field is called <a href="https://doi.org/10.1093%2Fgerona%2Fgln071">protein homeostasis, also known as proteostasis</a>. Our <a href="https://dx.doi.org/10.1073/pnas.2206103119">recently published study</a> details a way to make muscle cells behave more like liver cells by changing protein regulation networks, enhancing their ability to respond to gene therapy and treat genetic diseases.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/BxEoX6TkitY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Gene therapy involves replacing a defective gene with a functioning one that can direct cells to produce missing or dysfunctional proteins.</span></figcaption>
</figure>
<h2>Boosting protein factories</h2>
<p>One disease for which gene therapy has great potential is <a href="http://doi.org/10.1056/NEJMra1910234">alpha-1 antitrypsin (AAT) deficiency</a>, a condition in which liver cells are unable to make adequate amounts of the protein AAT. It results in a breakdown of lung tissue that can cause <a href="https://www.uncoveralpha1.com/what-is-alpha-1">serious respiratory problems</a>, including the development of severe lung diseases such as chronic obstructive pulmonary disease (COPD) or emphysema. </p>
<p>Patients are usually treated by <a href="https://www.nhlbi.nih.gov/health/alpha-1-antitrypsin-deficiency">receiving AAT via infusion</a>. But this requires patients to either make regular trips to the hospital or keep expensive equipment at home for the rest of their lives. Replacing the faulty gene that caused their AAT shortage in the first place could be a boon for patients. Current gene therapies inject the AAT-producing gene into muscle. One of our colleagues, <a href="https://scholar.google.com/citations?user=Sd6B6-UAAAAJ&hl=en">Terence Flotte</a>, developed a way to use a harmless version of an adeno-associated virus as a vehicle to deliver AAT gene therapies into the body via injection, allowing for <a href="https://doi.org/10.1016/j.ymthe.2017.03.029">sustained release of the protein</a> over several years.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of panlobular emphysema" src="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=404&fit=crop&dpr=1 600w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=404&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=404&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=507&fit=crop&dpr=1 754w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=507&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=507&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Lung damage from alpha-1 antitrypsin deficiency can lead to emphysema.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/8TqvpQ">Atlas of Pulmonary Pathology/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
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<p>But muscle cells aren’t very good at producing the AAT proteins the gene instructs them to make. Flotte and his team found that AAT levels one to five years after gene therapy were <a href="https://doi.org/10.1016/j.ymthe.2017.03.029">only 2% to 2.5%</a> of the optimal concentration for therapeutic effect.</p>
<p>We wanted to find a way to turn muscle cells into better protein factories, like liver cells. We tested a number of different molecules on mice muscle cells to determine if they would boost AAT secretion. We found that adding a molecule called <a href="https://doi.org/10.1074/jbc.M112.404707">suberoylanilide hydroxamic acid, or SAHA</a>, helps muscle cells make AAT at a production level more like that of liver cells. It works because SAHA is a <a href="https://doi.org/10.7554%2FeLife.15550">proteostasis regulator</a> with the ability to boost the cell’s protein output.</p>
<p>Down the road, we believe that adding SAHA or similar proteostasis regulators to gene therapies could help increase the effectiveness of these treatments for many genetic diseases.</p>
<h2>Beyond gene therapy</h2>
<p>Our findings have implications beyond just gene therapies. The effectiveness of <a href="https://doi.org/10.1038/s41573-021-00283-5">mRNA vaccines</a>, for example, is also affected by how well each cell produces a particular type of protein. Because most mRNA vaccines are given through an injection to the muscle, they may also face the same limitations as gene therapies and produce a lower-than-desirable immune response. Increasing the protein production of muscle cells could potentially improve vaccine immunity.</p>
<p>Additionally, many drugs created by the biotech industry called <a href="https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers">biologics</a> that are derived from natural sources rely heavily on a given cell’s <a href="https://doi.org/10.3389/fbioe.2019.00420">protein production capabilities</a>. But many of these drugs use <a href="https://weekly.biotechprimer.com/biomanufacturing-how-biologics-are-made/">cells that aren’t specialized to make large amounts of protein</a>. Adding a protein homeostasis enhancer to the cell could optimize protein yield and increase the effectiveness of the drug.</p>
<p>Protein homeostasis is a burgeoning field that goes beyond drug development. Many <a href="https://doi.org/10.1038/s41580-019-0101-y">neurodegenerative diseases</a> like Alzheimer’s and Parkinson’s are linked to abnormal protein regulation. The deterioration of a cell’s ability to manage protein production and use over time may contribute to age-related diseases. Further research on ways to improve the cellular machinery behind protein homeostasis could help delay aging and open many new doors for treating a wide range of diseases.</p><img src="https://counter.theconversation.com/content/187515/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Daniel N. Hebert receives funding from Alpha One Foundation and NIH/NIGMS. </span></em></p><p class="fine-print"><em><span>Lila Gierasch receives funding from NIH/NIGMS and the Alpha1 Foundation.</span></em></p>Gene therapies and vaccines are often injected into muscle cells that are inefficient at producing desired proteins. Making them work more like liver cells could lead to better treatment outcomes.Daniel N. Hebert, Professor of Biochemistry and Molecular Biology, UMass AmherstLila Gierasch, Distinguished Professor of Biochemistry and Molecular Biology, UMass AmherstLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/841792017-10-31T16:07:36Z2017-10-31T16:07:36ZSynthetic sex in yeast promises safer medicines for people<figure><img src="https://images.theconversation.com/files/192654/original/file-20171031-18720-13bi7tz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">What can mating yeast tell us about new drugs?</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/conchur/13316830914">Conor Lawless</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Our old friend <em>Saccharomyces cerevisiae</em> – the yeast that’s helped people bake bread and brew beer <a href="https://doi.org/10.1073/pnas.0407921102">for millennia</a> – has just had its sex life upgraded.</p>
<p>Bioengineers at the University of Washington have <a href="https://doi.org/10.1073/pnas.1705867114">reprogrammed the mating habits</a> of this single-celled organism, letting the fungus get it on like never before. The result? A sexual revolution that could lead scientists to safer future medicines.</p>
<h2>Yeast as lab guinea pig</h2>
<p>We already rely on yeast for a lot more than just fermented food. Much of our modern understanding of genetics and cell biology has come from careful study and manipulation of the fungus.</p>
<p>Scientists and drug designers love <a href="http://doi.org/10.1038/nrc1372">working with yeast</a> because of its rapid cell cycle (a new generation is born every 90 minutes) and the relative ease with which its genes can be tweaked. Even human genes and genes encoding protein-based drugs can be spliced in, allowing researchers to study them in the lab in detail. Anti-cancer drugs <a href="http://dx.doi.org/10.1038/nri1837">have been optimized</a> this way. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=408&fit=crop&dpr=1 600w, https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=408&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=408&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=512&fit=crop&dpr=1 754w, https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=512&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/186279/original/file-20170917-8076-cg1xmj.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=512&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Our species’ relationship with yeast predates our use of gold, horses and writing.</span>
<span class="attribution"><span class="source">Ian Haydon</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>One of the most popular techniques for this type of biomolecular research is known as <a href="https://doi.org/10.1038/nbt0697-553">yeast surface display</a>. Using this method, a gene can be added to yeast and the protein that results will appear on the easily accessible outer surface of the cell. With a new protein displayed on the surface, researchers can easily determine what other biomolecules the protein interacts with.</p>
<p>This method, pioneered in the laboratory of <a href="http://kdw-lab.mit.edu/">Dane Wittrup</a>, exploits aspects of the fungus’ sexual machinery.</p>
<p>Yes, even single-cell microbes can have sex. But as is often the case outside the animal kingdom, the way DNA gets swapped can seem unusual to human observers.</p>
<h2>Fungal fornication</h2>
<p>The terms “male” and “female” don’t really apply to budding yeast. Instead of forming sperm or eggs, the sex cells of yeast all look the same – like tiny, single-cell blobs. What makes two yeast blobs able to sexually reproduce are their so-called mating types.</p>
<p>The proteins that decorate the outside of a yeast sex cell, or gamete, determine that cell’s mating type. Put on copies of one protein and you’re one mating type; swap them out for a different protein and you’re the other. Agglutination (the unsexy term for yeast sex) only happens when the surface proteins of yeast gametes from opposite mating types interact.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=387&fit=crop&dpr=1 600w, https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=387&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=387&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=487&fit=crop&dpr=1 754w, https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=487&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/186262/original/file-20170916-8121-vevpb8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=487&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Single-celled yeast as seen under a scanning electron microscope.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Saccharomyces_cerevisiae_SEM.jpg">Mogana Das Murtey and Patchamuthu Ramasamy</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Inspired by this molecular precision, a team of synthetic biologists led by University of Washington graduate student David Younger realized they could convert the natural yeast mating system into a new tool that would let them precisely measure molecular interactions at a much larger scale. </p>
<p>Though tiny and difficult to measure, molecular interactions are a big deal in drug design. Virtually every drug works via specific interactions with its target, and drugs that bind where they shouldn’t can be lethal.</p>
<p>Some experts blame off-target interactions for last year’s failed phase III clinical trial of Alnylam Pharmaceuticals’ revusiran, an RNA drug designed to treat a rare heart disease. <a href="https://doi.org/10.1038/nbt1216-1213">Nineteen people died</a> before the trial was called off, and the company’s stock took a <a href="https://www.businessinsider.com.au/alnylam-stock-down-after-drug-trial-discontinued-2016-10">US$3 billion hit</a>.</p>
<p>Figuring out whether a new drug binds what it’s supposed to is relatively easy; figuring out whether it binds anything else in our cells is tough. Established laboratory techniques like yeast surface display have helped scientists screen new drugs for potentially dangerous off-target interactions before they make it to clinical trials, but that technique lets you look for off-target interactions only one at a time. Younger’s team envisioned a way to test hundreds of drugs against thousands of potential targets, all by redesigning yeast sex.</p>
<h2>Redesigning yeast sex with multiple mating types</h2>
<p>To start, Younger needed a way to precisely measure mating efficiency in lab-grown yeast. Perfect efficiency would mean every cell that could fuse would do so. The more efficient the mating, the better matched the two mating types.</p>
<p>The team linked genetically encoded fluorescent markers – one blue, one red – to each of the natural yeast mating types. That made it simple to measure mating efficiency for a whole yeast population: They could just count the cells that stayed blue or red (unmated) versus those that turned purple (mated). It turns out for typical yeast grown in the lab, mating efficiency is around 60 percent.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/192653/original/file-20171031-18730-17dpxn9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Example of fluorescent-tagged yeast, in this case red and green. Together the markers look yellow.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Yeast_membrane_proteins.jpg">Masur</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>The team then deleted the natural agglutination proteins and replaced them with a pair of foreign proteins known to interact weakly. The mating efficiency dropped tenfold to 5.7 percent. They swapped in another pair and saw it rise to 19 percent. When they tried a third pair of proteins known to interact with much higher affinity, mating efficiency rose to 51.6 percent – close to what was seen in natural agglutination.</p>
<p>Just by tracking mating efficiency, the team could tell how strongly any two protein molecules interact. When they checked a pair of proteins that shouldn’t interact at all, mating efficiency was a meager 0.2 percent.</p>
<p>Now, instead of just the two natural mating types, <a href="https://doi.org/10.1073/pnas.1705867114">scientists can quickly engineer thousands of “sexes”</a> by coaxing individual yeast to decorate the outside of their cells with new, human-specified proteins. If a pair of new mating types are sexually compatible – meaning the proteins decorating their cell surfaces interact – their offspring will rise in number. By tallying up each genetically distinct offspring in a tube not much bigger than a thimble, thousands of potential molecular interactions can be quantified.</p>
<h2>Improving drug safety</h2>
<p>To show that their new tool could aid in drug development, the team generated 1,400 distinct variants of an emerging anti-cancer drug known as <a href="https://doi.org/10.7554/eLife.20352">XCDP07</a>. The drug is supposed to disrupt the unrestrained growth of cancer cells by binding specific cellular targets, but as with every drug, significant off-target interactions could render it useless. By mixing yeast displaying different versions of the drug with other yeast displaying human proteins, the team was able to identify versions of XCDP07 which only bound to the intended target.</p>
<p>Younger is working to get his new tool into the hands of more scientists. He’s already gifted his engineered yeast strains to eager researchers at Stanford, Yale, UCSD and beyond. Concerns over the cost and safety of emerging drugs have motivated him to start a company – funded by scientific grants, not investors – to turn his results into the next generation of medicines. Younger says the goal is to provide “comprehensive preclinical drug screening, rather than the current practice of screening a very small subset of possible off-target interactions.”</p>
<p>The next blockbuster drugs may owe a debt to yeast and their mating practices. Who says you can’t teach an old fungus new tricks?</p><img src="https://counter.theconversation.com/content/84179/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Haydon is a researcher at the Institute for Protein Design at the University of Washington.</span></em></p>By exploiting the way yeast cells mate, researchers have figured out a quicker, easier way to identify on- and off-target drug interactions.Ian Haydon, Doctoral Student in Biochemistry, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/373122015-02-13T13:23:59Z2015-02-13T13:23:59ZArtificial proteins could bring the next biological revolution – starting with MRI<figure><img src="https://images.theconversation.com/files/71868/original/image-20150212-13192-1bv8ffj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Complex but mighty useful.</span> <span class="attribution"><span class="source">molekuul.be</span></span></figcaption></figure><p>Scientists and engineers have looked to nature for their inspiration for centuries. The field of <a href="https://theconversation.com/simply-copying-nature-is-no-way-to-succeed-at-inventing-just-ask-leonardo-da-vinci-27403">biomimetics</a> uses ideas from nature to solve complex human challenges. </p>
<p><a href="https://theconversation.com/if-synthetic-biologists-think-like-scientists-they-may-miss-their-eureka-moment-25960">Synthetic biology</a>, a more recent concept, focuses on the design of artificial devices or systems with biological or “bio-like” functions. This covers a wide range of applications – but perhaps the most fascinating biological “device” we could wish to emulate is the protein.</p>
<p>Proteins are responsible for many of the key processes of life such as respiration and photosynthesis. They perform complex functions such as transferring electrons or breaking chemical bonds. </p>
<p>But look closer into these systems and you quickly learn that the central part of the process is often not the protein itself, but the metal ion nestled inside the protein. The rest of the protein provides a sophisticated scaffold to delicately tune the properties of the metal ion.</p>
<p>If you have ever looked at a periodic table, you will know that there are a lot of metals. However, if you start looking at nature, you quickly realise that biology is not particularly imaginative. Metal-containing proteins – metalloproteins, as they are called – tend to use metals from the first row of the transition elements. Many of these only involve iron or copper. </p>
<p>On the whole, this is a matter of convenience. Some metals are more abundant than others. It makes sense that life should not need elements which are only found deep inside the earth’s crust.</p>
<p>And yet, with the few metals that it has chosen, life’s processes are some of the most efficient chemical processes we know. This is where the importance of the protein becomes apparent. This carefully folded, complex organic molecule is what enables the simple metal centre to perform such an astonishing range of tasks.</p>
<h2>Designer proteins</h2>
<p>Given this knowledge, it might seem that we can achieve anything. Surely if there is a reaction that needs to be performed, we just need to choose a metal and design the right environment for it? Unlike nature, we have the entire periodic table to play with.</p>
<p>The trouble is that proteins are so much more sophisticated than anything we can achieve synthetically. If we try and reproduce this biological activity we tend to fail. The other problem is that our required environments might contain features that are not found in native proteins. Also, proteins are stable only in a narrow temperature range and do not tolerate changes in their environment. So can we harness the advantages of nature but without the need for such enormous and complex molecules?</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&rect=0%2C56%2C568%2C462&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=555&fit=crop&dpr=1 600w, https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=555&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=555&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=697&fit=crop&dpr=1 754w, https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=697&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/71383/original/image-20150207-28601-um7wdi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=697&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">An atom of gallodinium, surrounded by artificial protein coiled-coils.</span>
<span class="attribution"><a class="source" href="http://pubs.acs.org/doi/pdf/10.1021/ja408741h">Matthew R. Berwick et al. JACS 2014</a></span>
</figcaption>
</figure>
<p>A <a href="http://www.birmingham.ac.uk/staff/profiles/chemistry/peacock-anna.aspx">group</a> led by Anna Peacock at the University of Birmingham is doing just this. They design miniature artificial proteins that bridge the gap between conventional synthetic molecules and the leviathans of biology. </p>
<p>Peacock is particularly interested in metals called lanthanides. There are no known biological roles for these metals, but huge industrial interest. She has recently collected some <a href="http://pubs.acs.org/doi/pdf/10.1021/ja408741h">remarkable evidence</a> to back up this idea. This evidence comes in the form of a rather beautiful gadolinium complex.</p>
<h2>Better markers for MRI</h2>
<p>Gadolinium, a lanthanide metal, is used widely in applications such as medical imaging. Compounds containing the metal are injected into the body to enhance contrast in MRI (magnetic resonance imaging) scans. What Peacock and colleagues have done is to capture gadolinium ions inside short sections of synthetic protein. </p>
<p>Many proteins form spiral structures called alpha helices. The new gadolinium miniature protein is made up of a gadolinium ion surrounded by three of these helices making a “coiled coil”. This is a bit like the multiple coiled structures you might see in a length of rope in which a coiled strong is then coiled again, multiple times to form something thicker and stronger.</p>
<p><a href="https://theconversation.com/fishing-for-artificial-muscles-nets-a-very-simple-solution-23417">Coiled coils</a> in themselves are not new. What is remarkable about this work is that by binding gadolinium inside a coiled coil, it is possible to achieve much greater MRI efficiency than standard gadolinium complexes made with small molecules. What is even more significant is that the position of the gadolinium within the coiled coil is critical to its function. This means that it is the extended environment of the miniature protein that is changing the properties of the metal.</p>
<p>This remarkable protein-like behaviour is just the beginning. The motivation for the work spreads far beyond this gadolinium story. As Peacock told me: “Nature can achieve so much with just a few metals. If we can carefully design new metal environments then perhaps we can achieve chemistry that were never thought possible.”</p><img src="https://counter.theconversation.com/content/37312/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Zoe Schnepp 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>Scientists and engineers have looked to nature for their inspiration for centuries. The field of biomimetics uses ideas from nature to solve complex human challenges. Synthetic biology, a more recent concept…Zoe Schnepp, Research Fellow in Chemistry, University of BirminghamLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/351132014-12-08T05:59:21Z2014-12-08T05:59:21ZGrannies get physical: how bodybuilding may hold the key to a major ageing problem<figure><img src="https://images.theconversation.com/files/66405/original/image-20141205-8636-1o6ueej.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Take the strain.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/zanthia/12559719874/in/photolist-dYDztz-mb5m5q-jY5ysa-77XGzc-4Jw5o6-g8qAXS-e4raaW-fH6Ph-HZE2q-49qQ6-5NJx7r-7i1ev7-3yjeZZ-4Th99-6MUCzs-oykbfG-cWzreC-k8RR9o-jdzB6-aBzRb3-2ucE28-dJfAWQ-ack1Um-3Nh2iX-6zZbT8-85vyQU-41Xxu6-7MPe4X-7dNx9J-7MTatq-6c6j58-GegbS-pXuzyn-aqYwvB-4fdWhG-5ms878-7fpw6k-ht5VXC-pkgLv8-ijvuXU-Q6gpV-9c3Nfe-jsAb5-abej5Y-4191na-mtYRPv-88gJ3-ATDA-4zDCFX-9qNDQC">Chris Zielecki</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>People have used bodybuilding to improve their physical performance for at least 1,500 years. The first recorded example was the sixth-century wrestler, <a href="http://www.britannica.com/EBchecked/topic/383062/Milo-of-Croton">Milo of Croton</a>, in southern Italy. Milo reportedly carried out his daily exercises with a calf on his back. As the calf grew into a full sized ox, so too did Milo’s legendary strength. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=839&fit=crop&dpr=1 600w, https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=839&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=839&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1055&fit=crop&dpr=1 754w, https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1055&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/66407/original/image-20141205-8658-15e3wjo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1055&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Milo, original muscle man.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/zanthia/12559719874/in/photolist-dYDztz-mb5m5q-jY5ysa-77XGzc-4Jw5o6-g8qAXS-e4raaW-fH6Ph-HZE2q-49qQ6-5NJx7r-7i1ev7-3yjeZZ-4Th99-6MUCzs-oykbfG-cWzreC-k8RR9o-jdzB6-aBzRb3-2ucE28-dJfAWQ-ack1Um-3Nh2iX-6zZbT8-85vyQU-41Xxu6-7MPe4X-7dNx9J-7MTatq-6c6j58-GegbS-pXuzyn-aqYwvB-4fdWhG-5ms878-7fpw6k-ht5VXC-pkgLv8-ijvuXU-Q6gpV-9c3Nfe-jsAb5-abej5Y-4191na-mtYRPv-88gJ3-ATDA-4zDCFX-9qNDQC">Wikimedia</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>In the 1940s this concept of what has come to be known as progressive resistance exercise was developed more scientifically by US Army physician <a href="http://www.ncbi.nlm.nih.gov/pubmed/22592167">Thomas DeLorme</a> to assist the recovery of injured service men and polio sufferers. It is a simple idea: lift a weight you can manage for a set routine and when after numerous training sessions it becomes too light, increase the weight. You repeat the process over and over and it leads to substantially improved strength. This is because the muscle adapts by growing to deal with heavier loads. DeLorme applied these principles to his own physical training and is said to have been formidably strong. </p>
<h2>Our little protein factories</h2>
<p>Thanks to these insights, in modern-day bodybuilding we now have a very good idea of how to improve muscle mass and strength. Muscle growth with progressive resistance exercise is a good example of how adaptable our skeletal muscle is. Part of the mechanism by which muscle grows is through a process called protein synthesis. Muscle grows by increasing the rate at which proteins are made, since muscle is made from protein. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/66408/original/image-20141205-8655-bv16rr.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>
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<span class="caption">So macho!</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/cat.mhtml?lang=en&language=en&ref_site=photo&search_source=search_form&version=llv1&anyorall=all&safesearch=1&use_local_boost=1&searchterm=bodybuilder&show_color_wheel=1&orient=&commercial_ok=&media_type=images&search_cat=&searchtermx=&photographer_name=&people_gender=&people_age=&people_ethnicity=&people_number=&color=&page=1&inline=234981475">Kiselev Andrey Valerevich</a></span>
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<p>Protein synthesis also responds to eating dietary protein. And when protein is consumed following resistance exercise, muscle production is enhanced even further. <a href="http://jap.physiology.org/content/106/5/1692">What’s more</a>, muscles that have been subjected to resistance exercises increase their protein synthesis rates more than non-exercised muscles after each meal for at least the next 48 hours. </p>
<p>Not only is this insight useful for bodybuilders, it also tells us something useful about muscle wasting. We know that slow wasting conditions such as <a href="http://www.webmd.com/healthy-aging/sarcopenia-with-aging">sarcopenia</a>, where muscle mass progressively diminishes with age, are <a href="http://journals.lww.com/co-clinicalnutrition/pages/articleviewer.aspx?year=2012&issue=01000&article=00010&type=abstract">due to</a> the impaired ability of muscle to increase protein production in response to feeding or loading. In effect, the muscle’s protein-building machinery becomes resistant to growth stimuli. This causes the protein, and hence the muscle, to be lost, which leads to reduced muscle function. </p>
<p>This is important because muscle loss with age is associated with impaired physical function and loss of independence. This is particularly true if it is combined with the muscle wasting that people experience if they are immobilised after injuries or surgery. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9302893">For example</a>, around 50% of women over the age of 65 who break a hip never walk again. The cause? Loss of muscle mass associated with the injury and the ensuing bed rest. </p>
<p>Sarcopenia is also associated with an increased risk of falling. <a href="http://jech.bmj.com/content/57/9/740.long">A review</a> of the cost of treating fall-related injuries in 1999 showed that falls in the over-60s cost the UK government close to a £1bn a year (more than £1.5bn in today’s money). There is therefore a huge public interest in developing safe and effective strategies to prevent muscle wasting. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=355&fit=crop&dpr=1 600w, https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=355&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=355&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=446&fit=crop&dpr=1 754w, https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=446&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/66410/original/image-20141205-8667-34m0wu.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=446&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Muscle wasting is worst when ageing and injury combine.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/mayoclinic/7351848916/in/photolist-ccE9xN-7jPtLB-7jPxRD-7jPx7M-7jPA7r-7jPzLM-7jPAbg-7jPuyX-7jPAgz-5Y2kh2-7jTnMs-7jTDi7-7jTqfC-7jTpPb-7jToX3-7jPwvz-7hNNTV-7jTu5G-5cEoHE-5TrHnZ-7jPBU6-7jTutG-7jPAs2-7jTFf3-7jPM3K-7jPB3x-7jPDmg-7jTFNd-7jPCnB-7jPCte-7jPJjR-7jTv2s-7jTxwf-5cA7ec-7jTygj-7jHgZs-7jHgkN-7jTDUh-7jPMbR-7jTyAq-7jTEbm-7jPL9F-7jPM6n-7jTF8J-7jTDqy-7jPK44-7jHxUo-7jHzPh-7jHseE-7jDFyc">Wikimedia</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
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<h2>The research race</h2>
<p>We have been aware of this link between muscle wasting and protein synthesis impairment for a long time. You don’t see many old people in the gym lifting weights, but that is exactly what they should be doing to try and offset these effects. </p>
<p>For the vast majority of abstainers, researchers have been looking for potential drug treatments in this area for more than 30 years. And for about the last 15 they have been employing biochemistry techniques in human studies to try and understand the molecular signals that tell the muscle to grow. </p>
<p>These molecular signals act like the foreman on a building site. They read the conditions by sensing whether there is sufficient building materials and manpower to build and whether there has been a change in demand on the existing muscle. They then relay that information into an appropriate growth response to meet the demands placed on the system by initiating or stopping muscle protein synthesis. </p>
<p>The question is which molecules are doing this foreman’s job, which has proved far harder to ascertain than initially might have been hoped. The combined efforts of researchers these past few years have pointed to the likelihood that the culprit is a molecule called p70S6K1. Various teams are now looking at how it potentially leads to more muscle protein being produced, including my own. </p>
<p>One reason why it has taken a long time for anyone to fully explain what happens is because it is hard to measure how this molecule functions in human skeletal muscle. This makes it harder to determine its role in making muscles grow. We <a href="http://jap.physiology.org/content/110/2/561">have optomised</a> a simple, cost-effective and accurate technique to solve this measuring difficulty. We have already been putting it through human trials, and hope to have a definitive answer in the next five to ten years. </p>
<p>While others take different approaches, the race is on to determine whether p70S6K1 will be a good drug target to treat muscle wasting. After that, it might take another couple of decades to develop commercial drugs. Needless to say, solving the riddle of muscle wasting is not a quick process. But if science finally triumphs here, it will be a great example of how the answers to problems can come from the most unlikely of sources. For now though, the best advice is to take the lead from bodybuilding and undertake a programme of progressive resistance exercise while ensuring you consume adequate amounts of protein.</p><img src="https://counter.theconversation.com/content/35113/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lee holds funding from the Insulin-dependant Diabetes Trust, the Society for Endocrinology and the American College of Sports Medicine.</span></em></p>People have used bodybuilding to improve their physical performance for at least 1,500 years. The first recorded example was the sixth-century wrestler, Milo of Croton, in southern Italy. Milo reportedly…Lee Hamilton, Lecturer in Sport, Health and Exercise Science, University of StirlingLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/296182014-07-25T11:51:09Z2014-07-25T11:51:09ZWhy cold-blooded animals don’t need to wrap up to keep warm<figure><img src="https://images.theconversation.com/files/54900/original/2f4wssjs-1406284877.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Yeah, I'm cool.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/mschmidt62/4180540000">mschmidt62</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Animals have evolved to occupy almost all corners of the Earth. To survive, no matter the weather outside, they all need temperature-sensitive bodily reactions to work. This is easy for warm-blooded animals, such as humans, because they have the ability to maintain their body temperature. </p>
<p>But cold-blooded animals can’t do that. When the weather changes and the mercury swings one way, their cells get exposed to that change in temperature. Yet cold blooded animals survive just fine. Michael Welte, associate professor of biology at the University of Rochester, may have just discovered how. His team’s findings have been published in the <a href="http://jcb.rupress.org/content/206/2/199.full">Journal of Cell Biology</a>.</p>
<p>At the molecular level, the key to survival is to ensure that proteins are being made at the right time and in the right amount. To do that every cell in the body has an assembly line. This is partly driven by motor proteins, which act like cargo trains delivering the messenger molecule RNA that comes from DNA located in the cell’s nucleus. RNA needs to reach the end of the assembly line where special organelles, called ribosomes, decode the message and make the protein.</p>
<p>“We have found a molecule that keeps protein production balanced when temperatures change,” said Welte. “It happens to do so by controlling cellular transport.”</p>
<p>Theirs was a serendipitous discovery. They were studying fruit flies, which happen to be cold blooded, when they found that making some proteins is difficult for the flies when temperatures change. </p>
<p>As temperatures fall, the protein assembly line slows down more than the cargo trains. This creates an imbalance where, when the motor proteins reach the ribosomes, if the messenger RNA molecules are not used up immediately, they could be lost forever. This could throw the cell completely off-balance, stopping protein synthesis altogether.</p>
<p>But Welte found a special protein, called Klar, that keeps the balance intact. Klar behaves like the emergency brakes of the cargo trains. As soon as the mercury level falls, Klar slows down the motor proteins carrying messenger RNA molecules. Now that the pace of delivery of the blueprints matches the rate of making proteins, the assembly line stays balanced.</p>
<p>In fruit flies, Welte found that the protein assembly line balance is especially important for making a protein called Oskar. Egg cells, from which a fruit fly will hatch, produce Oskar. In the egg cell that still has not decided its orientation, Oskar accumulates and defines where the posterior end will be. The posterior end of the cell will later give rise to the tail after hatching. If Oskar is not made properly that the eggs will not be able to hatch. </p>
<p>When Welte used genetic tools in fruit flies to remove Klar from the cell, he found that losing Klar had no effects on the baby flies that hatched at normal temperature. But as soon as the temperature was lowered, the eggs could not hatch. Development of the fruit fly is completed at colder temperatures only when Klar is present in the egg cell.</p>
<p>Klar is found in all insects in the animal kingdom, where Welte thinks that Klar might be playing a similar role. It would also be interesting to find a similar protein in other cold-blooded animals.</p>
<p>Body temperature in humans does not fluctuate as much as it does in flies. But, with fevers and other conditions, our cells could be exposed to fluctuations in temperature as well. Welte speculates that a similar mechanism could be taking place in our cells as well, keeping our protein production stable. “While we don’t have the Klar protein in our cells, the mechanism for producing proteins is very similar,” Welte said.</p><img src="https://counter.theconversation.com/content/29618/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Anwesha Ghosh 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>Animals have evolved to occupy almost all corners of the Earth. To survive, no matter the weather outside, they all need temperature-sensitive bodily reactions to work. This is easy for warm-blooded animals…Anwesha Ghosh, PhD student in Biology, University of RochesterLicensed as Creative Commons – attribution, no derivatives.