tag:theconversation.com,2011:/institutions/the-scripps-research-institute-2491/articlesThe Scripps Research Institute2022-11-22T13:25:50Ztag:theconversation.com,2011:article/1937052022-11-22T13:25:50Z2022-11-22T13:25:50ZScientists uncovered the structure of the key protein for a future hepatitis C vaccine – here’s how they did it<figure><img src="https://images.theconversation.com/files/496217/original/file-20221118-14-r6a8me.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1999%2C1499&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Imaging the proteins on the surface of HCV has been challenging because of the virus's shape-shifting nature.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/hepatitis-c-virus-particles-illustration-royalty-free-illustration/1042127452">Juan Gaertner/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The <a href="https://www.cdc.gov/hepatitis/hcv/index.htm">hepatitis C virus, or HCV</a>, causes a chronic liver infection that can lead to permanent liver scarring and, in dire cases, cancer. It affects around <a href="https://doi.org/10.1007/s42399-020-00588-3">71 million people worldwide</a> and causes approximately 400,000 deaths each year. While <a href="https://www.uptodate.com/contents/direct-acting-antivirals-for-the-treatment-of-hepatitis-c-virus-infection">treatments are available</a> for HCV-related infections, they are expensive, hard to access and do not protect against reinfection. A vaccine that can help prevent HCV infection is a major unmet medical and public health need. </p>
<p>One major reason there hasn’t been an HCV vaccine yet is that scientists have yet to identify the proper antigen, or the part of the virus would trigger a protective immune response in the body.</p>
<p>Decades of research have pinpointed <a href="https://doi.org/10.1038/nrmicro3098">HCV E1E2</a>, the only protein on the surface of the virus, as the most promising vaccine candidate. However, developing an HCV vaccine based on that protein is limited by uncertainty around what it looks like. Knowing the structure of the protein is necessary to figure out how the immune system responds to the virus.</p>
<p>So how do researchers capture the structure of single protein on a shape-shifting virus? </p>
<p>We are researchers who specialize in <a href="https://scholar.google.com/citations?user=Xejfx54AAAAJ&hl=en">microscopy</a> and <a href="https://scholar.google.com/citations?user=iQj9rSwAAAAJ&hl=en">vaccine design</a>. With new technology, we were able to <a href="https://doi.org/10.1126/science.abn9884">visualize the molecular details</a> of this elusive protein, unlocking key insights into how this virus works and offering a potential blueprint for a future vaccine.</p>
<p>This is how we did it.</p>
<h2>Challenges of capturing a shape-shifting virus</h2>
<p>One reason it has been so difficult to capture the structure of the HCV E1E2 protein is that it is both <a href="https://doi.org/10.1016/j.celrep.2022.110859">flexible and fragile</a>. It changes its shape so often and is so easily broken that it’s challenging to purify. </p>
<p>As an analogy, imagine a bowl of spaghetti drenched in tomato sauce. Now imagine trying to take a picture of each individual piece of spaghetti in the same position over time while the bowl is shaking. Hard to do, right? That’s what it was like to image the full E1E2 protein.</p>
<p>There were also <a href="https://doi.org/10.1126/science.1251652">technological barriers</a>. Until recently, available imaging techniques were limited in their ability to view microscopic proteins. <a href="https://chem.libretexts.org/Bookshelves/Analytical_Chemistry/Supplemental_Modules_(Analytical_Chemistry)/Instrumentation_and_Analysis/Diffraction_Scattering_Techniques/X-ray_Crystallography">X-ray crystallography</a>, for instance, is unable to capture molecules that frequently change and shape-shift, like HCV. Moreover, other options, such as <a href="https://chem.libretexts.org/Bookshelves/Analytical_Chemistry/Physical_Methods_in_Chemistry_and_Nano_Science_(Barron)/04%3A_Chemical_Speciation/4.07%3A_NMR_Spectroscopy">nuclear magnetic resonance spectroscopy</a>, required cutting large parts of the protein or chemically manipulating it in a way that would transform its physiological state and potentially alter its function.</p>
<p>So to examine the structure of E1E2, we needed a way to extract and purify, stabilize and trap the entire shape-shifting protein into one configuration.</p>
<h2>How to take a picture of protein</h2>
<p><a href="https://doi.org/10.1038/d41586-020-01658-1">Cryo-EM, or cryo-electron microscopy</a>, is a type of imaging technique that views specimens at cryogenic temperatures, in this case the boiling point of nitrogen: minus 320.8 degrees Fahrenheit (minus 196 Celsius). With temperatures that cold, ice freezes so quickly that it doesn’t have time to crystallize. That creates a beautiful glasslike frame around the protein of interest, allowing an unhindered view of every structural detail. Cryo-EM also requires very little protein to work, reducing the amount of material we would need to purify. </p>
<p>Winner of the <a href="https://www.nobelprize.org/prizes/chemistry/2017/press-release/">2017 Nobel Prize in chemistry</a> and <a href="https://doi.org/10.1038/nmeth.3730">Nature magazine’s 2015 “Method of the Year</a>” award, cryo-EM is superb for imaging biological macromolecules in their native, or natural, state in the aqueous environment of human blood. Cryo-EM was also pivotal for characterizing the <a href="https://doi.org/10.1038/nature17200">structure of the COVID-19 virus</a> and its variants.</p>
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<figcaption><span class="caption">Cryo-EM has allowed researchers to see complex proteins they weren’t able to before.</span></figcaption>
</figure>
<p>So how do you take a picture of a protein? </p>
<p>First, we embedded the genetic code to make E1E2 in human cells in a petri dish so we would have sufficient amounts of protein to study. After purifying the protein, we <a href="https://caic.bio.cam.ac.uk/electron-microscopy/SpecimenPrep/PlungeFreezing">plunged it into liquid ethane</a> followed by liquid nitrogen. Liquid ethane is used to freeze the protein because it has a higher boiling point than liquid nitrogen. This means it is able to capture more heat before turning to a gas, allowing the protein to freeze much more quickly than it would in liquid nitrogen and avoid structural damage. </p>
<p>Once the protein was vitrified, or in a glasslike ice state, we were able not just to see its overall structure, but also to capture multiple individual configurations of the protein that it takes when it shape-shifts, including its less stable forms.</p>
<p>At this point, our protein was ready for its close-up. We employed a microscope that <a href="https://www.ccber.ucsb.edu/ucsb-natural-history-collections-botanical-plant-anatomy/transmission-electron-microscope">uses a beam of focused, high energy electrons</a> and a very fancy camera that detects how the elections bounce off the protein’s surface. This created a 2D image that we then mathematically transformed into a 3D model. And that was how we got the coveted “close-up” of HCV’s surface protein. </p>
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<figcaption><span class="caption">This video shows the newly identified 3D structure of the E1E2 protein on the surface of the hepatitis C virus. The two main subunits of the protein are colored in pink and blue. Sugar molecules are colored in green.</span></figcaption>
</figure>
<p>Our next step was then to assess the location of each amino acid, or building block of the protein, in 3D space. Because every amino acid has a unique shape, we used a computer program that could identify each one in our 3D map. This allowed us to manually reconstruct a high-resolution model of the protein, one building block at a time.</p>
<h2>A new tool to design an HCV vaccine</h2>
<p>Our 3D map and model of the HCV E1E2 protein supports previous research describing its structure while providing new insights into features that will help pave the way for a long-sought vaccine design against this virus. </p>
<p>For example, our structure reveals that the interface between the two main parts of the protein is stabilized by sugars and hydrophobic patches, or areas that push out water molecules. This creates sticky binding hubs along the protein and keeps it from falling apart – a potential site for protective antibodies and new drugs to target. </p>
<p>Researchers now have the tools to design antiviral drugs and vaccines against HCV infection.</p><img src="https://counter.theconversation.com/content/193705/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lisa Eshun-Wilson receives funding from the National Science Foundation. </span></em></p><p class="fine-print"><em><span>Alba Torrents de la Peña receives funding from Netherlands Organization for Scientific Research (NWO) Rubicon Grant 45219118. </span></em></p>Using a Nobel Prize-winning technique called cryo-EM, researchers were able to identify potential areas on the hepatitis C virus that a vaccine could target.Lisa Eshun-Wilson, Postdoctoral Scholar in Molecular and Cell Biology, The Scripps Research InstituteAlba Torrents de la Peña, Postdoctoral Fellow in Integrative Structural and Computational Biology, The Scripps Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1868012022-09-28T12:32:30Z2022-09-28T12:32:30ZYour mighty tendons help you sprint, jump and move – a genetic mutation in one key protein may increase athletic performance<figure><img src="https://images.theconversation.com/files/486922/original/file-20220927-26-skh2t7.jpg?ixlib=rb-1.1.0&rect=0%2C3%2C2139%2C1396&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A variant of Piezo1 may boost tendon strength and, subsequently, athletic ability.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/sprinters-in-motion-royalty-free-image/a0091-000172">Yellow Dog Productions/The Image Bank via Getty Images</a></span></figcaption></figure><p>The ability to move is an essential part of daily life. The <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/locomotor-system">locomotor, or musculoskeletal, system</a> of the body consists of muscles, bones, tendons, ligaments, joints, cartilage and other connective tissue. <a href="https://www.physio-pedia.com/Ageing_and_the_Locomotor_System">Loss of motor function</a> due to disease or injury can result in a lifetime of disability. In a rapidly aging society, maintaining and improving motor function can be a significant challenge for many people.</p>
<p>But there are ways to get around motor failure. As <a href="https://scholar.google.com/citations?user=6NvNu40AAAAJ&hl=en">molecular biologists</a> and <a href="https://www.researchgate.net/profile/Ryo-Nakamichi">orthopedic surgeons</a> who study the locomotor system, we believe one key part of it has been underestimated – the tendons.</p>
<p><a href="https://my.clevelandclinic.org/health/body/21738-tendon">Tendons</a> are tough tissues that connect muscle to bone. Tendons are what allow <a href="https://a-z-animals.com/blog/how-high-and-far-can-a-kangaroo-jump/">kangaroos</a> to jump over 25 feet (7.62 meters) high and run up to 40 mph (64 kph). While their leg muscles are small, the kangaroos’ highly developed and long tendons act like powerful springs. People can also jump higher if they squat down first because their tendons <a href="https://spaniardperformance.com/muscle-tendon-unit-characteristic-to-potenciate-training/">store elastic energy</a> that helps propel them upward.</p>
<p>In our research, we found that the presence of <a href="https://doi.org/10.1126/scitranslmed.abj5557">one particular protein in tendons</a> plays a key role in how tendons heal – and a genetic mutation in that protein may also enhance athletic performance.</p>
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<figcaption><span class="caption">Tendons connect muscle to bone and are essential to movement.</span></figcaption>
</figure>
<h2>Identifying tendon proteins</h2>
<p>Tendon damage can be <a href="https://doi.org/10.1002/jor.22869">difficult to heal</a>. Approximately <a href="https://doi.org/10.1177/0363546520939897">60% of tendon injuries</a> lead to <a href="https://www.cdc.gov/arthritis/basics/osteoarthritis.htm">osteoarthritis</a>, a disease resulting from the breakdown of the cartilage in joints that can make movement even more difficult.</p>
<p>Developing treatments for tendon injuries has likewise been challenging. One of the reasons is that the proteins controlling the genes instructing the body to create tendons, called <a href="https://www.nature.com/scitable/definition/transcription-factor-167">transcription factors</a>, had been unknown.</p>
<p>To identify these proteins, we <a href="https://www.embrys.jp/embrys/html/MainMenu.html">created a catalog</a> of the 1,600 transcription factors in the human body. Based on this catalog, we examined what genes were active in the Achilles tendon of genetically engineered mice and found that a protein called Mkx was a central transcription factor for the health of tendons.</p>
<p>Researchers have long considered tendons to be inert tissue unable to contract like muscles can. But we discovered with our colleague, <a href="https://scholar.google.com/citations?user=2aSu29oAAAAJ&hl=en">Ardem Patapoutian</a>, the <a href="https://www.nobelprize.org/prizes/medicine/2021/advanced-information/">Nobel Prize-holder</a>, that one particular protein on the surface of tendon cells, Piezo1, can sense when the tendon is engaging in moderate exercise and stimulate the Mkx transcription factor.</p>
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<figcaption><span class="caption">The discovery of Piezo1’s role in the perception of touch won the 2021 Nobel Prize in physiology or medicine.</span></figcaption>
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<h2>Piezo1 and athletic performance</h2>
<p>We then wondered about the role that Piezo1 plays in athletic performance. We were particularly interested in a variant of Piezo1 called E756del, which is found in around <a href="https://doi.org/10.1016/j.cell.2018.02.047">a third of people of African descent</a> and thought to play a potential role in <a href="https://doi.org/10.1038/s41551-021-00716-x">how high people can jump</a>. </p>
<p>So we genetically engineered mice to produce an equivalent mouse version of Piezo1 E756del proteins throughout their body and then <a href="https://doi.org/10.1126/scitranslmed.abj5557">tested their performance</a> on different physical activities, including long jump and running on a treadmill. Surprisingly, we found that mice with E756del proteins were able to jump about 1.6 times farther without training than mice without the E756del proteins. Mice with Piezo1 in their tendons were also able to run about 1.2 times faster than those without Piezo1.</p>
<p>To identify which body part was producing this jumping ability, we then created mice that produced Piezo1 proteins either in their muscles or their tendons. The results were even more surprising: Mice with Piezo1 in their tendons improved in their jumping ability just as well as mice with Piezo1 throughout their entire body. Mice with Piezo1 only in their muscles, however, did not have any improvement in jumping ability.</p>
<p>We then decided to test the role of Piezo1 in human athletic performance. In collaboration with the <a href="http://www.athlomeconsortium.org/">Athlome Consortium</a>, an international athletic genomics organization, we compared the prevalence of the gene that codes for E756del in 91 Olympic-level Jamaican sprinters and 108 people in the general population in Jamaica. We found that 54% of Jamaican sprinters had an active gene for E756del, compared to just approximately 30% of the general population.</p>
<p>Our findings show that changing a single protein, in this case E756del, can play a role in athletic performance. Further research on tendons and other parts of the human motor systems could help improve treatments for musculoskeletal conditions.</p><img src="https://counter.theconversation.com/content/186801/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hiroshi Asahara receives funding from National Institute of Health, Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development.</span></em></p><p class="fine-print"><em><span>Ryo Nakamichi does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The discovery of the role that the protein Piezo1 plays in touch and body awareness won the 2021 Nobel Prize in physiology or medicine. Piezo1 may also be a significant player in motor function.Hiroshi Asahara, Professor of Molecular Medicine, The Scripps Research InstituteRyo Nakamichi, Postdoctoral Researcher in Molecular Medicine, The Scripps Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1046892018-10-11T15:05:29Z2018-10-11T15:05:29ZThere are many types of obesity – which one matters to your health<figure><img src="https://images.theconversation.com/files/240139/original/file-20181010-72106-x33i2e.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some forms of obesity severely disrupt the metabolic pathways that keep us healthy.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/fat-woman-icon-669690958?src=X-77hRSF8AiLL7bU6GijIA-5-86 and https://www.shutterstock.com/image-vector/body-mass-index-vector-illustration-underweight-716496511?src=X-77hRSF8AiLL7bU6GijIA-1-0">Farik gallery, MarShot / Shutterstock.com / Evans Love</a></span></figcaption></figure><p>Our society seems to have accepted that gaining weight is an inevitable consequence of growing up in a place with easy access to calories and where physical activity plays a declining role in our professional and private lives. Aging just makes weight loss even more difficult. </p>
<p>In the short term, the consequences of excess weight seem remote or unimportant; a problem of aesthetics, a minor limitation in mobility. But it may eventually lead to higher rates of diabetes and heart disease, and present a significant challenge for enjoying an active lifestyle. </p>
<p><a href="https://www.scripps.edu/faculty/telenti/">My own work</a> and that of my <a href="https://www.humanlongevity.com/">collaborators</a> <a href="https://www.metabolon.com/">here</a> <a href="https://www.unil.ch/cig/thorens">and</a> <a href="https://www.bcm.edu/people/view/c-caskey-md-facp-facmg-frsc/b2691b26-ffed-11e2-be68-080027880ca6">in</a> <a href="https://www.jcvi.org/">the</a> <a href="http://www.twinsuk.ac.uk/about-us/">U.K.</a> shows that obesity is more than just some more fat under the skin – it is a true modification of our <a href="https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/metabolism/art-20046508">metabolism</a>. It alters the way we process nutrients and modifies the chemical reactions that sustain our existence. Our most recent work, published in <a href="http://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30630-2">Cell Metabolism</a>, examined the consequences of obesity on our metabolism. My colleagues and I undertook this project because we recognized that there are many types of obesity – each one has different consequences for each person’s health. This is what we call disease “heterogeneity.” If we understand heterogeneity, we can personalize obesity treatments, hopefully with more success.</p>
<h2>My obesity, my metabolome</h2>
<p>We are a team of researchers with different backgrounds including medicine, technology and the analysis of complex data. We studied close to 2,500 obese people with two powerful new technologies: We sequenced the entire genome of each study participant, and we analyzed more than 1,000 blood chemicals, or metabolites. This collection of metabolites is what we now call the “metabolome” and includes well-known compounds such as glucose and uric acid, as well as tongue twisters such as 1-stearoyl-2-dihomo-linolenoyl-GPC. </p>
<p>We included the genome analysis to understand how an individual’s genes predisposes him or her to obesity. We chose the metabolome to capture in real time the impact of having excess weight. Many of the study participants were followed for more than 10 years; this enabled the assessment of long-term consequences of our observations. </p>
<p>The surprising and disturbing news is that the levels of many hundreds of unique metabolites are affected by changes in weight. Some of these changes were expected: Fats or lipids – including cholesterol – rise rapidly with increasing weight. However, we also observed changes for other types of metabolites and body processes: protein and carbohydrate metabolism, energy production and hormone concentrations. </p>
<p>The overall picture was that weight dramatically perturbs the body’s metabolism. The good news is that the alterations can be reversed with weigh loss. </p>
<h2>The healthy obese and the unhealthy skinny</h2>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=603&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=603&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=603&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=758&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=758&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240096/original/file-20181010-72117-13qf2uu.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=758&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This graphical abstract shows that the metabolome captures clinically relevant types of obesity and is a better health predictor than genetic risk.</span>
<span class="attribution"><span class="source">Cirulli et al. / Cell Metabolism</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>A second and fundamental observation was that the metabolic alterations carried more health consequences than the mere physical aspect: Some of the participants had what we labeled as an “obese” metabolome despite having a normal weight. On the other hand, some obese individuals had a pretty normal metabolome that was similar to those individuals with a healthy body mass index. </p>
<p>It is not clear to us how an obese person could have a normal metabolome. We do not know whether it is their genes or environment that are responsible for keeping this group of individuals more healthy. That will take more research to figure out.</p>
<p>Because we had medical information at the time that the metabolic analyses were performed and we had long-term follow up data, we could see the consequences of abnormal metabolism. </p>
<p>Those obese individuals who suffered the greatest deregulation of the metabolism developed diabetes, heart disease and hypertension. These same participants were also the ones that accumulated fat tissue inside the abdomen and in the liver – the “bad” locations – as opposed to just adding it under the skin of the waist or buttocks. Thus, physical obesity was important – but how the excess weight uniquely affected the inner workings of each individual was a more accurate measure of overall health. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240129/original/file-20181010-72106-1c1cimt.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">Body mass index vector illustration from underweight to extremely obese. BMI may not be an accurate reflection of whether an individual is in good or poor health.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/body-mass-index-vector-illustration-underweight-716496511?src=X-77hRSF8AiLL7bU6GijIA-1-0">MarShot / Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>Metabolome report may say more than your BMI</h2>
<p>It may be tempting to think of obesity as the consequence of genes – inherited from our parents. It is true, but the impact of our genes pales in comparison to the overwhelming impact of high caloric intake and sedentary lives. </p>
<p>There was one exception. We identified a few very obese individuals who had changes in a gene that controls appetite – the so-called <a href="https://doi.org/10.1086/302660">melanocortin-4 receptor (MC4R)</a>. These patients had a genetic mutation that made them permanently hungry and led them to eat more than they needed. There is great hope that this particular type of obesity will be soon treated with specific <a href="https://doi.org/10.1056/NEJMoa1512693">drugs</a>. As expected, this form of obesity severely disrupted the metabolism of the affected person. </p>
<p>We see all the time that science provides new understanding on important health problems that seems to fade once the news cycle is over. But after the hype comes the incubation of new strategies that may eventually find their place in medical practice. </p>
<p>Specific to research in obesity, I believe that bringing attention to the important changes in the metabolism provides a sense of urgency to the field. This work also provides a new way to measure the harmful impacts of obesity and to screen populations to identify those who could benefit from participation in clinical trials of new drugs. This includes individuals who are skinny and have an unhealthy metabolome, but are unaware of their state of health and would benefit from early intervention.</p><img src="https://counter.theconversation.com/content/104689/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Amalio Telenti was a previous employee and consultant of Human Longevity Inc.</span></em></p>Body mass index is often used to gauge health. But there may be more accurate measures. A report on your blood metabolites, your metabolome, may distinguish healthier-obese from sicker-obese.Amalio Telenti, Affiliate faculty in Pharmacy and Pharmaceutical Sciences at UCSD ; Professor of Genomics at Scripps, The Scripps Research InstituteLicensed as Creative Commons – attribution, no derivatives.