tag:theconversation.com,2011:/id/topics/drug-development-1083/articlesDrug development – The Conversation2024-01-04T13:45:37Ztag:theconversation.com,2011:article/2151992024-01-04T13:45:37Z2024-01-04T13:45:37ZDrugs of the future will be easier and faster to make, thanks to mRNA – after researchers work out a few remaining kinks<figure><img src="https://images.theconversation.com/files/567750/original/file-20240103-21-2oxdyb.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2448%2C1224&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Two hurdles mRNA drugs face are a short half-life and impurities that trigger immune responses.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/on-white-background-royalty-free-image/1411871727">BlackJack3D/iStock via Getty Images Plus</a></span></figcaption></figure><p>Vaccines have been reliably and affordably protecting people from diseases worldwide <a href="https://theconversation.com/from-smallpox-to-polio-vaccine-rollouts-have-always-had-doubters-but-they-work-in-the-end-161803">for centuries</a>. Until the COVID-19 pandemic, however, vaccine development was still a long and idiosyncratic process. Traditionally, researchers had to tailor manufacturing processes and facilities for each vaccine candidate, and the scientific knowledge gained from one vaccine was often not directly transferable to another. </p>
<p>But the COVID-19 mRNA vaccines brought a new approach to vaccine development that has far-reaching implications for how researchers make drugs to treat many other diseases. </p>
<p><a href="https://scholar.google.com/citations?user=C49y7YQAAAAJ&hl=en">I am a biochemist</a>, and <a href="https://www.umassmed.edu/LiLab/">my lab</a> at UMass Chan Medical School focuses on developing better ways to use mRNA as a drug. Although there are <a href="https://theconversation.com/customizing-mrna-is-easy-and-thats-what-makes-it-the-next-frontier-for-personalized-medicine-a-molecular-biologist-explains-216127">many possibilities</a> for what researchers can use mRNA to treat, some important limitations remain. Better understanding how mRNA-based drugs interact with the immune system and how they are degraded in human cells can help lead to safe, durable and effective treatments for a wide range of diseases.</p>
<h2>Some basics of mRNA drugs</h2>
<p>Messenger RNA, or mRNA, is made of four building blocks denoted by the letters A, C, G and U. The sequence of letters in an mRNA molecule conveys genetic information that directs how a protein is made. </p>
<p>An mRNA drug comprises two essential components: mRNA molecules, which code for desired proteins, and the lipid molecules – such as phospholipids and cholesterol – that encapsulate them. These <a href="https://doi.org/10.1016/j.jconrel.2015.08.007">mRNA-lipid nanoparticles, or LNPs</a>, are tiny spheres <a href="https://doi.org/10.1016/j.ymthe.2017.03.013">about 100 nanometers in diameter</a> that protect mRNA from degradation and facilitate its delivery into target cells. </p>
<p>Once inside cells, mRNA molecules instruct the cell’s machinery to produce the target protein required for a desired therapeutic effect. For example, the mRNA in the Pfizer-BioNTech and Moderna <a href="https://theconversation.com/how-mrna-vaccines-from-pfizer-and-moderna-work-why-theyre-a-breakthrough-and-why-they-need-to-be-kept-so-cold-150238">COVID-19 vaccines</a> directs cells to produce a harmless version of the virus’ spike protein that trains the immune system to recognize and better prepare for potential infection. </p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/v-NEr3KCug8?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The science behind COVID-19 mRNA vaccines has been decades in the making.</span></figcaption>
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<p>From a drug development perspective, mRNA drugs offer significant advantages over traditional drugs because they are <a href="https://theconversation.com/customizing-mrna-is-easy-and-thats-what-makes-it-the-next-frontier-for-personalized-medicine-a-molecular-biologist-explains-216127">easily programmable</a>. Hundreds of pounds of mRNA can be made from readily available DNA templates, such that producing a different mRNA drug is as simple as changing the corresponding DNA templates. </p>
<p>More importantly, different mRNA drugs produced by the same set of methods will have similar properties. They will be delivered to the same tissues, trigger similar levels of immune responses and degrade in similar ways. This predictability significantly reduces the development risks and financial costs of developing mRNA drugs.</p>
<p>In addition to being easy to program, mRNA drugs have several other unique properties. For example, just like the mRNAs your body naturally produces, therapeutic mRNAs have a short half-life in cells: <a href="https://doi.org/10.1016%2Fj.jconrel.2015.08.007">about one day</a>. As a result, current mRNA technology is ideal for treatments that aren’t meant to last long in the body. </p>
<p>This is why vaccines are popular candidates for mRNA technology: They provide long-term protection against disease after brief exposure to the drug with few side effects. There are currently <a href="https://www.mdpi.com/1422-0067/24/3/2700">more than 30 mRNA vaccine candidates</a>, not including vaccines for COVID-19, in clinical trials.</p>
<h2>Self vs. nonself</h2>
<p>Another critical feature of mRNA drugs is their intrinsic ability to stimulate the immune system. This may sound paradoxical – after all, your cells already contain large amounts of mRNAs. Why would other mRNAs activate your immune system? How does your immune system distinguish between self and nonself mRNAs?</p>
<p>The first reason involves location. Therapeutic mRNAs enter cells using endosomes – sacs made of the cell’s membrane that take in materials from the cell’s environment. Your immune system can detect mRNA in endosomes because this is usually a sign of an RNA virus infection – cellular mRNAs normally don’t enter endosomes. When your immune system labels therapeutic mRNAs as viral material, it triggers <a href="https://doi.org/10.1016/j.immuni.2005.06.008">a strong inflammatory response</a> that can lead to severe side effects. </p>
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<a href="https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing molecules entering a depression in the cell membrane which closes off to form a sac" src="https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/567748/original/file-20240103-25-lqiluh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Endocytosis is the process by which material outside the cell, such as mRNA molecules, is engulfed within the cell.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/endocytosis-process-cells-absorb-external-royalty-free-illustration/1621615509">alfa md/iStock via Getty Images Plus</a></span>
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<p>One solution to this problem is to modify mRNA’s building blocks – specifically, changing the U, or uridine, to its chemical cousins, <a href="https://doi.org/10.1016/j.immuni.2005.06.008">pseudouridine</a> and <a href="https://doi.org/10.1016/j.jconrel.2015.08.051">N1-methylpseudouridine</a>. This subtle chemical change prevents the unwanted immune response while allowing the therapeutic mRNA to <a href="https://doi.org/10.1038%2Fmt.2008.200">direct the cell to make the protein it encodes</a>. The <a href="https://theconversation.com/tenacious-curiosity-in-the-lab-can-lead-to-a-nobel-prize-mrna-research-exemplifies-the-unpredictable-value-of-basic-scientific-research-214770">2023 Nobel Prize in physiology or medicine</a> was awarded to the scientists who made this breakthrough discovery. Both the Pfizer-BioNTech and Moderna <a href="https://doi.org/10.1021/acscentsci.1c00197">COVID-19 mRNA vaccines</a> use this technique.</p>
<p>The second source of unwanted immune response is impurities from mRNA production. To prepare mRNA from a DNA template, scientists use a protein called <a href="https://www.nature.com/scitable/definition/rna-polymerase-106/">RNA polymerase</a> that tends to make a small amount of side product called <a href="https://doi.org/10.1093/nar/gkr695">double-stranded RNA</a>. Unlike mRNA, which is single-stranded, double-stranded RNA has two chains that form a double helix. RNA viruses also form double-stranded RNA when they replicate, and exposing cells to double-stranded RNA can lead to a strong immune response.</p>
<p>Removing double-stranded RNA is challenging, especially at the industrial scale. Fortuitously, for mRNA vaccines, the residual amount of double-stranded RNA can stimulate the immune system to <a href="https://doi.org/10.1038/s41590-022-01163-9">enhance antibody responses</a>. However, for applications other than vaccines, a cleaner RNA product is necessary to reduce side effects.</p>
<h2>Moving beyond vaccines</h2>
<p>Although mRNA has the potential to transform drug development for various medical purposes, careful consideration is required to identify targets that align with the technology’s strengths.</p>
<p>For example, because there is currently a limit to how long mRNA can last in the body, treatments that need a protein to be present for only a short period of time to achieve a lasting therapeutic effect are ideal. One promising example in development is using mRNA that encodes CRISPR-Cas9 gene-editing proteins to knock out genes that cause specific diseases.</p>
<p>Researchers are exploring this strategy to develop a single-dose treatment for <a href="https://doi.org/10.1056/NEJMoa2107454">hereditary transthyretin amyloidosis</a>, a rare genetic disease caused by the accumulation of misfolded proteins in the heart and nerves. This disease is an ideal target for mRNA-based CRISPR gene therapy because the target protein is produced by the liver. Because most drugs pass through the liver, this makes it easier to deliver CRISPR-Cas9 mRNA to its target. In the next few years, a new generation of more precise <a href="https://doi.org/10.1038/d41586-023-03797-7">mRNA-based genome editing therapies</a> will enter clinical trials.</p>
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<a href="https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of SARS-CoV-2 virus particles lining the a few vesicles in a cell" src="https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=449&fit=crop&dpr=1 600w, https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=449&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=449&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=564&fit=crop&dpr=1 754w, https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=564&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/567751/original/file-20240103-17-vch2ou.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=564&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">Because the virus that causes COVID-19 (gold) and other RNA viruses enter cells through endosomes, mRNA drug impurities can elicit similar immune responses.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/2mrqrnx">NIAID/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
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<p>For treatments that need a specific protein to be present in the body for long periods of time or need to prompt little to no immune reaction, further advancements in mRNA technology are necessary to extend mRNA’s half-life and eliminate immune-triggering contaminants. Notable new developments in these areas include using <a href="https://doi.org/10.1101/2021.03.29.437587">computational algorithms</a> to optimize mRNA sequences in ways that enhance their stability and <a href="https://doi.org/10.1038/s41587-022-01525-6">engineering RNA polymerases</a> that introduce fewer side products that may cause an immune response. </p>
<p>Further advancements have the potential to enable a new generation of safe, durable and effective mRNA therapeutics for applications beyond vaccines.</p><img src="https://counter.theconversation.com/content/215199/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Li Li receives funding from NIH. </span></em></p>The COVID-19 pandemic demonstrated the promise of using mRNA as medicine. But before mRNA drugs can go beyond vaccines, researchers need to identify the right diseases to treat.Li Li, Assistant Professor of Biomedical Sciences, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2195722023-12-14T13:10:22Z2023-12-14T13:10:22ZCRISPR and other new technologies open doors for drug development, but which diseases get prioritized? It comes down to money and science<figure><img src="https://images.theconversation.com/files/565611/original/file-20231213-19-56i402.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2070%2C1449&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">So many diseases to treat, so little money and time.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/covid-19-vaccine-loop-royalty-free-image/1288570747">Andriy Onufriyenko/Moment via Getty Images</a></span></figcaption></figure><p>Prescription drugs and vaccines revolutionized health care, dramatically decreasing death from disease and improving quality of life across the globe. But how do researchers, universities and hospitals, and the pharmaceutical industry decide which diseases to pursue developing drugs for?</p>
<p>In <a href="https://scholar.google.com/citations?user=lWAD9d8AAAAJ&hl=en">my work</a> as director of the <a href="https://pharmacy.uconn.edu/hopes/">Health Outcomes, Policy, and Evidence Synthesis</a> group at the University of Connecticut School of Pharmacy, I assess the effectiveness and safety of different treatment options to help clinicians and patients make informed decisions. My colleagues and I study ways to create new drug molecules, deliver them into the body and improve their effectiveness while reducing their potential harms. Several factors determine which avenues of drug discovery that people in research and pharmaceutical companies focus on.</p>
<h2>Funding drives research decisions</h2>
<p>Research funding amplifies the pace of scientific discovery needed to create new treatments. Historically, <a href="https://doi.org/10.1001/jamahealthforum.2023.1921">major supporters of research</a> like the National Institutes of Health, pharmaceutical industry and private foundations funded studies on the most common conditions, like heart disease, diabetes and mental health disorders. A <a href="https://doi.org/10.18553%2Fjmcp.2022.28.7.732">breakthrough therapy</a> would help millions of people, and a small markup per dose would generate hefty profits.</p>
<p>As a consequence, research on rare diseases was not well-funded for decades because it would help fewer people and the costs of each dose had to be very high to turn a profit. Of the <a href="https://www.fda.gov/patients/rare-diseases-fda">more than 7,000 known rare diseases</a>, defined as <a href="https://rarediseases.info.nih.gov/about">fewer than 200,000 people affected</a> in the U.S., <a href="https://www.ncbi.nlm.nih.gov/books/NBK56187/">only 34 had a therapy approved</a> by the Food and Drug Administration before 1983.</p>
<p>The passage of the <a href="https://doi.org/10.1371%2Fjournal.pmed.1002191">Orphan Drug Act</a> changed this trend by offering tax credits, research incentives and prolonged patent lives for companies actively developing drugs for rare diseases. From 1983 to 2019, <a href="https://doi.org/10.1186/s13023-021-01901-6">724 drugs</a> were approved for rare diseases.</p>
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<a href="https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Person sluicing a bucket of ice water over another person's head" src="https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/565616/original/file-20231213-27-em9ehu.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>
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<span class="caption">The viral ALS ice bucket challenge in 2014 was a fundraising success.</span>
<span class="attribution"><a class="source" href="https://newsroom.ap.org/detail/IceBucketChallenge/4dd78b9ab4044aef8a09a6f7d688b168">Elise Amendola/AP Photo</a></span>
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<p>Emerging social issues or opportunities can significantly affect funding available to develop drugs for certain diseases. When COVID-19 raged across the world, funding from <a href="https://www.nationaldefensemagazine.org/articles/2023/9/19/learning-lessons-from-mrap-operation-warp-speed">Operation Warp Speed</a> led to vaccine development in record time. Public awareness campaigns such as the <a href="https://www.npr.org/2022/10/01/1126397565/the-ice-bucket-challenge-wasnt-just-for-social-media-it-helped-fund-a-new-als-dr">ALS ice bucket challenge</a> can also directly raise money for research. This viral social media campaign provided 237 scientists <a href="https://www.als.org/stories-news/ice-bucket-challenge-dramatically-accelerated-fight-against-als#">nearly US$90 million</a> in research funding from 2014 to 2018, which led to the discovery of five genes connected to amyotrophic lateral sclerosis, commonly called Lou Gehrig’s disease, and new clinical trials.</p>
<h2>How science approaches drug development</h2>
<p>To create breakthrough treatments, researchers need a basic understanding of what disease processes they need to enhance or block. This requires developing <a href="https://doi.org/10.1002/jcph.1569">cell and</a> <a href="https://theconversation.com/expanding-alzheimers-research-with-primates-could-overcome-the-problem-with-treatments-that-show-promise-in-mice-but-dont-help-humans-188207">animal models</a> that can simulate human biology. </p>
<p>It can <a href="https://www.fda.gov/drugs/development-approval-process-drugs">take many years</a> to vet potential treatments and develop the finished drug product ready for testing in people. Once scientists identify a potential biological target for a drug, they use <a href="https://theconversation.com/discovering-new-drugs-is-a-long-and-expensive-process-chemical-compounds-that-dupe-screening-tools-make-it-even-harder-175972">high-throughput screening</a> to rapidly assess hundreds of chemical compounds that may have a desired effect on the target. They then modify the most promising compounds to enhance their effects or reduce their toxicity. </p>
<p>When these compounds have lackluster results in the lab, companies are likely to <a href="https://doi.org/10.1186%2Fs12967-016-0838-4">halt development</a> if the estimated potential revenue from the drug is less than the estimated cost to improve the treatments. Companies can charge more money for drugs that <a href="https://digital.kwglobal.com/publication/?i=456831&p=13&view=issueViewer&pp=1">dramatically reduce deaths or disability</a> than for those that only reduce symptoms. And researchers are more likely to continue working on drugs that have a greater potential to help patients. In order to obtain FDA approval, companies ultimately need to show that the drug causes more benefits for patients than harms. </p>
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<figcaption><span class="caption">Casgevy, a CRISPR-based treatment for sickle cell anemia, is considered a milestone in gene therapy.</span></figcaption>
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<p>Sometimes, researchers know a lot about a disease, but available technology is insufficient to produce a successful drug. For a long time, scientists knew that <a href="https://doi.org/10.1056/NEJMoa2031054">sickle cell disease</a> results from a defective gene that leads cells in the bone marrow to produce poorly formed red blood cells, causing severe pain and blood clots. Scientists lacked a way to fix the issue or to work around it with existing methods. </p>
<p>However, in the early 1990s, basic scientists discovered that bacterial cells have a mechanism to <a href="https://theconversation.com/human-genome-editing-offers-tantalizing-possibilities-but-without-clear-guidelines-many-ethical-questions-still-remain-200983">identify and edit DNA</a>. With that model, researchers began painstaking work developing a <a href="https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crispr-timeline">technology called CRISPR</a> to identify and edit genetic sequences in human DNA. </p>
<p>The technology finally progressed to the point where scientists were able to successfully target the problematic gene in patients with sickle cell and edit it to produce normally functioning red blood cells. In December 2023, <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease">Casgevy became the first CRISPR-based drug</a> approved by the FDA.</p>
<p>Sickle cell disease made a great target for this technology because it was caused by a single genetic issue. It was also an attractive disease to focus on because it affects around 100,000 people in the U.S. and is <a href="https://doi.org/10.2147/ijgm.s257340">costly to society</a>, causing many hospitalizations and lost days of work. It also <a href="https://theconversation.com/sickle-cell-disease-can-be-deadly-and-the-persistent-health-inequities-facing-black-americans-worsen-the-problem-212434">disproportionately affects Black Americans</a>, a population that has been <a href="https://theconversation.com/yes-black-patients-do-want-to-help-with-medical-research-here-are-ways-to-overcome-the-barriers-that-keep-clinical-trials-from-recruiting-diverse-populations-185337">underrepresented in medical research</a>.</p>
<h2>Real-world drug development</h2>
<p>To put all these pieces of drug development into perspective, consider the <a href="https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm">leading cause of death in the U.S.</a>: cardiovascular disease. Even though there are several drug options available for this condition, there is an ongoing need for more effective and less toxic drugs that reduce the risk of heart attacks and strokes. </p>
<p>In 1989, epidemiologists found that patients with <a href="https://doi.org/10.1001/jama.300.11.1343">higher levels of bad, or LDL, cholesterol</a> had more heart attacks and strokes than those with lower levels. Currently, <a href="https://www.cdc.gov/cholesterol/facts.htm#">86 million American adults</a> have elevated cholesterol levels that can be treated with drugs, like the popular statins Lipitor (atorvastatin) or Crestor (rosuvastatin). However, <a href="https://www.pharmacypracticenews.com/Clinical/Article/06-22/Using-National-Guidelines-to-Determine-Hyperlipidemia-Treatment/67209">statins alone</a> cannot get everyone to their cholesterol goals, and many patients develop unwanted symptoms limiting the dose they can receive.</p>
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<a href="https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Two blister packs of burnt orange pills with days of the week listed on each dose" src="https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=386&fit=crop&dpr=1 600w, https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=386&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=386&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=485&fit=crop&dpr=1 754w, https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=485&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/565617/original/file-20231213-14492-77b8o9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=485&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">There are several statins on the market to treat high cholesterol levels.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/daily-statin-dose-royalty-free-image/643755285">Peter Dazeley/The Image Bank via Getty Images</a></span>
</figcaption>
</figure>
<p>So scientists developed models to understand how LDL cholesterol is created in and removed from the body. They found that LDL receptors in the liver removed bad cholesterol from the blood, but a <a href="https://doi.org/10.1177/1074248418769040">protein called PCSK9</a> prematurely destroys them, boosting bad cholesterol levels in the blood. This led to the development of the drugs <a href="https://doi.org/10.1177/1074248418769040">Repathy (evolocumab) and Praluent (alirocumab)</a> that bind to PCSK9 and stop it from working. Another drug, <a href="https://doi.org/10.1002/jcph.2045">Leqvio (inclisiran)</a>, blocks the genetic material coding for PCSK9. </p>
<p>Researchers are also developing a <a href="https://www.pharmacypracticenews.com/Online-First/Article/12-23/Novel-Gene-Therapy-Slashes-LDL-in-Patients-With-Hypercholesterolemia/72152">CRISPR-based method</a> to more effectively treat the disease.</p>
<h2>The future of drug development</h2>
<p>Drug development is driven by the priorities of their funders, be it governments, foundations or the pharmaceutical industry. </p>
<p>Based on the market, companies and researchers tend to study highly prevalent diseases with devastating societal consequences, such as <a href="https://pubmed.ncbi.nlm.nih.gov/33756057/">Alzheimer’s disease</a> and <a href="https://www.cdc.gov/opioids/data/index.html">opioid use disorder</a>. But the work of advocacy groups and foundations can enhance research funding for other specific diseases and conditions. Policies like the Orphan Drug Act also create successful incentives to discover treatments for rare diseases. </p>
<p>However, in 2021, 51% of drug discovery spending in the U.S. was directed at <a href="https://www.evernorth.com/articles/specialty-drug-trends-and-utilization">only 2% of the population.</a>. How to strike a balance between providing incentives to develop <a href="https://theconversation.com/the-price-of-a-miracle-should-we-limit-spending-on-lifesaving-drugs-79609">miracle drug therapies</a> for a few people at the expense of the many is a question researchers and policymakers are still grappling with.</p><img src="https://counter.theconversation.com/content/219572/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>C. Michael White 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>Drug development takes a great deal of time, money and effort. While future profits play a big factor in which diseases gets prioritized, advocacy and research incentives can also tilt the scale.C. Michael White, Distinguished Professor of Pharmacy Practice, University of ConnecticutLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2187842023-12-12T19:53:39Z2023-12-12T19:53:39ZCanada owes its veterans new mental health tools: Access to psychedelic therapies is overdue<iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/canada-owes-its-veterans-new-mental-health-tools-access-to-psychedelic-therapies-is-overdue" width="100%" height="400"></iframe>
<p>The Canadian Senate Subcommittee on Veterans Affairs recently released a striking report entitled <a href="https://sencanada.ca/en/info-page/parl-44-1/veac-psychedelic-therapies/"><em>The Time is Now: Granting Equitable Access to Psychedelic Therapies</em></a>. </p>
<p>To address high rates of suicide and post-traumatic stress disorder (PTSD) among veterans, the report calls on Veterans Affairs Canada (VAC) to immediately implement “a robust research program funded by VAC and the Department of National Defence (DND) in partnership with Health Canada, the Canadian Institutes of Health Research, and all other relevant partners.”</p>
<p>With psychedelic research, Veterans Affairs Canada has a real chance to live up to its mandate “to provide exemplary, client-centred services and benefits that respond to the needs of veterans, our other clients and their families.” </p>
<p>As a psychedelics researcher with an interest in veteran health, I couldn’t be happier, especially with the Senate focus on timeliness, equity and access. </p>
<p>Not only is <a href="https://www.researchgate.net/publication/372244882_Knowledge_Synthesis_in_the_Science_of_Psilocybin_Scoping_Reviews_of_Clinical_and_Preclinical_Research">my PhD on the therapeutic application of psilocybin</a>, but my father was a veteran of the Canadian Forces, as is my brother and two uncles and both of my grandfathers. I grew up on Canadian Forces bases.</p>
<h2>Canada’s veterans</h2>
<p>Lt. Col. (ret’d) Jack Shore, my father, graduate of the <a href="https://www.btb.termiumplus.gc.ca/tpv2alpha/alpha-eng.html?lang=eng&srchtxt=APPRENTICE%20SOLDIER">Soldier Apprentice Program</a> and a United Nations Peacekeeper in the <a href="https://peacekeeping.un.org/sites/default/files/past/onucB.htm">Congo mission</a> of the early 1960s, passed away as I was working as a guest co-editor of a special edition of the <a href="https://jmvfh.utpjournals.press/toc/jmvfh/current"><em>Journal of Military, Veteran and Family Health</em></a>. The theme of the edition is “Therapeutic use of psychedelics, entheogens, entactogens, cannabinoids and dissociative anesthetics for military members and veterans.” </p>
<p>While my Dad rarely talked about his time in the Congo, he experienced what we would now recognize as moral injury, and most likely PTSD. These conditions directly shaped our family life and upbringing. That was before Sudan, Rwanda, the Yugoslav wars and Afghanistan.</p>
<p>My childhood on bases occurred in time of relative peace, but Canada has now had a few generations of soldiers experience active combat. </p>
<p>The <a href="https://patientsmedicalhome.ca/resources/best-advice-guides/best-advice-guide-caring-for-veterans/">629,000 veterans living in Canada have rates of depression, anxiety and substance use disorder that are higher than the civilian population</a>. <a href="https://doi.org/10.1002/jts.21956">One in seven is living with PTSD</a>. Veterans are <a href="https://www.mcgill.ca/maxbellschool/files/maxbellschool/ofha_veteran_homelessness_policy_brief_-_2023.pdf">two to three times more likely</a> to experience homelessness compared to the general population. </p>
<h2>Duty of care</h2>
<p>To veterans of the Canadian Forces and to their families, we owe a duty of care, and not just to provide services and access to novel treatments. We also have a duty to care enough to do the science well and to tackle the public policy challenges (including regulatory drug reform) necessary to provide Canadian veterans with effective care.</p>
<blockquote>
<p>“It is the Government of Canada’s duty to assure veterans that it is doing everything in its power, immediately, to respect its solemn commitment to support, at any cost, those who chose to defend us with honour.” — <a href="https://sencanada.ca/en/info-page/parl-44-1/veac-psychedelic-therapies/">The Subcommittee on Veterans Affairs, Senate of Canada</a> </p>
</blockquote>
<p>The role of the VAC includes paying for the cost of health-care benefits and other services for veterans through the <a href="https://www.canada.ca/en/treasury-board-secretariat/topics/benefit-plans/plans/health-care-plan.html">Public Service Health Care Plan</a> and supplemental treatment benefits. While this single-payer provider model has advantages, it relies heavily on VAC staff and managers to assess and approve plans of care. </p>
<p>Developing a psychedelics research program for veterans should be seen as a public health priority. It will most likely require an independent panel of experts and stakeholders, including veterans, to help shape the agenda in a timely manner for the VAC. </p>
<h2>Psychedelic therapies</h2>
<p><a href="https://cimvhr.ca/">The Canadian Institute for Military and Veteran Health Research</a> (CIMVHR), founded in 2010, is well positioned as the Canadian hub for military, veteran and family health research to provide the infrastructure to foster collaboration, ensure stakeholder engagement and work on the knowledge translation so necessary to rapidly developing the capacity and expertise of Canadian researchers.</p>
<p>We can build on the work of the U.S. Department of Veterans Affairs, which is <a href="https://clinicaltrials.gov/study/NCT05876481?term=Veteran&intr=Psilocybin&rank=1">currently conducting several psilocybin trials</a>, and the long-standing work of <a href="https://maps.org/">MAPS (Multi-disciplinary Association of Psychedelic Studies)</a> in advancing MDMA-assisted therapy for PTSD towards regulatory approval. We can also listen to the experts, such as Canada Health Research Chair in Mental Health Disparities Monnica Williams, who are calling for <a href="https://doi.org/10.1007/s11469-023-01160-5">greater equity and improved inclusion of BIPOC veterans and researchers</a>. </p>
<blockquote>
<p>“When we have tried everything in our toolbox but still cannot help our patients, it is truly time for some new tools.” —<a href="https://jmvfh.utpjournals.press/toc/jmvfh/9/5">Monnica Williams</a>, Canada Health Research Chair in Mental Health Disparities </p>
</blockquote>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-potential-of-psychedelics-to-heal-our-racial-traumas-218233">The potential of psychedelics to heal our racial traumas</a>
</strong>
</em>
</p>
<hr>
<p>Psychedelic ketamine appears to have <a href="https://doi.org/10.1192%2Fbjo.2021.1061">positive but short-lived outcomes</a> in the treatment of mood disorders, and ketamine clinics require evaluation given recent <a href="https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine">FDA warnings</a> about risks of commercialized mental health telemedicine and take-home doses.</p>
<p>Ultimately, the Canadian public may want to reconsider the policy framework that still severely limits access to these promising compounds for researchers, clinicians and those in need. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/albertas-new-policy-on-psychedelic-drug-treatment-for-mental-illness-will-canada-lead-the-psychedelic-renaissance-195061">Alberta’s new policy on psychedelic drug treatment for mental illness: Will Canada lead the psychedelic renaissance?</a>
</strong>
</em>
</p>
<hr>
<p>Veterans have taken it upon themselves to support each other and to advocate for change. <a href="https://heroicheartsproject.org/">The Heroic Hearts Project</a> helps veterans access psychedelic therapies and has long championed the potential benefits of plant medicine ceremony.</p>
<p><a href="https://www.heroicheartsproject.ca/">Heroic Hearts Canada</a>, which aims to provide Canadian veterans with equitable access to safe, effective and affordable psychedelic therapies, has recently partnered with University of Calgary for some <a href="https://www.ucalgary.ca/research/participate/study/16168/are-you-veteran-canadian-armed-forces-have-you-investigated-working-psychedelics-legally">important observational research</a>.</p>
<h2>Faster progress to medical use</h2>
<p>The time lag from drug discovery to patient care is often decades, prompting the expression “<a href="https://doi.org/10.1186/s41231-019-0050-7">valley of death</a>” to refer to the gap between bench science and bedside care. </p>
<p>Given the real mental health needs of Canadian veterans, and the known limits on effectiveness for current standards of care, we must aim for quicker progress towards medical use, <a href="https://www.unodc.org/res/WDR-2023/WDR23_B3_CH2_psychedelics.pdf">as both the United States and Australia have done</a>. However, this progress must not be at the expense of safety and quality, and definitely not simply for commercialization. </p>
<p>Thought needs to be given to the development, evaluation and quality assurance of accessible programs for veteran-centred care, with Veterans’ voices at the table. It is time for more emphasis on psychedelics-related <a href="https://doi.org/10.1016/j.psychres.2019.04.025">implementation science</a>, the study of methods to promote the uptake (and identify barriers) of research findings into routine clinical use in order to improve effectiveness of health services.</p>
<p>There is <a href="https://healthsci.queensu.ca/source/Psychedelics%2520Research/Psychedelic%2520Medicine%2520Report%2520-%2520Final.pdf">robust and mounting evidence to support regulatory approval for MDMA and psilocybin-assisted therapies</a>. Their availability and uptake by clinicians and the public is only a matter of time. </p>
<h2>The need for more diverse research</h2>
<p>Research funds now are best allocated towards large Phase 3 trials that treat wider cross-sections of the veteran community, to begin to assess the safety and efficacy of interventions such as the naturally ocurring and culturally significant psychedelic compounds <a href="https://doi.org/10.1080/00952990.2023.2220874">ibogaine and 5-MeO-DMT</a> <a href="https://www.proquest.com/openview/2d897baa8a8203979eaf5ee7deb9037e/1?pq-origsite=gscholar&cbl=18750&diss=y">and ayahuasca</a>, and to invest in knowledge translation, program evaluation and training researchers and clinicians. </p>
<p>Apart from new biomedical research, it is time we recognized the widespread personal use of psychedelics, including among veterans, and develop safer use guidelines for psychedelics like those in place <a href="https://www.canada.ca/en/health-canada/services/substance-use/alcohol/low-risk-alcohol-drinking-guidelines.html">for alcohol</a> and <a href="https://doi.org/10.1007/BF03404169">cannabis</a>.</p>
<p>While the Senate report does not mention cannabis, it is worth noting that veterans in Canada have been <a href="https://dimensionsretreats.com/dimensions-retreats-algonquin-elevate-veterans-only/#:%7E:text=The%2520program%2520does%2520not%2520include,mind%252Dbody%2520practices%2520in%2520nature.">approved for treatment with cannabis-assisted therapy</a>. </p>
<p>This includes the use of <a href="https://doi.org/10.1177/0269881121997099">cannabis as a psychedelic</a> and mimics the <a href="https://doi.org/10.1007/s40429-021-00401-8">preparation-session-integration protocols</a> of psychedelic therapies. This intervention is also worth rapid evaluation and possible expansion. </p>
<p>Given the pressing needs of Canadian veterans and the limitations of our current tools, the need for research on psychedelic therapies, as well as for timely and equitable access, is urgent.</p><img src="https://counter.theconversation.com/content/218784/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ron Shore worked for, and consulted to Dimensions Health Centres in 2021 and 2022; he continues to own shares in the company.</span></em></p>One in seven Canadian veterans is living with PTSD. Developing a psychedelics research program for veterans should be a public health priority.Ron Shore, Research Scientist, Queen's Health Sciences and Assistant Professor, Department of Psychiatry, Queen's University, OntarioLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2159802023-11-29T20:06:32Z2023-11-29T20:06:32ZMiniature organs on chips could revolutionize health-care research<iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/miniature-organs-on-chips-could-revolutionize-health-care-research" width="100%" height="400"></iframe>
<p>To understand how bodies work, medical researchers and scientists have created mini models of organs, called organoids. This field of scientific research has had profound impacts on biological discovery and pharmaceutical development.</p>
<p>An organoid is a <a href="https://doi.org/10.1038/s43586-022-00174-y">miniaturized version of an organ</a>. As the name suggests with the Greek suffix <em>oid</em>, meaning “like,” an organoid is designed to mimic the organ it represents. These three-dimensional structures are generated from stem cells and, although only about one millimetre in size, they effectively emulate the morphology or function of the actual organs. </p>
<p>Yet this is only half the narrative. “<a href="https://doi.org/10.1038/s43586-022-00118-6">Organs-on-chips</a>” are a technology that uses intricately carved tunnels (microchannels) on a piece of plastic or polymer that can house cells. These channels facilitate the flow of cell culture media, replicating blood flow in the human body. </p>
<p>Organs-on-chips act like a miniature version of the body’s organs in the lab, making it easier to see if new drugs will work. They act as a dynamic in vitro (artificial) system to better replicate the in vivo (actual living) environment of cells.</p>
<p>These technologies emerged as a solution to the challenges of drug development, which is both time-consuming and exorbitantly expensive.</p>
<h2>Safe drug development</h2>
<p>Developing new drugs has become an arduous and costly process, requiring an average of <a href="https://doi.org/10.1001/jama.2020.1166">14 years and over US$1 billion</a> to bring a drug to market. In addition, developing new drugs includes a high likelihood of failure. </p>
<p>One of the main reasons for the <a href="https://doi.org/10.1038/nrd4539">slow development of new drugs</a> is the inadequate tools for accurately predicting how a drug will work in the human body. To address this, there is a growing recognition of the need for new models, such as organoids and organs-on-chips, which could revolutionize our ability to evaluate drug efficacy more effectively and efficiently.</p>
<h2>Game-changing research</h2>
<p>While both organoids and organs-on-chips hold individual promise, the combination of the two — “organoids-on-chips” — is a game changer. Organoids, despite their excellent biological complexity, lack certain biophysical cues, crucial for a comprehensive representation of human tissues. </p>
<p>On the other hand, organs-on-chips, while incorporating dynamic micro-environments, often incorporate less-than-optimal biological models. Labs often use commercially produced cell lines with genetically altered features.</p>
<p><div data-react-class="InstagramEmbed" data-react-props="{"url":"https://www.instagram.com/p/CwTDM3LRrJJ","accessToken":"127105130696839|b4b75090c9688d81dfd245afe6052f20"}"></div></p>
<p>By combining these technologies, we can leverage the biological accuracy of organoids with the dynamic capabilities of organs-on-chips. This synergy offers a platform that mirrors in vivo physiology, enabling a more accurate study of disease traits and responses to drugs.</p>
<p>In <a href="https://medgen.med.ubc.ca/josef-penninger/">our lab</a>, our primary focus is on incorporating a functional vascular system to organoids. A major breakthrough came in 2019 when we generated <a href="https://doi.org/10.1038/s41586-018-0858-8">blood vessel organoids from human stem cells</a>, providing an unprecedented model for vascular structures. </p>
<p>By integrating these blood vessel models into microfluidic chips and supplying them with blood, immune cells or drugs, we are paving the way for advanced organoids-on-chips that embody the necessary complexity. This enhanced vascular model enables us to vascularize a variety of biological tissues, improving their lifespan, function, growth and maturation.</p>
<h2>Merging physics and biology</h2>
<p>The interdisciplinary foundation of organoids-on-chips combines biology and physics to reflect the intricate interplay of physiological and physical processes in the human body. By integrating principles from both fields, we can develop more sophisticated and accurate physiological models that encompass this inherent complexity.</p>
<p>The pioneering work of researchers at the <a href="https://wyss.harvard.edu/">Wyss Institute at Harvard University</a> is a striking example of the potential of this interdisciplinary approach. In 2010, they developed a “<a href="https://doi.org/10.1126/science.1188302">lung-on-chip</a>” model that not only mimics the biological structure of lung cells, but also replicates the mechanical function of human breathing. </p>
<p>In a remarkable display of innovation, they also created a <a href="https://www.youtube.com/watch?v=VewOqUnwXG0">smoking robot to simulate the effects of cigarette smoke on this lung-on-chip device</a>, and <a href="https://wyss.harvard.edu/news/human-organ-chips-enable-rapid-drug-repurposing-for-covid-19/">tested COVID-19 drugs</a> during the pandemic.</p>
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<figcaption><span class="caption">Researchers at Harvard University look at the impact of smoking on lung cells.</span></figcaption>
</figure>
<p>From its initial conception, the field of organs-on-chips has grown exponentially. Highlighting this trend, the geneticist and microbiologist Hans Clevers now leads <a href="https://www.roche.com/about/leadership/hans-clevers">the pharmaceutical giant Roche’s research division</a>. “In 20 years,” Clevers said, “I think organoids will have <a href="https://doi.org/10.1007/s00109-020-02025-3">replaced animal experimentation in toxicology testing</a>.”</p>
<p>In a parallel move, Roche set up <a href="https://institutehumanbiology.com/">the Institute of Human Biology</a>, under the direction of bioengineer <a href="https://doi.org/10.1016/j.stemcr.2021.08.012">Matthias Lutolf</a>. The institute merges the study of organoids with microfluidic technology. </p>
<h2>Future of organoids</h2>
<p>A pivotal development in 2023 was the U.S. <a href="https://doi.org/10.1126/science.adg6264">Food and Drug Administration’s decision to no longer mandate animal testing for new drugs</a> before advancing to human trials. This change underscores the potential of alternatives like organoids and organs-on-chips in early drug testing, and marks a significant milestone for the field.</p>
<p>The <a href="https://doi.org/10.1126/science.aaw7894">potential of organoids-on-chips</a> extends beyond drug screening and toxicity tests. The technology holds promise for a range of exciting applications, including unravelling the fundamental biological principles underlying development and disease. Their applications extend to <a href="https://doi.org/10.1038/s41576-018-0051-9">regenerative medicine</a>, where organs grown from a patient’s own stem cells could be used to replace damaged ones.</p><img src="https://counter.theconversation.com/content/215980/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Clément Quintard 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>Organoids — clusters of specialized cells designed to mimic organs — enable researchers to study biological processes and the effects of drugs.Clément Quintard, Postdoctoral fellow, Penninger Lab, University of British ColumbiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2113962023-11-29T13:38:49Z2023-11-29T13:38:49ZMicroRNA is the master regulator of the genome − researchers are learning how to treat disease by harnessing the way it controls genes<figure><img src="https://images.theconversation.com/files/561973/original/file-20231127-27-vqtw0l.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1400&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">RNA is more than just a transitional state between DNA and protein.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/molecule-of-mrna-illustration-royalty-free-illustration/1450368774">Kateryna Kon/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The Earth <a href="https://www.scientificamerican.com/article/evolution-of-earth/">formed 4.5 billion years ago</a>, and life less than a billion years after that. Although life as we know it is <a href="https://sciencing.com/abundant-organic-compound-earth-22851.html">dependent on four major macromolecules</a> – DNA, RNA, proteins and lipids – only one is thought to have been present at the beginning of life: RNA. </p>
<p>It is no surprise that <a href="https://www.khanacademy.org/science/ap-biology/natural-selection/origins-of-life-on-earth/a/rna-world">RNA likely came first</a>. It is the only one of those major macromolecules that can both replicate itself and catalyze chemical reactions, both of which are essential for life. Like DNA, RNA is made from individual nucleotides linked into chains. Scientists initially understood that genetic information flows in one direction: DNA is transcribed into RNA, and RNA is translated into proteins. That principle is called the <a href="https://www.genome.gov/genetics-glossary/Central-Dogma">central dogma of molecular biology</a>. But there are many deviations.</p>
<p>One major example of an exception to the central dogma is that some RNAs are never translated or coded into proteins. This fascinating diversion from the central dogma is what led me to <a href="https://scholar.google.com/citations?user=4JMQMLgAAAAJ&hl=en">dedicate my scientific career</a> to understanding how it works. Indeed, research on RNA has lagged behind the other macromolecules. Although there are multiple classes of these so-called noncoding RNAs, researchers like myself have started to focus a great deal of attention on short stretches of genetic material called <a href="https://www.ibiology.org/genetics-and-gene-regulation/introduction-to-micrornas/">microRNAs</a> and their potential to treat various diseases, including cancer.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/t5jroSCBBwk?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">MicroRNAs play a key role in regulating gene expression.</span></figcaption>
</figure>
<h2>MicroRNAs and disease</h2>
<p>Scientists regard microRNAs as <a href="https://doi.org/10.1146/annurev-pharmtox-010510-100517">master regulators of the genome</a> due to their ability to bind to and alter the expression of many protein-coding RNAs. Indeed, a single microRNA can regulate anywhere from 10 to 100 protein-coding RNAs. Rather than translating DNA to proteins, they instead can bind to protein-coding RNAs to silence genes. </p>
<p>The reason microRNAs can regulate such a diverse pool of RNAs stems from their ability to bind to target RNAs they don’t perfectly match up with. This means a single microRNA can often regulate a pool of targets that are all involved in similar processes in the cell, leading to an enhanced response.</p>
<p>Because a single microRNA can regulate multiple genes, many microRNAs can contribute to disease when they become dysfunctional.</p>
<p>In 2002, researchers first identified the role dysfunctional microRNAs play in disease through patients with a type of blood and bone marrow cancer called <a href="https://doi.org/10.1073/pnas.242606799">chronic lymphocytic leukemia</a>. This cancer results from the <a href="https://doi.org/10.1038/cdd.2009.69">loss of two microRNAs</a> normally involved in blocking tumor cell growth. Since then, scientists have identified <a href="https://mirbase.org/browse/results/?organism=hsa">over 2,000 microRNAs in people</a>, many of which are altered in various diseases. </p>
<p>The field has also developed a fairly solid understanding of how microRNA dysfunction contributes to disease. Changing one microRNA can change several other genes, resulting in a plethora of alterations that can collectively reshape the cell’s physiology. For example, over half of all cancers have significantly reduced activity in a <a href="https://doi.org/10.3389/fcell.2021.640587">microRNA called miR-34a</a>. Because miR-34a regulates many genes involved in preventing the growth and migration of cancer cells, losing miR-34a can increase the risk of developing cancer.</p>
<p>Researchers are looking into using microRNAs as therapeutics for cancer, heart disease, neurodegenerative disease and others. While results in the laboratory have been promising, bringing microRNA treatments into the clinic has <a href="https://doi.org/10.1016/j.tig.2022.02.006">met multiple challenges</a>. Many are related to inefficient delivery into target cells and poor stability, which limit their effectiveness.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing a loop of microRNA binding to a strand of mRNA as it's being translated from DNA" src="https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=385&fit=crop&dpr=1 600w, https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=385&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=385&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=484&fit=crop&dpr=1 754w, https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=484&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/561975/original/file-20231127-26-jqjjuh.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=484&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">MicroRNA can silence genes by binding to mRNA.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Conceptual_overview_of_multiomics_-_digital_skewed.png">Kajsa Mollersen/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>Delivering microRNA to cells</h2>
<p>One reason why delivering microRNA treatments into cells is difficult is because microRNA treatments need to be delivered specifically to diseased cells while avoiding healthy cells. Unlike <a href="https://theconversation.com/how-mrna-and-dna-vaccines-could-soon-treat-cancers-hiv-autoimmune-disorders-and-genetic-diseases-170772">mRNA COVID-19 vaccines</a> that are taken up by scavenging immune cells whose job is to detect foreign materials, microRNA treatments need to fool the body into thinking they aren’t foreign in order to avoid immune attack and get to their intended cells.</p>
<p>Scientists are studying various ways to deliver microRNA treatments to their specific target cells. One method garnering a great deal of attention relies on directly <a href="https://doi.org/10.1093/narcan/zcab030">linking the microRNA to a ligand</a>, a kind of small molecule that binds to specific proteins on the surface of cells. Compared with healthy cells, diseased cells can have a disproportionate number of some surface proteins, or receptors. So, ligands can help microRNAs home specifically to diseased cells while avoiding healthy cells. The first ligand approved by the U.S. Food and Drug Administration to deliver small RNAs like microRNAs, <a href="https://doi.org/10.1007/s40265-020-01269-0">N-acetylgalactosamine, or GalNAc</a>, preferentially delivers RNAs to liver cells.</p>
<p>Identifying ligands that can deliver small RNAs to other cells requires finding receptors expressed at high enough levels on the surface of target cells. Typically, <a href="https://doi.org/10.1038/nrd4519">over one million copies per cell</a> are needed in order to achieve sufficient delivery of the drug.</p>
<p>One ligand that stands out is <a href="https://theconversation.com/adding-folic-acid-to-staple-foods-can-prevent-birth-defects-but-most-countries-dont-do-it-55533">folate, also referred to as vitamin B9</a>, a small molecule critical during periods of rapid cell growth such as fetal development. Because some tumor cells have over one million folate receptors, this ligand provides sufficient opportunity to deliver enough of a therapeutic RNA to target different types of cancer. For example, my laboratory developed a new molecule <a href="https://doi.org/10.1126/scitranslmed.aam9327">called FolamiR-34a</a> – folate linked to miR-34a – that reduced the size of breast and lung cancer tumors in mice.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image juxtaposing endothelial cells sprouting extensions to form new blood vessels and a cell bathed in microRNA unable to sprout" src="https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=387&fit=crop&dpr=1 600w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=387&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=387&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=486&fit=crop&dpr=1 754w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=486&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=486&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Tumors can exploit healthy cells to grow blood vessels that provide them nutrients, as seen in the endothelial cells to the left sprouting extensions. Exposing these cells to certain microRNAs, however, can disable that growth, as seen in the cell to the right.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/2hrJ3g4">Dudley Lab, University of Virginia School of Medicine/NIH via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<h2>Making microRNAs more stable</h2>
<p>One of the other challenges with using small RNAs is their <a href="https://doi.org/10.1093/narcan/zcab030">poor stability</a>, which leads to their rapid degradation. As such, RNA-based treatments are generally short-lived in the body and require frequent doses to maintain a therapeutic effect. </p>
<p>To overcome this challenge, researchers are <a href="https://doi.org/10.1093/narcan/zcab030">modifying small RNAs</a> in various ways. While each RNA requires a specific modification pattern, successful changes can <a href="https://doi.org/10.1038/s41388-023-02801-8">significantly increase their stability</a>. This reduces the need for frequent dosing, subsequently decreasing treatment burden and cost. </p>
<p>For example, <a href="https://doi.org/10.1089%2Fnat.2018.0736">modified GalNAc-siRNAs</a>, another form of small RNAs, reduces dosing from every few days to once every six months in nondividing cells. My team developed <a href="https://doi.org/10.1038/s41388-023-02801-8">folate ligands</a> linked to modified microRNAs for cancer treatment that reduced dosing from once every other day to once a week. For diseases like cancer where cells are rapidly dividing and quickly diluting the delivered microRNA, this increase in activity is a significant advancement in the field. We anticipate this accomplishment will facilitate further development of this folate-linked microRNA as a cancer treatment in the years to come.</p>
<p>While there is still considerable work to be done to overcome the hurdles associated with microRNA treatments, it’s clear that RNA shows promise as a therapeutic for many diseases.</p><img src="https://counter.theconversation.com/content/211396/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrea Kasinski receives funding from the National Institutes of Health, Department of Defense, and the American Lung Association. Kasinski is also the inventor on multiple patients associated with her discoveries in the RNA therapeutics field. </span></em></p>When just one of the thousands of microRNAs in people go awry, it can cause diseases ranging from heart disease to cancer.Andrea Kasinski, Associate Professor of Biological Sciences, Purdue UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2121822023-08-30T20:35:41Z2023-08-30T20:35:41ZWe won’t always have to use animals for medical research. Here’s what we can do instead<figure><img src="https://images.theconversation.com/files/545212/original/file-20230829-23-6du48r.jpg?ixlib=rb-1.1.0&rect=29%2C266%2C3265%2C2089&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/funny-white-rat-looking-out-cage-592100393">Shutterstock</a></span></figcaption></figure><p>Animals have been used for medical research for thousands of years, dating back to ancient Greece where the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495509/">first dissections</a> were performed. </p>
<p>These days, one of the main uses of animals is to ensure the safety of medical products before they’re trialled in humans. </p>
<p>But in addition to the important ethical reasons for minimising animal use, the reality is sometimes animals just aren’t that good at predicting human responses. No animal model, for example, has captured all the human characteristics of complex illnesses like <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543097/">Alzheimer’s disease</a> or <a href="https://ncats.nih.gov/news/releases/2022/researchers-create-3-D-model-for-rare-neuromuscular-disorders-setting-stage-for-clinical-trial">chronic inflammatory demyelinating polyneuropathy</a> (a neuromuscular disease). This makes is hard to develop effective treatments and cures.</p>
<p>Thankfully, researchers are making progress in developing a collection of alternative approaches, called “non-animal models”. A new <a href="https://www.csiro.au/nonanimalmodels">report</a> from our team at CSIRO Futures examines the potential of non-animal models and the actions Australia will need to take to pursue their use.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/can-we-ethically-justify-harming-animals-for-research-196387">Can we ethically justify harming animals for research?</a>
</strong>
</em>
</p>
<hr>
<h2>What are non-animal models?</h2>
<p>Non-animal models are an alternative set of models that use human cells, tissues and data. </p>
<p>These have the potential to better mimic human responses. In doing so, this can more accurately predict if a medical product is likely to fail, allowing reinvestment in products that are more likely to succeed. </p>
<p>Computer simulations or “in silico models” are one example. These can be used across the medical product development process to complement – and in time potentially replace – other model types. They can be used in drug studies to model a drug’s behaviour within the body, from cellular interactions to processes that involve multiple organs.</p>
<p>Complex three-dimensional biological models are also maturing quickly. Examples include:</p>
<ul>
<li><p><a href="https://hsci.harvard.edu/organoids">organoids</a> – organ “buds” that can be propagated from stem cells or taken from biopsies </p></li>
<li><p><a href="https://www.nature.com/articles/s43586-022-00118-6">organs-on-chips</a> – cells cultured in a miniature engineered chip. These attempt to replicate the physical environment of human organs.</p></li>
</ul>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1613253802144026624"}"></div></p>
<h2>What can we use non-animal models for?</h2>
<p>In theory, we can use non-animal models for everything we use animal models for – and more.</p>
<p>Simple non-animal models (human cells cultured over a flat surface) are <a href="https://www.novartis.com/stories/systematically-exposing-vulnerabilities-cancer-cells">already used to help identify drug targets</a> due to their ability to test a large number of compounds and experimental conditions. </p>
<p>In the future, non-animal models will reduce – and eventually replace – animal use across a range of applications:</p>
<ul>
<li>screening potential drugs to see how well they work</li>
<li>toxicology (safety) testing</li>
<li>helping to screen, select and stratify shortlisted participants for clinical trials. This might include an assessment of their unique response to a potential drug.</li>
<li>using patient cells to identify the treatment most likely to help that individual.</li>
</ul>
<p>Outside of medical products designed for humans, non-animal models can also support innovation in veterinary and agricultural medicines, cosmetic testing and eco-toxicology.</p>
<figure class="align-center ">
<img alt="Woman applies lipstick" src="https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=316&fit=crop&dpr=1 600w, https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=316&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=316&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=398&fit=crop&dpr=1 754w, https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=398&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/545213/original/file-20230829-15-sw8ysk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=398&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Non-animal models can be used to test cosmetics.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/hispanic-latina-putting-lipstick-front-bathroom-2028019892">Shutterstock</a></span>
</figcaption>
</figure>
<h2>An export opportunity for Australia</h2>
<p>Non-animal models present an economic opportunity for Australia, where the models, their components, and surrounding services could be exported to the world.</p>
<p>Our novel economic analysis sized the potential Australian market for two non-animal models: organoids and organs-on-chips. Other models were unable to be sized due to a lack of global market data. </p>
<p>We estimate the Australian organoid market could be worth A$1.3 billion annually by 2040 and create 4,200 new jobs. </p>
<p>The organs-on-chips market could be worth A$300 million annually by 2040 and create 1,000 new jobs. This estimate is lower as this technology is currently less advanced but holds the potential to grow significantly beyond 2040.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/mechanical-forces-in-a-beating-heart-affect-its-cells-dna-with-implications-for-development-and-disease-173484">Mechanical forces in a beating heart affect its cells' DNA, with implications for development and disease</a>
</strong>
</em>
</p>
<hr>
<p>Several Australian entities are already contributing to these opportunities. The Murdoch Children’s Research Institute, for example, provides stem cell and modelling expertise as part of <a href="https://novonordiskfonden.dk/en/projects/novo-nordisk-foundation-center-for-stem-cell-medicine-renew">reNEW</a>, a €300 million international collaboration. </p>
<p>Another example is from <a href="https://schott-minifab.com/">Schott Minifab</a>, an international biotech and medical device company with Australian roots, which has successfully established scaled production of non-animal model components in Australia for domestic and export markets.</p>
<h2>Making it a reality</h2>
<p>Non-animal models have already begun to complement and replace animal use in some areas, such as identifying drug targets. </p>
<p>However, accelerating their development and adoption across a wider range of applications will require further technical advances to lower cost and validate their performance as superior models. </p>
<p>Australia has several research strengths in this field but we need a concentrated effort to help our research make it through to real world impact. </p>
<p>Our report makes ten recommendations for supporting Australia’s pursuit of these opportunities. Critical activities over the next five years include:</p>
<ul>
<li>coordinating local capabilities </li>
<li>investing in upgraded infrastructure</li>
<li>creating and collating data that compares animal and non-animal model performance.</li>
</ul>
<p>Governments, industry and research must collaborate to deliver against these actions. Success will only come from collective efforts.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/is-it-time-for-australia-to-be-more-open-about-research-involving-animals-103439">Is it time for Australia to be more open about research involving animals?</a>
</strong>
</em>
</p>
<hr>
<img src="https://counter.theconversation.com/content/212182/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>As well as the important ethical reasons for minimising animal use in research, the reality is sometimes animals just aren’t that good at predicting human responses.Greg Williams, Associate Director, CSIRO Futures, CSIROLaura Anne Thomas, Strategy Manager, CSIRO Futures, CSIROLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2083432023-06-27T12:24:42Z2023-06-27T12:24:42ZLab-grown meat techniques aren’t new – cell cultures are common tools in science, but bringing them up to scale to meet society’s demand for meat will require further development<figure><img src="https://images.theconversation.com/files/533777/original/file-20230623-15-zpv5wg.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cell cultures are often grown in petri dishes.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/barcoded-petri-dishes-royalty-free-image/478184231">Wladimir Bulgar/Science Photo Library via Getty Images</a></span></figcaption></figure><p>You might be old enough to remember the famous “<a href="https://www.yahoo.com/news/the-inside-story-of-wendys-wheres-the-beef-ad-140051010.html">Where’s the Beef?</a>” Wendy’s commercials. This question may be asked in a different context since <a href="https://apnews.com/article/cultivated-meat-lab-grown-cell-based-a88ab8e0241712b501aa191cdbf6b39a">U.S. regulators approved</a> the sale of lab-grown chicken meat made from cultivated cells in June 2023.</p>
<p>Growing animal cells in the lab isn’t new. Scientists have been culturing animal cells in artificial environments <a href="https://doi.org/10.1007/978-3-319-07758-1_3">since the 1950s</a>, initially focusing on studying developmental biology and cancer. This technique remains one of the major tools in life science research, especially for <a href="https://doi.org/10.1016%2Fj.jsps.2014.04.002">drug development</a>. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/XdkskowAHkY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The USDA approved cell-cultivated chicken on June 21, 2023.</span></figcaption>
</figure>
<h2>What are cell cultures?</h2>
<p>Cell cultures are typically grown using either <a href="https://dx.doi.org/10.13070/mm.en.3.175">natural or artificial growth media</a>. Natural media comprise naturally-derived biological fluids, whereas artificial media comprise both organic and inorganic nutrients and compounds. Both contain the necessary ingredients to foster the growth and development of cells. These ingredients typically contain nutrients such as vitamins, carbohydrates, amino acids and other molecules that provide the fuel for cells to grow and multiply.</p>
<p>Researchers use cells grown using tissue culture to answer a <a href="https://doi.org/10.1016%2Fj.jsps.2014.04.002">variety of experimental questions</a>. <a href="https://scholar.google.com/citations?user=zLwzHqcAAAAJ&hl=en">As a biochemist</a>, I use plant tissue culture techniques in my courses and research program. Researchers can add viruses, bacteria, fungi, hormones, vitamins and other pathogens or compounds to cells grown in culture to observe how different factors affect the cells’ behavior or function, especially as it relates to which genes are turned on or off in the cell and which proteins respond to those pathogens or compounds. </p>
<p>In <a href="https://theconversation.com/from-the-research-lab-to-your-doctors-office-heres-what-happens-in-phase-1-2-3-drug-trials-138197">drug development</a>, growing cells in culture is usually the first step before potential drug candidates can be tested in animals.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/RpDke-Sadzo?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cell cultures involve growing cells outside of their native environment.</span></figcaption>
</figure>
<h2>How is lab-grown meat made?</h2>
<p>Researchers use similar techniques to <a href="https://thehumaneleague.org/article/lab-grown-meat">grow meat in the lab</a>. The process can generally be broken down into <a href="https://www.youtube.com/watch?v=u468xY1T8fw">three major steps</a>. </p>
<p>The first step involves removing a small number of cells – typically muscle or stem cells – from an animal during a harmless and painless procedure. <a href="https://theconversation.com/triggering-cancer-cells-to-become-normal-cells-how-stem-cell-therapies-can-provide-new-ways-to-stop-tumors-from-spreading-or-growing-back-191559">Stem cells</a> are cells from an organism that are not specialized and can be manipulated in the lab to turn into the many different types of cells of that organism.</p>
<p>The next step is culturing the cells. The cells are placed in an artificial environment favorable to their growth. Because of the large amount of cells that have to be grown to produce meat, the cells are incubated <a href="https://www.engr.colostate.edu/CBE101/topics/bioreactors.html">in a bioreactor</a> – a steel tank that provides controlled temperature, humidity, pressure and sterile conditions – with the appropriate medium to facilitate growth. The growth media are changed a number of times to encourage the cells to differentiate and multiply into the three major components of meat: muscle, fat and connective tissue. </p>
<p>In last step of the process, known as scaffolding, the cells are organized and packed tightly together to create the desired size, shape and cut of meat for consumption. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/M-weFARkGi4?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Making cultured meat has seen lots of progress in the lab, but there is still a long way to go.</span></figcaption>
</figure>
<h2>Pros and cons of cultured meat</h2>
<p>There are pros and cons to growing meat through cell culture techniques. While cultured meat may produce relatively less greenhouse gas than conventional livestock production in <a href="https://doi.org/10.1038/s43016-020-0112-z">certain conditions</a>, researchers <a href="https://doi.org/10.3389/fsufs.2019.00005">need to refine the process</a> before it can be cost-efficient and brought to scale. </p>
<p>A 2021 analysis estimated that lab-grown meat will <a href="https://doi.org/10.1002/bit.27848">cost US$17 to $23 per pound</a> to produce, and that does not include grocery store markups. In comparison, conventionally grown ground beef typically costs <a href="https://www.bls.gov/regions/mid-atlantic/data/averageretailfoodandenergyprices_usandmidwest_table.htm">a little under $5 per pound</a>. </p>
<p>A 2021 <a href="https://www.mckinsey.com/industries/agriculture/our-insights/cultivated-meat-out-of-the-lab-into-the-frying-pan">McKinsey report</a> estimates that it will take approximately <a href="https://www.greenbiz.com/article/lab-meat-has-3-big-problems-it-time-pivot">220 million to 440 million liters of bioreactor capacity</a> to meet 1% of current protein market share, but current bioreactor capacity tops out at 200 million liters. There are also concerns about the biological limitations of growing large numbers of various cell types in the same bioreactor.</p>
<p>Lab-grown meat may <a href="https://theconversation.com/no-animal-required-but-would-people-eat-artificial-meat-72372">improve animal welfare</a> and be less likely to carry disease or cause food-borne illnesses. However, consumers may also perceive lab-grown meat to be unnatural or have concerns about its taste.</p>
<p>Companies are likely paying attention and adapting to the public’s response. To put things in perspective, the <a href="https://www.forbes.com/sites/lanabandoim/2022/03/08/making-meat-affordable-progress-since-the-330000-lab-grown-burger/?sh=523ac7c24667">first lab-grown burger</a> cost $330,000 to create in 2013. The price has fallen to just under $10 per burger today, which is remarkable progress in just a decade.</p><img src="https://counter.theconversation.com/content/208343/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>André O. Hudson receives funding from the National Institutes of Health </span></em></p>Cell cultures are common tools in biology and drug development. Bringing them up to scale to meet the meat needs of societies will require further development.André O. Hudson, Dean of the College of Science, Professor of Biochemistry, Rochester Institute of TechnologyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2045222023-05-30T12:24:11Z2023-05-30T12:24:11ZYour body naturally produces opioids without causing addiction or overdose – studying how this process works could help reduce the side effects of opioid drugs<figure><img src="https://images.theconversation.com/files/528436/original/file-20230525-27-cw53qp.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2309%2C1299&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Opioid neurotransmitters are located in many areas of the body, including the brain, spine and gut.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/neurotransmitter-release-mechanisms-royalty-free-image/1396888608">ALIOUI Mohammed Elamine/iStock via Getty Images Plus</a></span></figcaption></figure><p>Opioid drugs such as morphine and fentanyl are like the two-faced Roman god Janus: The kindly face delivers pain relief to millions of sufferers, while the grim face drives an opioid abuse and overdose crisis that <a href="https://www.cdc.gov/drugoverdose/deaths/index.html">claimed nearly 70,000 lives</a> in the U.S. in 2020 alone. </p>
<p><a href="https://scholar.google.com/citations?user=LXVL7f0AAAAJ&hl=en">Scientists like me who study pain and opioids</a> have been seeking a way to separate these two seemingly inseparable faces of opioids. Researchers are trying to design drugs that deliver effective pain relief without the risk of side effects, including addiction and overdose.</p>
<p>One possible path to achieving that goal lies in understanding the molecular pathways opioids use to carry out their effects in your body.</p>
<h2>How do opioids work?</h2>
<p>The <a href="https://pubmed.ncbi.nlm.nih.gov/16082232/">opioid system in your body</a> is a set of neurotransmitters your brain naturally produces that enable communication between neurons and activate protein receptors. These neurotransmitters include small proteinlike molecules like <a href="https://doi.org/10.1124/mol.120.119388">enkephalins and endorphins</a>. These molecules regulate a tremendous number of functions in your body, including pain, pleasure, memory, the movements of your digestive system and more.</p>
<p>Opioid neurotransmitters activate receptors that are <a href="https://www.ncbi.nlm.nih.gov/books/NBK546642/">located in a lot of places</a> in your body, including pain centers in your spinal cord and brain, reward and pleasure centers in your brain, and throughout the neurons in your gut. Normally, opioid neurotransmitters are released in only small quantities in these exact locations, so your body can use this system in a balanced way to regulate itself.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/NDVV_M__CSI?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The opioids your body produces and opioid drugs bind to the same receptors.</span></figcaption>
</figure>
<p>The problem comes when you take an opioid drug like morphine or fentanyl, especially at high doses for a long time. These drugs <a href="https://theconversation.com/how-do-drugs-know-where-to-go-in-the-body-a-pharmaceutical-scientist-explains-why-some-medications-are-swallowed-while-others-are-injected-182488">travel through the bloodstream</a> and can activate every opioid receptor in your body. You’ll get pain relief through the pain centers in your spinal cord and brain. But you’ll also get a euphoric high when those drugs hit your brain’s reward and pleasure centers, and that could <a href="https://doi.org/10.1016%2FS2215-0366(16)00104-8">lead to addiction</a> with repeated use. When the drug hits your gut, you may develop constipation, along with other common <a href="https://www.asahq.org/madeforthismoment/pain-management/opioid-treatment/what-are-opioids/">opioid side effects</a>.</p>
<h2>Targeting opioid signal transduction</h2>
<p>How can scientists design opioid drugs that won’t cause side effects?</p>
<p>One approach my research team and I take is to understand how cells respond when they receive the message from an opioid neurotransmitter. Neuroscientists call this process <a href="https://doi.org/10.1097%2FALN.0b013e318238bba6">opioid receptor signal transduction</a>. Just as neurotransmitters are a communication network within your brain, each neuron also has a communication network that connects receptors to proteins within the neuron. When these connections are made, they trigger specific effects like pain relief. So, after a natural opioid neurotransmitter or a synthetic opioid drug activates an opioid receptor, it activates proteins within the cell that carry out the effects of the neurotransmitter or the drug.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/FQFBygnIONU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cells communicate with one another in multiple ways.</span></figcaption>
</figure>
<p>Opioid signal transduction is complex, and scientists are just starting to figure out how it works. However, one thing is clear: Not every protein involved in this process does the same thing. Some are more important for pain relief, while some are more important for side effects like <a href="https://theconversation.com/pain-and-anxiety-are-linked-to-breathing-in-mouse-brains-suggesting-a-potential-target-to-prevent-opioid-overdose-deaths-174187">respiratory depression</a>, or the decrease in breathing rate that makes overdoses fatal.</p>
<p>So what if we target the “good” signals like pain relief, and avoid the “bad” signals that lead to addiction and death? Researchers are tackling this idea in different ways. In fact, in 2020 the U.S. Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-new-opioid-intravenous-use-hospitals-other-controlled-clinical-settings">approved the first opioid drug based on this idea</a>, oliceridine, as a painkiller with fewer respiratory side effects.</p>
<p>However, relying on just one drug has downsides. That drug might not work well for all people or for all types of pain. It could also have other side effects that show up only later on. Plenty of options are needed to treat all patients in need.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="drawing depicting a tangle of red, blue and yellow curly and straight lines" src="https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=800&fit=crop&dpr=1 600w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=800&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=800&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1006&fit=crop&dpr=1 754w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1006&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1006&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 figure shows the structure of Hsp90.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/heat-shock-protein-90-chaperone-complex-royalty-free-illustration/185759601">Laguna Design/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>My research team is targeting a protein called <a href="https://doi.org/10.1007/128_2012_356">Heat shock protein 90, or Hsp90</a>, which has many functions inside each cell. Hsp90 has been a hot target in the <a href="https://doi.org/10.3390/ijms221910317">cancer field</a> for years, with researchers developing Hsp90 inhibitors as a treatment for many cancer types. </p>
<p>We’ve found that Hsp90 is also really important in regulating opioid signal transduction. <a href="https://doi.org/10.1074/jbc.m116.769489">Blocking Hsp90 in the brain</a> blocked opioid pain relief. However, <a href="https://doi.org/10.1126/scisignal.aaz1854">blocking Hsp90 in the spinal cord</a> increased opioid pain relief. Our recently published work uncovered more details on exactly how <a href="https://doi.org/10.1126/scisignal.ade2438">inhibiting Hsp90 leads to increased pain relief</a> in the spinal cord.</p>
<p>Our work shows that manipulating opioid signaling through Hsp90 offers a path forward to improve opioid drugs. Taking an Hsp90 inhibitor that targets the spinal cord along with an opioid drug could improve the pain relief the opioid provides while decreasing its side effects. With improved pain relief, you can take less opioid and reduce your risk of addiction. We are <a href="https://reporter.nih.gov/search/zF-FuD_ZC0CFwl6deU7tQw/project-details/10294366">currently developing</a> a new generation of Hsp90 inhibitors that could help realize this goal. </p>
<p>There may be many paths to developing an improved opioid drug without the burdensome side effects of current drugs like morphine and fentanyl. Separating the kindly and grim faces of the opioid Janus could help provide pain relief we need without addiction and overdose.</p><img src="https://counter.theconversation.com/content/204522/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Streicher receives funding from the National Institutes of Health, the Arizona Biomedical Research Commission, the Flinn Foundation, and the University of Arizona. He is an equity holder in Teleport Pharmaceuticals, LLC, and Botanical Results, LLC, however, no company products or interests were discussed in this article. </span></em></p>Unlike opioid drugs like morphine and fentanyl that travel throughout the body, the opioids your body produces are released in small quantities to specific locations.John Michael Streicher, Associate Professor of Pharmacology, University of Arizona Health SciencesLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2046562023-05-26T12:27:10Z2023-05-26T12:27:10ZDrilling down on treatment-resistant fungi with molecular machines<figure><img src="https://images.theconversation.com/files/523869/original/file-20230502-26-xj4lbv.jpg?ixlib=rb-1.1.0&rect=19%2C12%2C2098%2C1387&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Newly developed molecular drills may be able to fight treatment-resistant fungal infections like *Candida auris*.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/candida-auris-fungi-emerging-multidrug-resistant-royalty-free-image/1028379354?phrase=Candida%20auris%20fungi%2C%20emerging%20multidrug%20resistant%20fungus">Dr_Microbe/iStock via Getty Images</a></span></figcaption></figure><p>Fungi are present on the skin of around 70% of the population, without causing harm or benefit. Some fungal infections, like athlete’s foot, are minor. Others, like <em>Candida albicans</em>, can be deadly – especially for individuals with <a href="https://doi.org/10.1038/s41577-022-00826-w">weakened immune systems</a>. </p>
<p><a href="https://doi.org/10.1086/322685">Fungal infections are on the rise</a> because of an aging population and an increased prevalence of chronic diseases. At the same time, fungi are becoming <a href="https://doi.org/10.1038/s41579-022-00720-1">more resistant to treatment</a>. As a result, fungal infections could soon become a serious public health threat.</p>
<p>In 2022, the World Health Organization released its first-ever “<a href="https://www.who.int/publications/i/item/9789240060241">Fungal Priority Pathogen List</a>,” calling for improved surveillance, public health interventions and the development of new antifungal drugs. </p>
<p>We are an <a href="https://www.jmtour.com/">interdisciplinary team</a> of <a href="https://scholar.google.com/citations?user=7g-Vv80AAAAJ&hl=en&oi=sra">chemists</a> and <a href="https://scholar.google.com/citations?user=adrn7L0AAAAJ&hl=en">biologists</a> charting a new path to tackle drug-resistant infections. We are using tiny nanoscale drills that combat harmful pathogens at the molecular level. As the traditional antimicrobial research pipeline struggles, our approach has the potential to rejuvenate the fight against these stubborn infections.</p>
<h2>Molecular machines as alternative antifungals</h2>
<p>While doctors urgently need new antifungal drugs, <a href="https://doi.org/10.1101/cshperspect.a019703">developing them is challenging</a>. First, it is difficult to develop drugs that selectively kill fungi without harming human cells because of their <a href="https://doi.org/10.2174/1389557516666160118112103">many similarities</a>.</p>
<p>Second, fungi can <a href="https://www.cdc.gov/fungal/antifungal-resistance.html">rapidly develop resistance to multiple antifungal drugs at once</a> when medications are misused or overused. As such, developing antifungal drugs is much less rewarding for drug companies than developing medications for chronic conditions like diabetes and hypertension that require long-term use.</p>
<p>One solution to this problem could lie in a <a href="https://www.nobelprize.org/prizes/chemistry/2016/summary/">Nobel Prize-winning technology</a>: molecular machines.</p>
<p>Molecular machines are synthetic compounds that rapidly rotate their components at about 3 million times per second when exposed to light. Doctors can use a light-tipped probe to activate these molecular machines to treat internal infections, or a lamp for skin infections. The light starts the machines spinning, and that rotational motion pushes them to drill through and puncture the cell’s membranes and organelles, which results in cell death. </p>
<p>Our group first used <a href="https://doi.org/10.1038/nature23657">this technology to kill cancer cells</a> in 2017. To target the right cells, molecular machines can be linked to specific peptides that bind only to the desired cells, allowing, for instance, the <a href="https://doi.org/10.1038/nature23657">targeting of specific cancer types</a>. Since then, we have used these molecules to <a href="https://doi.org/10.1126/sciadv.abm2055">kill bacteria</a>, <a href="https://doi.org/10.1021/acsami.9b22595">destroy tissue</a> and <a href="https://doi.org/10.1101/2022.11.04.515191">stimulate muscle contraction</a>. These properties make molecular machines an <a href="https://doi.org/10.1002/advs.202205781">enticing candidate technology</a> to address the growing fungal threat.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram showing the structure of a molecular machine as gray lines connected in the shape of several hexagons" src="https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=581&fit=crop&dpr=1 600w, https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=581&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=581&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=730&fit=crop&dpr=1 754w, https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=730&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/526327/original/file-20230515-14468-odbqrr.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=730&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The 3D structure of a molecular machine. The molecular machine consists of rotor (top) and stator (bottom) portions connected by a central axle. Following light activation, molecular machines rotate rapidly, drilling into fungal cells.</span>
<span class="attribution"><span class="source">Tour Lab, Rice University</span></span>
</figcaption>
</figure>
<h2>Testing antifungal molecular machines</h2>
<p>Researchers first tested the ability of light-activated molecular machines to kill fungi in <em><a href="https://www.ncbi.nlm.nih.gov/books/NBK560624/">Candida albicans</a></em>. This yeastlike fungus can cause <a href="https://doi.org/10.1155/2013/204237">life-threatening infections</a> in immunocompromised people. Compared with conventional drugs, molecular machines killed <em>C. albicans</em> much faster.</p>
<p>Subsequent studies found that molecular machines could also kill other fungi, including molds like <em><a href="https://www.ncbi.nlm.nih.gov/books/NBK482464/">Aspergillus fumigatus</a></em> and species of dermatophytes, the types of fungi that cause skin, scalp and nail infections. Molecular machines even eliminated <a href="https://doi.org/10.3389/fmed.2018.00028">fungal biofilms</a>, which are slimy, antimicrobial-resistant communities of microorganisms that stick together on surfaces and commonly cause medical device-associated infections. </p>
<p>Unlike <a href="https://www.ncbi.nlm.nih.gov/books/NBK538168/">conventional antifungals</a>, which target the fungal cell membrane or cell wall, molecular machines localize to the fungal mitochondria. Often referred to as the “<a href="https://www.ncbi.nlm.nih.gov/books/NBK9896/">powerhouses of the cell</a>,” mitochondria produce energy to power other cellular activities. When activated with visible light, molecular machines destroy the fungal mitochondria. Once the fungal cell’s mitochondria stop working, the cell loses its energy supply and dies. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Two black-and-white electron microscopy images of a fungal cell. The left image shows a large, round, healthy cell, while the cell on the right is shrunken following treatment with light-activated molecular machines." src="https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=360&fit=crop&dpr=1 600w, https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=360&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=360&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=452&fit=crop&dpr=1 754w, https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=452&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/524506/original/file-20230504-19-347m02.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=452&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"><em>Candida albicans</em> before and after being exposed to light-activated molecular machines. Molecular machines puncture <em>C. albicans</em>‘ cell wall and intracellular organelles, eventually killing the fungal cell.</span>
<span class="attribution"><span class="source">Matthew Meyer/Rice University.</span></span>
</figcaption>
</figure>
<p>At the same time, molecular machines also <a href="https://doi.org/10.4155/fmc-2016-0050">disrupt the tiny pumps</a> that remove antifungal agents from the cell, thus preventing the cell from fighting back. Because these molecular machines act by a mechanical instead of a chemical mechanism, fungi are unlikely to develop defenses against this treatment.</p>
<p>In lab experiments, combining light-activated molecular machines with conventional antifungal drugs also reduced the amount of fungi in <em>C. albicans</em>-infected worms and in pig nails infected with <em>Trichophyton rubrum</em>, the most common cause of <a href="https://www.ncbi.nlm.nih.gov/books/NBK8301/">athlete’s foot</a>.</p>
<h2>New frontiers for fighting fungal infections</h2>
<p>These results suggest that combining molecular machines with conventional antifungals can improve existing therapies and provide new options for treating resistant fungal strains. This strategy could also help reduce the side effects of traditional antifungals, such as gastrointestinal upset and skin reactions. </p>
<p>Fungal infection rates will likely continue to rise. As such, the need for new treatments will only become more urgent. Climate change is already causing <a href="https://doi.org/10.1371/journal.ppat.1009503">new human pathogenic fungi</a> to emerge and spread, including <a href="https://www.ncbi.nlm.nih.gov/books/NBK563297/"><em>Candida auris</em></a>. <em>C. auris</em> is often resistant to treatment and spread rapidly in health care facilities <a href="https://doi.org/10.1111/myc.13471">during the COVID-19 pandemic</a>. <a href="https://www.cdc.gov/media/releases/2023/p0320-cauris.html">According to the Centers for Disease Control and Prevention</a>, strained health care systems, overuse of immunosuppressants and misuse of antibiotics have all been implicated in <a href="https://theconversation.com/how-do-candida-auris-and-other-fungi-develop-drug-resistance-a-microbiologist-explains-203495">outbreaks of <em>C. auris</em></a>.</p>
<p>In the future, researchers could use <a href="https://doi.org/10.1038/s41586-023-05905-z">artificial intelligence</a> to create better antifungal molecular machines. By using AI to predict how different molecular machines will interact with fungi and human cells, we can develop safer and more effective antifungal molecules that specifically kill fungi without harming healthy cells.</p>
<p>Antifungal molecular machines are still in the early stages of development and are not yet available for routine clinical use. However, continuing research gives hope that these machines could one day provide better treatments for fungal infections and other infectious diseases.</p><img src="https://counter.theconversation.com/content/204656/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ana L. Santos receives funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 843116.</span></em></p><p class="fine-print"><em><span>Jacob Beckham receives funding from the National Science Foundation Graduate Research Fellowship Program. </span></em></p><p class="fine-print"><em><span>James M. Tour receives funding from the Discovery Institute and the Robert A. Welch Foundation (C-2017-20190330). Rice University owns intellectual property on the use of electromagnetic (light) activation of molecular machines for the killing of cells. This intellectual property has been licensed to a company in which James M. Tour is a stockholder, although he is not an officer or director of that company.</span></em></p>Fungal infections can be among the hardest to treat, and since the pandemic began they’ve become only more common. To prevent future antifungal resistance, scientists have developed tiny molecular drills.Ana L. Santos, Postdoctoral Fellow in Microbiology, Rice UniversityJacob Beckham, Graduate Student in Chemistry, Rice UniversityJames Tour, Professor of Chemistry, Rice UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2047742023-05-17T12:40:51Z2023-05-17T12:40:51ZVaccines using mRNA can protect farm animals against diseases traditional ones may not – and there are safeguards to ensure they won’t end up in your food<figure><img src="https://images.theconversation.com/files/525981/original/file-20230512-28-6v7puj.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3008%2C2008&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Vaccines help protect farm animals from various diseases.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/veterinarian-and-pigs-royalty-free-image/512631046">dusanpetkovic/iStock via Getty Images Plus</a></span></figcaption></figure><p>While effective vaccines for COVID-19 should have heralded the benefits of mRNA vaccines, <a href="https://theconversation.com/misinformation-is-a-common-thread-between-the-covid-19-and-hiv-aids-pandemics-with-deadly-consequences-187968">fear and misinformation</a> about their supposed dangers circulated at the same time. These misconceptions about mRNA vaccines have recently spilled over into worries about whether their use in agricultural animals could expose people to components of the vaccine <a href="https://www.usatoday.com/story/news/factcheck/2023/02/15/fact-check-false-claim-mrna-vaccines-food-supply/11218991002/">within animal products</a> such as meat or milk.</p>
<p>In fact, a number of states are drafting or considering legislation outlawing the use of mRNA vaccines in food animals or, at minimum, requiring their labeling on animal products in grocery stores. <a href="https://legislature.idaho.gov/sessioninfo/2023/legislation/H0154/">Idaho introduced a bill</a> that would make it a misdemeanor to administer any type of mRNA vaccine to any person or mammal, including COVID-19 vaccines. A <a href="https://www.house.mo.gov/Bill.aspx?bill=HB1169&year=2023&code=R">Missouri bill</a> would have required the labeling of animal products derived from animals administered mRNA vaccines but failed to get out of committee. <a href="https://www.azleg.gov/legtext/56leg/1R/summary/H.HB2762_020823_LARA.DOCX.htm">Arizona</a> and <a href="https://wapp.capitol.tn.gov/apps/BillInfo/Default.aspx?BillNumber=SB0099&GA=113">Tennessee</a> have also proposed labeling bills. <a href="https://www.oklahomafarmreport.com/okfr/2023/04/21/mike-deering-corrects-false-accusations-of-cattle-industry-using-mrna-vaccines/">Several other</a> <a href="https://www.texasagriculture.gov/News-Events/Article/7596/Commissioner-Miller-Statement-on-mRNA-Vaccines-in-Livestock">state legislatures</a> are discussing similar measures.</p>
<p>I am a <a href="https://scholar.google.com/citations?user=yTZZQ3QAAAAJ&hl=en">researcher who has been making vaccines</a> for a number of years, and I started studying mRNA vaccines before the pandemic started. My research on using <a href="https://portal.nifa.usda.gov/web/crisprojectpages/1027610-novel-mrna-vaccine-technology-for-prevention-of-bovine-respiratory-syncytial-virus.html">mRNA vaccines for cattle respiratory viruses</a> has been referenced by social media users and anti-vaccine activists who say that using these vaccines in animals will endanger the health of people who eat them.</p>
<p>But these vaccines have been shown to reduce disease on farms, and it’s all but impossible for them to end up in your food.</p>
<h2>Traditional animal vaccine approaches</h2>
<p>In food animals, <a href="https://www.merckvetmanual.com/pharmacology/vaccines-and-immunotherapy/types-of-vaccines-for-animals">several types of vaccines</a> have long been available for farmers to protect their animals from common diseases. These include inactivated vaccines that contain a killed version of a pathogen, live attenuated vaccines that contain a weakened version of a pathogen and subunit vaccines that contain one part of a pathogen. All can elicit good levels of protection from disease symptoms and infection. Producing these vaccines is <a href="https://pubmed.ncbi.nlm.nih.gov/17892154/">often inexpensive</a>.</p>
<p>However, each of these vaccines <a href="https://doi.org/10.1007%2F978-1-4939-3389-1_1">has drawbacks</a>. </p>
<p>Inactivated and subunit vaccines often do not produce a strong enough immune response, and pathogens can quickly mutate into variants that <a href="https://doi.org/10.3389/fvets.2021.697839">limit vaccine effectiveness</a>. The weakened pathogens in live attenuated vaccines have the remote possibility of <a href="https://doi.org/10.1093%2Fve%2Fvev005">reverting back</a> to their full pathogenic form or mixing with other circulating pathogens and becoming new vaccine-resistant ones. They also must be grown in specific cell cultures to produce them, which can be time-consuming.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/mvA9gs5gxNY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Each type of vaccine has pros and cons.</span></figcaption>
</figure>
<p>There are also <a href="https://doi.org/10.1186/s13567-018-0560-8">several pathogens</a> – such as porcine reproductive and respiratory syndrome virus, foot and mouth disease virus, <a href="https://theconversation.com/bird-flu-is-killing-millions-of-chickens-and-turkeys-across-the-us-180299">H5N1 influenza</a> and African swine fever virus – for which all three traditional approaches have yet to yield an effective vaccine.</p>
<p>Another major drawback for all three of these vaccine types is the <a href="https://doi.org/10.1016%2Fj.tvjl.2007.11.009">time it takes</a> to test and obtain federal approval to use them. Typically, animal vaccines take <a href="https://doi.org/10.1016%2Fj.vaccine.2020.05.007">three or more years</a> from development to licensure by the U.S. Department of Agriculture. Should new viruses make it to farms, playing catch-up using traditional vaccines could take too long to contain an outbreak. </p>
<h2>Advantages of animal mRNA vaccines</h2>
<p>All cells use <a href="https://theconversation.com/what-is-mrna-the-messenger-molecule-thats-been-in-every-living-cell-for-billions-of-years-is-the-key-ingredient-in-some-covid-19-vaccines-158511">mRNA, which contains the instructions</a> to make the proteins needed to carry out specific functions. The mRNA used in vaccines encode instructions to make a protein from a pathogen of interest that immune cells learn to recognize and attack. This process builds <a href="https://theconversation.com/how-long-does-protective-immunity-against-covid-19-last-after-infection-or-vaccination-two-immunologists-explain-177309">immunological memory</a>, so that when a pathogen carrying that same protein enters the body, the immune system will be ready to mount a quick and strong response against it.</p>
<p>Compared to traditional vaccines, mRNA vaccines have several advantages that make them ideal for protecting people and farm animals from both emerging and persistent diseases.</p>
<p>Unlike killed or subunit vaccines, mRNA vaccines increase the buildup of vaccine proteins in cells over time and train the immune system using conditions that look more like a viral infection. Like live attenuated vaccines, this process fosters the development of <a href="https://medicine.wustl.edu/news/what-makes-an-mrna-vaccine-so-effective-against-severe-covid-19/">strong immune responses</a> that may build better protection. In contrast to live attenuated viruses, mRNA vaccines cannot revert to a pathogenic form or mix with circulating pathogens. Furthermore, once the genetic sequence of a pathogen of interest is known, mRNA vaccines can be <a href="https://www.businessinsider.com/moderna-designed-coronavirus-vaccine-in-2-days-2020-11/">produced rather quickly</a>.</p>
<p>The mRNA in vaccines can come in either a form that is structurally similar to what is normally found in the body, like those used in COVID-19 vaccines for people, or in a form that is <a href="https://doi.org/10.1038/s41434-020-00204-y?">self-amplifying, called saRNA</a>. Because saRNA allows for higher levels of protein synthesis, researchers think that less mRNA would be needed to generate similar levels of immunity. However, a COVID-19 saRNA vaccine for people developed <a href="https://www.reuters.com/business/healthcare-pharmaceuticals/curevac-covid-19-vaccine-records-only-48-efficacy-final-trial-readout-2021-06-30/#">by biopharmaceutical company CureVac</a> elicited less protection than traditional mRNA approaches.</p>
<p><a href="https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinary-biologics/product-summaries/Vet-Label-Data/d611b51a-9eca-4d56-9556-dcc61fb96d5f">Merck’s Sequivity</a> is currently the only saRNA vaccine licensed for use in animals, and it is available by prescription to protect against swine flu in pigs.</p>
<h2>Persistance of mRNA vaccine components</h2>
<p>All mRNA vaccines are made in the laboratory using methods that were <a href="https://publichealth.jhu.edu/2021/the-long-history-of-mrna-vaccines">developed decades ago</a>. Only recently has the technology advanced to the point where the body doesn’t immediately reject it by activating the antiviral defenses intrinsic to each of your cells. This rejection would occur before the immune system even had the chance to mount a response.</p>
<p>The COVID-19 mRNA vaccines used in people <a href="https://doi.org/10.1021/acscentsci.1c00197">mix in modified nucleotides</a> – the building blocks of RNA – with unmodified nucleotides so the mRNA can hide from the intrinsic antiviral sensors of the cell. These modified nucleotides are what allow the mRNA to persist in the body’s cells <a href="https://theconversation.com/no-covid-vaccines-dont-stay-in-your-body-for-years-169247">for a few days</a> rather than <a href="https://doi.org/10.1016/0022-2836(73)90119-8">just a few hours</a> like natural mRNAs.</p>
<p>New methods of delivering the vaccine using <a href="https://theconversation.com/nanoparticles-are-the-future-of-medicine-researchers-are-experimenting-with-new-ways-to-design-tiny-particle-treatments-for-cancer-180009">lipid nanoparticles</a> also ensure the mRNA isn’t degraded before it has a chance to enter cells and start making proteins.</p>
<p>Despite this stability, mRNA vaccines do not last long enough within animals after injection for any component of the vaccine to end up on grocery store shelves. Unlike for human vaccines, animal vaccine manufacturers must determine the <a href="https://www.aphis.usda.gov/animal_health/vet_biologics/publications/pel_4_9.pdf">withdrawal period</a> in order to obtain USDA approval. This means any component of a vaccine cannot be found in the animal prior to milking or slaughter. Given the short lifespan of some of the agriculture animals and intensive milking schedules, withdrawal periods often need to be very short.</p>
<p>Between the mandatory vaccine withdrawal period, flash pasteurization for milk, degradation on the shelf and the cooking process for food products, there could not be any residual vaccine left for humans to consume. Even if you were to consume residual mRNA molecules, your gastrointestinal tract will <a href="https://doi.org/10.1016/j.matt.2021.12.022">rapidly degrade them</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Dairy cows lined up for milking" src="https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/525996/original/file-20230512-24902-28dwi7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Withdrawal periods are intended to ensure no component of the vaccine is present in the animal’s body before milking or slaughter.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/dairy-cows-ready-for-milking-royalty-free-image/1267197465">kolderal/Moment via Getty Images</a></span>
</figcaption>
</figure>
<p>Several mRNA vaccines for use in animals <a href="https://portal.nifa.usda.gov/web/crisprojectpages/1027610-novel-mrna-vaccine-technology-for-prevention-of-bovine-respiratory-syncytial-virus.html">are in</a> <a href="https://www.genengnews.com/topics/drug-discovery/bayer-partners-with-biontech-to-develop-mrna-vaccines-drugs-for-animal-health/">early stages</a> <a href="https://www.porkbusiness.com/news/industry/genvax-technologies-secures-65-million-advance-novel-vaccine-platform">of development</a>. Merck’s USDA-licensed Sequivity does not use the modified nucleotides or lipid nanoparticles that allow those vaccine components to circulate for slightly longer periods in the body, so long-term persistence is unlikely.</p>
<p>Like in people, animal vaccines are <a href="https://www.aphis.usda.gov/animal_health/vet_biologics/publications/memo_800_202.pdf">tested for their safety and effectiveness</a> in clinical trials. Approval for use from the <a href="https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinary-biologics/CT_Vb_licensed_products">USDA Center for Vaccine Biologics</a> requires a modest level of protection against infection or disease symptoms. As with all animal vaccines, future mRNA vaccines will also need to be fully cleared from the animal’s body before they can be used in animals for human consumption.</p>
<h2>mRNA vaccines for more farm animals</h2>
<p>Whether mRNA vaccines will displace other vaccine types for livestock is yet to be determined. The <a href="https://www.kff.org/coronavirus-covid-19/issue-brief/how-much-could-covid-19-vaccines-cost-the-u-s-after-commercialization/">cost of manufacturing these vaccines</a>, their need to <a href="https://www.vox.com/21552934/moderna-pfizer-covid-19-vaccine-biontech-coronavirus-cold-chain">kept very cold and warm up before use</a> to avoid degradation, and the efficacy of different types of mRNA vaccines all still need to be addressed before large-scale use can take place. </p>
<p>Traditional vaccines for food animals have <a href="https://pressbooks.umn.edu/vetprevmed/chapter/chapter-4-vaccines-and-vaccinations-production/">protected them against many diseases</a>. Limiting the use of mRNA vaccines right now would mean losing a new way to protect animals from pesky pathogens that current vaccines can’t fend off.</p><img src="https://counter.theconversation.com/content/204774/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Verhoeven received funding from Merck and USDA. Those funding are now expired.</span></em></p>While mRNA vaccines are designed to last longer in the body than mRNA molecules typically would, they are also tested to ensure they are eliminated from livestock long before milking or slaughter.David Verhoeven, Assistant Professor of Vet Microbiology and Preventive Medicine, Iowa State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2034952023-05-03T12:10:09Z2023-05-03T12:10:09ZHow do ‘Candida auris’ and other fungi develop drug resistance? A microbiologist explains<figure><img src="https://images.theconversation.com/files/523473/original/file-20230428-18-9slhum.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2073%2C1368&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Candidiasis is a severe fungal infection that can spread easily in medical facilities.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/8ysD2e">Atlas of Pulmonary Pathology/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>One of the scariest things you can be told when at a doctor’s office is “You have an antimicrobial-resistant infection.” That means the bacteria or fungus making you sick can’t be easily killed with common antibiotics or antifungals, making treatment more challenging. You might have to take a combination of drugs for weeks to overcome the infection, which could result in more severe side effects.</p>
<p>Unfortunately, this diagnosis is <a href="https://www.who.int/publications/i/item/9789240062702">becoming more common around the world</a>.</p>
<p>The yeast <em><a href="https://doi.org/10.1128/jcm.01588-17">Candida auris</a></em> has recently emerged as a potentially dangerous fungal infection for hospital patients and nursing home residents. First <a href="https://doi.org/10.3947%2Fic.2022.0008">discovered in the late 2000s</a>, <em>Candida auris</em> has very quickly become a <a href="https://doi.org/10.3390/microorganisms9040807">major health challenge</a> due to its ease of spread and ability to resist common antifungal drugs.</p>
<p>How did this fungus become so strong, and what can researchers and physicians do to combat it? </p>
<p><a href="https://scholar.google.com/citations?user=U69z9VsAAAAJ&hl=en&oi=ao">I am a microbiologist</a> researching new ways to kill fungi. <em>Candida auris</em> and other fungi use three common cellular tricks to overcome treatments. Luckily, exciting new research hints at ways we can still fight this fungus.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/VOn5Udfx7eQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Drug-resistant <em>Candida auris</em> infections are on the rise in the U.S. and around the world.</span></figcaption>
</figure>
<h2>Targeting the sensitive parts of fungal cells</h2>
<p>Fungal cells contain a structure called a <a href="https://doi.org/10.1128/microbiolspec.funk-0035-2016">cell wall</a> that helps maintain their shape and protects them from the environment. Fungal cell walls are constructed in part from several different types of polysaccharides, which are long strings of sugar molecules linked together. </p>
<p>Two polysaccharides found in almost all fungal cell walls are <a href="https://doi.org/10.1016/j.mib.2010.05.002">chitin</a> and <a href="https://doi.org/10.1016/j.tcsw.2019.100022">beta-glucan</a>. The fungal cell wall is an attractive target for drugs because human cells do not have a cell wall, so drugs that block chitin and beta-glucan production will have fewer side effects. </p>
<p>Some of the most common drugs used to treat fungal infections are called <a href="https://doi.org/10.4103%2F0253-7613.62396">echinocandins</a>. These drugs stop fungal cells from making beta-glucan, which significantly weakens their cell wall. This means the fungal cell can’t maintain its shape well. While the fungus is struggling to grow or is breaking apart, your immune system has a much better chance of fighting off the infection. </p>
<h2>How fungi become drug resistant</h2>
<p>Unfortunately, some strains of <em>Candida auris</em> are resistant to echinocandin treatment. But how does the fungus actually do it? For decades, scientists have been studying how fungi overcome drugs designed to weaken or kill them. In the case of echinocandins, <em>Candida auris</em> commonly uses three tricks to beat these treatments: <a href="https://doi.org/10.1128/AAC.00238-18">hide</a>, <a href="https://doi.org/10.1101%2Fcshperspect.a019752">build</a> and <a href="https://doi.org/10.3389/fmicb.2019.02573">change</a>. </p>
<p>The first trick is to hide in a complex mixture of sugars, proteins, DNA and cells <a href="https://doi.org/10.1128/msphere.00458-19">called a biofilm</a>. Made with irregular 3D structures, biofilms have lots of places for cells to hide. Drugs aren’t good at penetrating biofilms, so they can’t access and kill cells deep inside. Biofilms are especially problematic when they <a href="https://doi.org/10.3390/antibiotics4010001">grow on</a> <a href="https://doi.org/10.2147/ijn.s353071">medical equipment</a> like ventilators or catheters. Once free of a biofilm, cells that have gained the ability to resist the drugs a patient was taking become more dangerous.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of two types of Candida attaching to each other" src="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=300&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=300&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=300&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=377&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=377&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=377&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 image shows <em>Candida albicans</em> (red) producing branching filaments that allow it to attach to <em>Candida glabrata</em> (green), forming biofilms. Both of these species can cause infections in people.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/HE7JbY">Edgerton Lab, State University of New York at Buffalo/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>The second trick fungi use to evade treatment is to build cell walls differently. Fungal cells treated with echinocandins can’t make beta-glucan. So instead, they start to <a href="https://doi.org/10.3109/13693786.2011.577104">make more chitin</a>, another important polysaccharide in the fungal cell wall. Echinocandins are unable to stop chitin production, so the fungus is still able to build a strong cell wall and avoid being killed. While there are some drugs that can <a href="https://doi.org/10.3390/jof6040261">stop chitin production</a>, none are currently approved for use in people. </p>
<p>The third trick fungi rely on is to <a href="https://doi.org/10.3389/fmicb.2019.02788">change the shape of the</a> <a href="https://doi.org/10.1093/cid/civ791">beta-glucan production enzyme</a> so echinocandins cannot block it. These mutations allow beta-glucan production to continue even in the presence of the drug. It is not surprising that <em>Candida</em> uses this trick to resist antifungal drugs since it is <a href="https://doi.org/10.1111%2Fnyas.12831">very effective</a> at keeping the cells alive. </p>
<h2>New tactics to fight fungi</h2>
<p>What can be done to treat echinocandin-resistant fungal infections? Thankfully, scientists and physicians are researching new ways to kill <em>Candida auris</em> and similar fungi. </p>
<p>The first approach is to find new drugs. For example, there are two drugs in development, <a href="https://doi.org/10.3390/antibiotics9050227">rezafungin</a> and <a href="https://doi.org/10.4155%2Ffmc-2018-0465">ibrexafungerp</a>, that appear to be able to stop beta-glucan production even in fungi resistant to echinocandins. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of budding yeast cells" src="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This microscopy image shows budding yeast cells.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/budding-yeast-cell-in-gram-stain-royalty-free-image/1464904014">toeytoey2530/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>A complementary approach my research group is exploring is whether a class of enzymes called <a href="https://doi.org/10.1007/s11274-016-2068-6">glycoside hydrolases</a> might also be able to combat drug-resistant fungi. Some of these enzymes actively destroy the fungal cell wall, breaking apart both beta-glucan and chitin at the same time, which could potentially help prevent fungi from surviving on medical equipment or on hospital surfaces.</p>
<p>My lab’s work on discovering enzymes that strongly degrade fungal cell walls is part of a new strategy to combat antifungal resistance that uses a combination of approaches to kill fungi. But the end goal of this research is the same: having a physician tell you, “You’ve got a fungal infection, but we have a good treatment for it now.”</p><img src="https://counter.theconversation.com/content/203495/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeffrey Gardner receives funding from the National Science Foundation (NSF) and the National Institutes of Health (NIH).</span></em></p>Multidrug-resistant fungal infections are an emerging global health threat. Figuring out how fungi evade treatments offers new avenues to counter resistance.Jeffrey Gardner, Associate Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1991482023-02-08T13:42:23Z2023-02-08T13:42:23ZCells routinely self-cannibalize to take out their trash, aiding in survival and disease prevention<figure><img src="https://images.theconversation.com/files/508693/original/file-20230207-23-r0tkni.png?ixlib=rb-1.1.0&rect=0%2C0%2C907%2C679&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Illustration of an autophagosome (light blue double-membrane to the right) engulfing cellular material.</span> <span class="attribution"><a class="source" href="https://doi.org/10.2210/rcsb_pdb/goodsell-gallery-012">David S. Goodsell and Daniel Klionsky/RCSB PDB-101</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Don’t let the textbook diagram of a simplified two-dimensional cell fool you – within this tiny structure of life is a complex universe of molecular machinery that is continually being built, put into motion and eventually broken down. </p>
<p>Cells use the thousands of different proteins within them as tools to shape their internal environment. In this environment are specialized compartments known as <a href="https://www.genome.gov/genetics-glossary/Organelle">organelles</a> that carry out the cell’s functions. Two important organelles within cells are mitochondria and the endoplasmic reticulum, which <a href="https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/04%3A_Cell_Structure_of_Bacteria_Archaea_and_Eukaryotes/4.07%3A_Internal_Structures_of_Eukaryotic_Cells/4.7B%3A_Mitochondria">produce energy</a> and <a href="https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Cells_-_Molecules_and_Mechanisms_(Wong)/11%3A_Protein_Modification_and_Trafficking/11.03%3A_Protein_Folding_in_the_Endoplasmic_Reticulum">assemble proteins</a>, respectively. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of endoplasmic reticulum surrounded by an autophagosome" src="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=749&fit=crop&dpr=1 600w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=749&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=749&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=942&fit=crop&dpr=1 754w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=942&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=942&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This microscopy image shows an endoplasmic reticulum engulfed by an autophagosome.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1371/journal.pbio.0040442.g001">Liza Gross/PLoS Biology</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
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<p>Since routine cellular activity generates toxic byproducts that can damage the cell, a disposal system is needed to degrade and recycle these molecules within cells. One of these processes is <a href="https://doi.org/10.1038/sj.cdd.4401765">autophagy</a>, a form of self-consumption cells use to eliminate and recycle abnormal or excess components, including proteins and organelles. Derived from Greek, the term literally translates to “self-eating.” In 2016, cell biologist Yoshinori Ohsumi won the <a href="https://www.nobelprize.org/prizes/medicine/2016/press-release/">Nobel Prize in Physiology or Medicine</a> for his work on autophagy. Autophagy is essential for cellular health and longevity. When this process is not working well, it’s <a href="https://doi.org/10.1056/nejmra2022774">linked to several human diseases</a>, including neurodegenerative and cardiovascular diseases and cancer. </p>
<p><a href="https://gustafssonlabucsd.org/team/">We are researchers</a> studying how autophagy is activated in cells. In our <a href="http://dx.doi.org/10.1126/scisignal.abo4457">recently published research</a>, we examined two key regulators of this process and identified a unique role one of them plays in degrading mitochondria that may serve as a potential target to treat certain diseases.</p>
<h2>Autophagy and human disease</h2>
<p>The connection between autophagy and disease is complex and not well understood. </p>
<p>For instance, autophagy appears to play a <a href="https://doi.org/10.1038/s41418-019-0474-7">paradoxical role in cancer</a>. On one hand, some studies have shown that because this process suppresses tumors by eliminating potentially harmful material, reduced or impaired autophagy can turn a cell cancerous. On the other hand, activating autophagy after a tumor has formed can promote cancer by helping it adapt and survive, potentially leading to treatment resistance.</p>
<p>These findings suggest that it is especially important to understand the precise steps and timing of autophagy when it comes to targeting this process as a cancer treatment strategy. Researchers are evaluating the anticancer effects of two malaria drugs, <a href="https://doi.org/10.3389/fphar.2020.00408">chloroquine and hydroxychloroquine</a>, that block the final steps of autophagy. So far, they have varying efficacy depending on cancer type and stage.</p>
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<figcaption><span class="caption">Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Medicine for his discoveries of the mechanisms of autophagy.</span></figcaption>
</figure>
<p>Dysfunctional autophagy also plays an important role in <a href="https://doi.org/10.1111/bpa.12545">most neurodegenerative diseases</a>. The aggregation of abnormal proteins in brain cells are common features in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS. Some scientists believe that the accumulation of these proteins is due at least in part to a decline in their degradation through autophagy.</p>
<p>Autophagy is also important for heart health. Researchers have found that autophagy in the heart <a href="https://doi.org/10.1161/CIRCRESAHA.118.312208">declines</a> <a href="https://doi.org/10.1111/acel.13187">with age</a> and contributes to cardiovascular disease. Decreased autophagy in cardiac muscle cells results in accumulating cellular garbage that can affect their ability to contract and even cause their death. With fewer cells and less contraction, the buildup of toxic material in cardiac muscle cells can ultimately lead to heart failure. </p>
<h2>Breaking down mitochondria with mitophagy</h2>
<p>For autophagy to be efficient, it needs to specifically get rid of only damaged proteins or organelles within the cell. Uncontrolled degradation would deprive a cell of its basic needs. </p>
<p>This is particularly true for mitochondria, as cells rely on them for much of their energy production. Our team has been very interested in how cells ensure that autophagy of mitochondria, also known as mitophagy, eliminates only dysfunctional mitochondria while sparing the healthy parts of the cell. Dysfunctional mitophagy has been linked to <a href="https://doi.org/10.1016/j.semcancer.2019.07.015">cancer</a>, <a href="https://doi.org/10.1111/cns.13140">neurodegeneration</a> and <a href="https://doi.org/10.1016/j.molmed.2022.06.007">cardiovascular disease</a>, among other diseases. </p>
<p>The process of autophagy starts when the cell begins to form a membrane near damaged proteins or organelles. This membrane will expand into a vesicle, or sac, known as an autophagosome, that engulfs the damaged material. It will then fuse with another internal cell structure full of acid called a lysosome that helps degrade its cargo. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting autophagy process" src="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Autophagy involves the formation of a membrane around the cellular material to be eliminated. This autophagosome eventually joins with another organelle called a lysosome (orange sphere, fifth step) which releases chemicals that break down its contents.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/stages-of-autophagy-illustration-royalty-free-illustration/713780595">Kateryna Kon/Science Photo Library via Getty Images</a></span>
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<p>Beclin1 is a protein known to promote the formation of autophagosomes in cells. However, its role in mitophagy is controversial, in part because very little is known about its <a href="https://doi.org/10.1016/j.cell.2013.07.035">close relative Beclin2</a>. We wanted to <a href="http://dx.doi.org/10.1126/scisignal.abo4457">disentangle the functions</a> of these two proteins and determine their role in mitophagy. To do this, we used mouse and human cell models to examine how the presence or absence of these two proteins affected autophagy. </p>
<p>We discovered that activating a region unique to Beclin1 enables it to promote autophagosome formation next to dysfunctional mitochondria, facilitating their degradation in human cells. Because a similar region isn’t found in Beclin2, this meant that only Beclin1 may be essential for mitophagy.</p>
<p>Interestingly, we also observed Beclin1 at discrete points of contact between mitochondria and endoplasmic reticulum during mitophagy. This supports <a href="https://doi.org/10.1038/s41580-020-0241-0">emerging research</a> suggesting that physical interactions between these organelles facilitate the transfer of certain molecules needed to make autophagosomes. Our work indicates that only Beclin1 promotes engulfment of damaged mitochondria at these sites. Beclin2 may perform a different role in autophagy in other conditions.</p>
<h2>Targeting autophagy for treatments</h2>
<p>Autophagy represents a potential treatment target for many different diseases. Our team is currently studying how autophagy contributes to protein aggregation and mitochondrial dysfunction in the heart, and we are working to develop new tools to measure this process in cell and animal models.</p>
<p>However, therapeutic strategies to regulate autophagy is complicated by the fact that it is a complex multi-step process that involves many different proteins. Some diseases may require targeting the early steps of autophagsosome formation, while others may require focusing on when they fuse with lysosomes. Furthermore, different disease states may benefit from either autophagy activation or inhibition. More work needs to be done to identify all of the specific proteins that regulate each step of the autophagy pathway and how cells finetune this process in both health and disease. </p>
<p>We believe that helping cells better harness the power of autophagy in a complex molecular universe can train them to follow the three Rs – reduce, reuse, recycle – to promote health and longevity.</p><img src="https://counter.theconversation.com/content/199148/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Åsa Gustafsson receives funding from NIH. </span></em></p><p class="fine-print"><em><span>Justin Quiles receives funding from The American Heart Association. </span></em></p>Cells degrade and recycle damaged parts of themselves through a process called autophagy. When this “self-devouring” goes awry, it may promote cancer and neurodegenerative disease.Åsa Gustafsson, Professor of Pharmacy and Pharmaceutical Sciences, University of California, San DiegoJustin Quiles, Postdoctoral Scholar of Pharmacy and Pharmaceutical Science, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1958072023-02-07T13:33:23Z2023-02-07T13:33:23ZHow do you make a universal flu vaccine? A microbiologist explains the challenges, and how mRNA could offer a promising solution<figure><img src="https://images.theconversation.com/files/508472/original/file-20230206-31-mtkppf.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2309%2C1299&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Broad protection from a universal flu vaccine could replace seasonal flu shots.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/influenza-vaccine-vials-pattern-background-royalty-free-image/1365216790">Flavio Coelho/Moment via Getty Images</a></span></figcaption></figure><p>To everything there is a season, and for the flu, it’s wintertime. Flu cases <a href="https://www.cdc.gov/flu/about/season/flu-season.htm">peak between December and February</a>, and the flu vaccine is your best defense. Getting the vaccine means you <a href="https://www.cdc.gov/flu/prevent/keyfacts.htm">will be less sick</a> even if you get a breakthrough infection. </p>
<p>However, your immune system is in a constant race against the flu virus. Like the virus that causes COVID-19, influenza rapidly changes and mutates into new variants, so manufacturers have to update the flu shot to <a href="https://www.doi.org/10.1126/science.aaq0105">try to keep pace</a>. After identifying a new flu variant, it takes manufacturers about six months to update the vaccine – and in the meantime the virus can mutate again. This phenomenon is called <a href="https://doi.org/10.1146/annurev-virology-010320-044746">antigenic drift</a>, and can reduce the effectiveness of the flu vaccine for that season. </p>
<p>An ongoing threat is that a major change in the flu virus, or <a href="https://www.cdc.gov/flu/about/viruses/change.htm">antigenic shift</a>, could cause the next flu pandemic. This happens when a flu virus from animals, such as birds or swine, gains the ability to transmit between humans. Most people will have no immunity against this new animal-origin virus, so it could quickly spread into a pandemic. If that happens, the annual flu shot will not be effective and can’t be updated fast enough to stop a global spread.</p>
<p><a href="https://scholar.google.com/citations?user=eNprtJEAAAAJ&hl=en">I am a researcher</a> developing new vaccines to prevent future pandemics. Nearly 20 years ago, my lab and several others developed a vision of building a <a href="https://doi.org/10.1101%2Fcshperspect.a028845">universal influenza vaccine</a> that could give us the leading edge in the race against influenza and prevent the next flu pandemic by effectively combating any eventual flu strain. One potential way to do this is with messenger RNA, or mRNA.</p>
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<figcaption><span class="caption">A primary challenge in developing vaccines against influenza is how rapidly the virus mutates.</span></figcaption>
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<h2>What is a universal influenza vaccine?</h2>
<p>A universal influenza vaccine is one that does not need to be updated each year because it is designed to protect against all or most influenza variants. Scientists are exploring several ways to develop universal influenza vaccines. Most fall into <a href="https://doi.org/10.1093/infdis/jiy103">one of two buckets</a>. </p>
<p>The first includes vaccines that focus on conserved, or unchanging, parts of the virus. This strategy directs the immune system against parts of the virus, or antigens, that are shared among all variants and can’t mutate without weakening or killing the virus.</p>
<p>The second includes mosaic vaccines. These are like a cocktail of protein pieces taken from different variants. The blend is made up of versions of the protein hemagglutinin – essential to the influenza virus’s ability to infect cells – that is found in all flu variants circulating in animals and people. The goal is to induce immunity against nearly all variants so there will be fewer gaps in the immune system’s defenses for the virus to slip through.</p>
<h2>Using mRNA for a universal flu vaccine</h2>
<p>The recent success of mRNA vaccines for COVID-19 shows promise for their use in achieving the vision of an effective universal influenza vaccine. </p>
<p>There are 20 known subtypes of influenza. Prior to the development of mRNA vaccines, it wasn’t feasible to make a single flu vaccine against all 20 subtypes due to the complexities and costs in manufacturing. Unlike traditional vaccines, constructing and producing mRNA vaccines is rapid and simple because manufacturers don’t have to produce and purify the protein directly. Instead, mRNA vaccines provide the genetic sequence of the protein and then use the body’s own cells to generate that protein <a href="https://doi.org/10.1073/pnas.2123477119">in its natural structure</a>. This makes it relatively easy to incorporate any antigen or many antigens.</p>
<p>Recently, a team of researchers <a href="https://doi.org/10.1126/science.abm0271">designed a mosaic mRNA vaccine</a> with sequences from multiple versions of the hemagglutinin protein, each representing one of the 20 influenza subtypes. This vaccine induced broad immunity against each variant in mice and ferrets.</p>
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<figcaption><span class="caption">mRNA vaccines circumvent some of the manufacturing challenges traditional vaccines face.</span></figcaption>
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<p>Several research groups are also exploring the conserved antigen approach with mRNA vaccines. Animal studies have shown that it’s possible to design mRNA vaccines that can both focus immune responses against highly conserved, vulnerable parts of the virus and <a href="https://doi.org/10.1126/sciadv.adc9937">induce</a> <a href="https://doi.org/10.1016/j.ymthe.2020.04.018">broad immunity</a> against a wide range of different influenza subtypes. These include <a href="https://doi.org/10.1073/pnas.2206333119">avian flu viruses</a> that share many genetic sequences with human influenza. </p>
<p>Another promising approach uses <a href="https://give.uwmedicine.org/stories/designing-a-pandemic-free-future/">computational modeling</a> to leverage both conserved and mosaic approaches. This strategy displays multiple hemagglutinins from different influenza subtypes <a href="https://doi.org/10.3389/fimmu.2019.00022">on a nanoparticle</a>. Nanoparticles are structures that give researchers more precise control over how the immune system sees the viral antigens, subsequently allowing them to induce stronger immune responses against multiple variants. Here, both conserved and variable regions of the virus are exposed to the immune system and can lead to <a href="https://doi.org/10.1038/s41586-021-03365-x">broad immunity</a>.</p>
<h2>Obstacles to a universal flu mRNA vaccine</h2>
<p>There are still several challenges before a universal influenza mRNA vaccine can be made available. </p>
<p>For one, it is not clear which conserved antigens provide the broadest protection, and some don’t naturally induce strong immune responses. So, mRNA vaccines may need improvements like additional components that help activate immune cells. One such addition could include <a href="https://doi.org/10.1073/pnas.2217533119">using mRNA to express nanoparticles</a> that stimulate stronger immune responses against the conserved antigens presented by the vaccine.</p>
<p>The mosaic approach is also limited by the <a href="https://doi.org/10.1056/NEJMoa2022483">maximum dose possible</a> for mRNA vaccines, because higher doses could cause increased adverse reactions to the vaccine. When that dose gets divided into 20 or more antigens, the dose of one or more of those antigens may drop below the threshold needed for protection.</p>
<p>Scientists are working on these challenges, including by developing <a href="https://doi.org/10.1126/science.abq6562">new mRNA technologies</a> that work with a much lower dose. If mRNA vaccines work for universal protection from influenza, the same strategies could also <a href="https://theconversation.com/how-mrna-and-dna-vaccines-could-soon-treat-cancers-hiv-autoimmune-disorders-and-genetic-diseases-170772">apply to other frequently mutating viruses</a>, such as the virus that causes COVID-19 and maybe even HIV.</p>
<p>In the meantime, mRNA vaccines may soon <a href="https://doi.org/10.1073/pnas.2217533119">usher in a new era</a> of more effective annual flu vaccines by providing a better match to each flu season’s new variants. <a href="https://www.clinicaltrialsarena.com/features/mrna-vaccine-trials-to-watch/">Two seasonal influenza mRNA vaccines</a> are currently in human clinical trials. If successful, they may offer more effective protection from the annual flu than our current flu vaccines. With mRNA vaccines, I believe that we are at the beginning of starting a new race against flu that we may finally win.</p><img src="https://counter.theconversation.com/content/195807/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Deborah Fuller is a co-founder of Orlance, Inc. a biotechnology company developing a needle-free delivery technology for DNA and RNA vaccine. She also serves as a consultant for HDT Bio, a biotechnology company developing nanoparticle-based formulations to deliver RNA vaccines and Abacus Inc., a therapeutic vaccine company developing B cell targeted therapies for chronic infectious diseases and cancer. She receives grant funding from the National Institutes of Health, the Washington Research Foundation and the Department of Defense.</span></em></p>Annual flu vaccines are in a constant race against a rapidly mutating virus that may one day cause the next pandemic. A one-time vaccine protecting against all variants could give humanity a leg up.Deborah Fuller, Professor of Microbiology, School of Medicine, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1961002023-01-10T13:30:06Z2023-01-10T13:30:06ZOrgan-on-a-chip models allow researchers to conduct studies closer to real-life conditions – and possibly grease the drug development pipeline<figure><img src="https://images.theconversation.com/files/501906/original/file-20221219-18-6xab1c.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2044%2C1581&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The lung-on-a-chip can mimic both the physical and mechanical qualities of a human lung.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/HQBa1g">Wyss Institute for Biologically Inspired Engineering, Harvard University/Flickr</a></span></figcaption></figure><p><a href="https://doi.org/10.1007/s40273-021-01065-y">Bringing a new drug to market</a> costs billions of dollars and can take over a decade. These high monetary and time investments are both strong contributors to today’s skyrocketing health care costs and significant obstacles to delivering new therapies to patients. One big reason behind these barriers is the lab models researchers use to develop drugs in the first place.</p>
<p><a href="https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research">Preclinical trials</a>, or studies that test a drug’s efficacy and toxicity before it enters clinical trials in people, are mainly conducted on cell cultures and animals. Both are limited by their poor ability to mimic the conditions of the human body. <a href="https://doi.org/10.1016%2FB978-0-12-803077-6.00009-6">Cell cultures</a> in a petri dish are unable to replicate every aspect of tissue function, such as how cells interact in the body or the dynamics of living organs. And <a href="https://doi.org/10.1093/bioinformatics/btu611">animals</a> are not humans – even small genetic differences between species can be amplified to major physiological differences. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902221/">Fewer than 8%</a> of successful animal studies for cancer therapies make it to human clinical trials. Because animal models often fail to predict drug effects in human clinical trials, these late-stage failures can significantly drive up both costs and patient health risks. </p>
<p>To address this translation problem, researchers have been developing a promising model that can more closely mimic the human body – organ-on-a-chip. </p>
<p>As an <a href="https://scholar.google.com/citations?user=FppSA-0AAAAJ&hl=en">analytical chemist</a>, I have been working to develop organ and tissue models that avoid the simplicity of common cell cultures and the discrepancies of animal models. I believe that, with further development, organs-on-chips can help researchers study diseases and test drugs in conditions that are closer to real life.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/CpkXmtJOH84?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Organs-on-chips offer an alternative model for early-phase biomedical research.</span></figcaption>
</figure>
<h2>What are organs-on-chips?</h2>
<p>In the late 1990s, researchers figured out a way to <a href="https://gmwgroup.harvard.edu/files/gmwgroup/files/1073.pdf">layer elastic polymers</a> to control and examine fluids at a microscopic level. This launched the field of <a href="https://doi.org/10.1016/j.mne.2019.01.003">microfluidics</a>, which for the biomedical sciences involves the use of devices that can mimic the dynamic flow of fluids in the body, such as blood.</p>
<p>Advances in microfluidics have provided researchers a platform to culture cells that function more closely to how they would in the human body, specifically with <a href="https://doi.org/10.1038/s41578-018-0034-7">organs-on-chips</a>. The “chip” refers to the microfluidic device that encases the cells. They’re commonly made using the same technology as computer chips. </p>
<p>Not only do organs-on-chips mimic blood flow in the body, these platforms have microchambers that allow researchers to integrate multiple types of cells to mimic the diverse range of cell types normally present in an organ. The fluid flow connects these multiple cell types, allowing researchers to study how they interact with each other.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/M37ZU0Ptkww?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Microfluidics can be used for many applications in biological research.</span></figcaption>
</figure>
<p>This technology can overcome the limitations of both static cell cultures and animal studies in several ways. First, the presence of fluid flowing in the model allows it to mimic both what a cell experiences in the body, such as how it receives nutrients and removes wastes, and how a drug will move in the blood and interact with multiple types of cells. The ability to control fluid flow also enables researchers to fine-tune the optimal dosing for a particular drug.</p>
<p>The <a href="https://doi.org/10.1126/science.1188302">lung-on-a-chip</a> model, for instance, is able to integrate both the mechanical and physical qualities of a living human lung. It’s able to mimic the dilation and contraction, or inhalation and exhalation, of the lung and simulate the interface between the lung and air. The ability to replicate these qualities allows researchers to better study lung impairment across different factors.</p>
<h2>Bringing organs-on-chips to scale</h2>
<p>While organ-on-a-chip pushes the boundaries of early-stage pharmaceutical research, the technology has <a href="https://doi.org/10.1016/j.drudis.2019.03.011">not been widely integrated</a> into drug development pipelines. I believe that a core obstacle for wide adoption of such chips is its high complexity and low practicality.</p>
<p>Current organ-on-a-chip models are difficult for the average scientist to use. Also, because most models are single-use and allow only one input, which limits what researchers can study at a given time, they are both expensive and time- and labor-intensive to implement. The <a href="https://doi.org/10.1039/c6lc01554a">high investments required</a> to use these models might dampen enthusiasm to adopt them. After all, researchers often use the least complex models available for preclinical studies to reduce time and cost.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Close-up of blood-brain barrier on a chip" src="https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=433&fit=crop&dpr=1 600w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=433&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=433&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=544&fit=crop&dpr=1 754w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=544&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/501643/original/file-20221216-13-pjt0d0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=544&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 chip mimics the blood-brain barrier. The blue dye marks where brain cells would go, and the red dye marks the route of blood flow.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/HRUHqg">Vanderbilt University/Flickr</a></span>
</figcaption>
</figure>
<p>Lowering the technical bar to make and use organs-on-chips is critical to allowing the entire research community to take full advantage of their benefits. But this does not necessarily require simplifying the models. <a href="https://chenresearchlab.umbc.edu">My lab</a>, for example, has designed various <a href="https://doi.org/10.26434/chemrxiv.12964604.v1">“plug-and-play” tissue chips</a> that are standardized and modular, allowing researchers to readily assemble premade parts to run their experiments.</p>
<p>The advent of <a href="https://pubs.acs.org/doi/full/10.1021/ac403397r">3D printing</a> has also significantly facilitated the development of organ-on-a-chip, allowing researchers to directly manufacture entire tissue and organ models on chips. 3D printing is ideal for fast prototyping and design-sharing between users and also makes it easy for mass production of standardized materials.</p>
<p>I believe that organs-on-chips hold the potential to enable breakthroughs in drug discovery and allow researchers to better understand how organs function in health and disease. Increasing this technology’s accessibility could help take the model out of development in the lab and let it make its mark on the biomedical industry.</p><img src="https://counter.theconversation.com/content/196100/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Chengpeng Chen receives funding from the NIH.</span></em></p>Successes in the lab mostly don’t translate to people. Research models that better mimic the human body could close the gap.Chengpeng Chen, Assistant Professor of Chemistry and Biochemistry, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1973352023-01-09T19:57:15Z2023-01-09T19:57:15ZHow the pharmaceutical industry uses disinformation to undermine drug price reform<figure><img src="https://images.theconversation.com/files/503452/original/file-20230106-9978-995yzp.jpg?ixlib=rb-1.1.0&rect=0%2C94%2C5742%2C3721&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The pharma industry warned that if proposed new prescription price guidelines go ahead, drug launches would be delayed and 'Canadian patients will be deprived of potentially life-saving new medicines.'
</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Canada’s drug prices are the <a href="https://www.canada.ca/en/patented-medicine-prices-review/services/annual-reports/annual-report-2020.html">fourth highest in the developed world</a>. Despite this, Innovative Medicines Canada (IMC), the lobby group for Big Pharma, <a href="https://innovativemedicines.ca/newsroom/all-news/implementation-patented-medicine-prices-review-boards-proposed-guidelines-will-harm-canadian-patients/">put out a call</a> in November 2022 for the Canadian government to suspend consultations on guidelines aimed at lowering prescription drug prices. </p>
<p><a href="https://www.canada.ca/en/patented-medicine-prices-review/services/consultations/2022-proposed-updates-guidelines.html">The proposed guidelines</a> were expected to come into effect on Jan. 1, but were postponed in late December. </p>
<p>IMC warned that if the new guidelines went ahead, drug launches would be delayed and “Canadian patients will be deprived of potentially life-saving new medicines.”</p>
<p>Just a few days later, IMC took out a <a href="https://www.theglobeandmail.com/business/adv/article-shortening-the-regulatory-timeline-will-benefit-patients-and-the/">full-page ad in the <em>Globe and Mail</em></a> claiming that “Canadians wait twice as long for new medicines.” </p>
<p>The first statement is false and the second is a half-truth. Both are typical of an industry that <a href="https://www.citizen.org/article/twenty-seven-years-of-pharmaceutical-industry-criminal-and-civil-penalties-1991-through-2017/">paid US$38.6 billion in fines</a> in civil and criminal cases in the United States between 1991 and 2017.</p>
<h2>Falsehoods and half-truths</h2>
<p>IMC has been <a href="https://archive.innovativemedicines.ca/pmprb-still-time-regulations/">claiming since the end of 2020</a> that “new drugs are not being launched in Canada” because our drug prices might be lowered. However, between 2011 and 2020, there was <a href="https://doi.org/10.1016/j.healthpol.2022.08.006">no change in the timing</a> between when drugs were approved by the United States Food and Drug Administration (FDA) and then by Health Canada. </p>
<p>Drug companies did not wait longer to introduce new drugs here compared to the U.S. There was a <a href="https://doi.org/10.1016/j.healthpol.2022.08.006">decline in the per cent of drugs first approved by the FDA and then by Health Canada</a>, but the same thing happened in Australia where drug prices were not being lowered.</p>
<p>What about the claim that Canadians are losing out on new potentially life-saving drugs? </p>
<p>Only 10-15 per cent of new drugs are actually <a href="https://doi.org/10.1136/bmjopen-2018-023605">major therapeutic breakthroughs</a>. The industry claims the other 85-90 per cent <a href="https://ethics.harvard.edu/blog/new-prescription-drugs-major-health-risk-few-offsetting-advantages">give patients more choice</a>. But companies don’t test their new drugs on patients who can’t tolerate or don’t get better on older ones. So, nobody really knows if those choices mean anything positive for patients. </p>
<h2>Wait times</h2>
<figure class="align-center ">
<img alt="A piggy bank seen from above beside a prescription box" src="https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/503453/original/file-20230106-24-vj99yn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">For over 50 years, drug companies have been suggesting that access to medications will be at risk every time governments do something that threatens their profits.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>Do Canadians wait longer for new drugs? If the comparison is to patients in the U.S. or the European Union (EU), then the answer is yes. </p>
<p>Why is the wait longer? After companies submit drugs for approval in the U.S. or the EU, <a href="https://www.cirsci.org/publications/cirs-rd-briefing-81-new-drug-approvals-in-six-major-authorities-2011-2020/">they take an extra year</a> before submitting them to Health Canada. Is that wait because of Canadian drug prices? No. Drug prices are higher in Switzerland than in Canada, but the wait to get drugs approved in Switzerland is also longer than in Canada. </p>
<p>If drug prices were the reason for the wait, then companies should be submitting applications sooner in Switzerland compared to Canada.</p>
<p>In Canada, newly approved drugs are available for people with private insurance <a href="https://doi.org/10.9778/cmajo.20220063">about a year</a> before they can be prescribed to people covered by provincial/territorial drug formularies. But a substantial proportion of that time difference is in the hands of drug companies.</p>
<p>If pharma companies want to get their drugs publicly covered, they first have to submit them to the <a href="https://www.cadth.ca/about-cadth">Canadian Agency for Drugs and Technologies in Health</a> (CADTH). CADTH then does a value-for-money audit and makes a recommendation to the provinces and territories about funding. </p>
<p>In an effort to speed up decision-making about whether the public should pay for new drugs, ever since April 2018 companies can <a href="https://doi.org/10.3389/fphar.2019.00196">submit applications to CADTH up to 180 days</a> before Health Canada approves the drugs. But instead of taking full advantage of this provision, <a href="http://doi.org/10.9778/cmajo.20220063">companies only submit a median of 13 days before approval</a>, adding 5.5 months to the time it takes to make a final decision. </p>
<h2>Protecting profits</h2>
<p>Drug companies have been making threats for over 50 years every time governments do something that threatens their profits. </p>
<p>In 1972, the NDP government of Manitoba passed a law making it mandatory for pharmacists to substitute cheaper generic drugs for those named on prescriptions, unless prohibited by the physician writing the prescription. Furthermore, the substitute could not be sold at a price higher than that of the lowest priced equivalent drug. After this legislation passed, the <a href="https://utorontopress.com/9781442619609/private-profits-versus-public-policy/">president of the industry association made a thinly veiled threat to the Manitoba government</a>:</p>
<blockquote>
<p>“It will remain to be seen how much value would be put on the Manitoba market by research-oriented companies. It is each company’s decision whether the size of their Manitoba market will merit the cost of properly servicing that market. If they can’t meet the prices they could be forced out of business.”</p>
</blockquote>
<p>After the Liberal government in Ontario passed legislation in 2017 requiring companies to report how much money they gave to doctors, hospitals and other health care personnel and institutions, <a href="https://www.theglobeandmail.com/canada/article-ford-pcs-leave-drug-company-transparency-law-in-limbo/">IMC made the same threat</a> about not launching new drugs in Canada because of the regulatory burden of having to make reports.</p>
<p>Now, they are making a similar threat based on potentially lower drug prices in Canada.</p>
<p>Drug companies make threats to maintain their ability to make <a href="https://doi.org/10.1001/jama.2020.0442">extraordinarily high profits</a>. The rest of us need to stand up for the right of patients to get drugs at affordable prices.</p><img src="https://counter.theconversation.com/content/197335/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>In 2019-2022, Joel Lexchin received payments for writing a brief on the role of promotion in generating prescriptions for Goodmans LLP and from the Canadian Institutes of Health Research for presenting at a workshop on conflict-of-interest in clinical practice guidelines. He is a member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare. He receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. </span></em></p>The pharma industry claims lower prescription drug prices will mean less access to new medication for Canadians. It’s an old threat that pits profits against patients’ rights to affordable drugs.Joel Lexchin, Professor Emeritus of Health Policy and Management, York University, CanadaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1966522023-01-05T13:26:24Z2023-01-05T13:26:24ZNanomedicines for various diseases are in development – but research facilities produce vastly inconsistent results on how the body will react to them<figure><img src="https://images.theconversation.com/files/502207/original/file-20221220-6047-jjdm3d.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C1637&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Nanoparticles (white disks) can be used to deliver treatment to cells (blue).</span> <span class="attribution"><a class="source" href="https://flic.kr/p/KjvnhT">Brenda Melendez and Rita Serda/National Cancer Institute, National Institutes of Health</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p><a href="https://doi.org/10.3389/fchem.2018.00360">Nanomedicines</a> took the spotlight during the COVID-19 pandemic. Researchers are using these very small and intricate materials to develop diagnostic tests and treatments. Nanomedicine is already used for various diseases, such as the <a href="https://doi.org/10.1038/s41565-020-0757-7">COVID-19 vaccines</a> and therapies for <a href="https://doi.org/10.1038/nnano.2017.167">cardiovascular disease</a>. The “nano” refers to the use of particles that are only a few hundred nanometers in size, which is <a href="https://www.nano.gov/nanotech-101/what/nano-size">significantly smaller than</a> the width of a human hair.</p>
<p>Although researchers have developed <a href="https://doi.org/10.1007/s40820-022-00922-5">several methods</a> to improve the reliability of nanotechnologies, the field still faces one major roadblock: a lack of a standardized way to analyze <a href="https://doi.org/10.1016/j.tibtech.2016.08.011">biological identity</a>, or how the body will react to nanomedicines. This is essential information in evaluating how effective and safe new treatments are. </p>
<p>I’m a researcher studying <a href="https://scholar.google.com/citations?user=D-qg1JwAAAAJ&hl=en">overlooked factors in nanomedicine development</a>. In our <a href="https://doi.org/10.1038/s41467-022-34438-8">recently published research</a>, my colleagues and I found that analyses of biological identity are highly inconsistent across proteomics facilities that specialize in studying proteins.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/QorK2X7GsVU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Gold is one of the materials used in nanotechnologies.</span></figcaption>
</figure>
<h2>Inconsistent results</h2>
<p>Nanomedicines, just like with all medications, are surrounded by proteins from the body once they come into contact with the bloodstream. This protein coating, known as a <a href="https://doi.org/10.1016/j.ijbiomac.2020.12.108">protein corona</a>, gives nanoparticles a biological identity that determines how the body will recognize and interact with it, like how the immune system has specific reactions against certain pathogens and allergens.</p>
<p>Knowing the precise type, amount and configuration of the proteins and other biomolecules attached to the surface of nanomedicines is critical to determine safe and effective dosages for treatments. However, one of the <a href="https://doi.org/10.1038/s41467-021-27643-4">few available approaches</a> to analyze the composition of protein coronas requires instruments that many nanomedicine laboratories lack. So these labs typically send their samples to separate proteomics facilities to do the analysis for them. Unfortunately, many facilities use <a href="https://doi.org/10.1038/s41587-019-0037-y">different sample preparation methods and instruments</a>, which can lead to differences in results.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Cryo-electron microscopy images of protein coronas on nanoparticles" src="https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1131&fit=crop&dpr=1 754w, https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1131&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/502192/original/file-20221220-20-iflyr8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1131&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Protein coronas give nanoparticles their biological identities. Images A to C show nanoparticles without protein coronas, while images D to F show proteins (black dots) coating the surface of the particles.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41467-022-34438-8">Ashkarran et al. (2022)/Nature Communications</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
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<p>We wanted to test how consistently these proteomics facilities analyzed protein corona samples. To do this, my colleagues and I sent biologically identical protein coronas to 17 different labs in the U.S. for analysis. </p>
<p>We had striking results: <a href="https://doi.org/10.1038/s41467-022-34438-8">Less than 2%</a> of the proteins the labs identified were the same. </p>
<p>Our results reveal an extreme lack of consistency in the analyses researchers use to understand how nanomedicines work in the body. This may pose a significant challenge not only to ensuring the accuracy of diagnostics, but also the effectiveness and safety of treatments based on nanomedicines.</p>
<h2>Why standardize nanomedicine?</h2>
<p>Researchers have been working to improve the safety and efficacy of nanomedicine through various approaches. These include modifying study protocols, methodologies and analytical techniques to <a href="https://doi.org/10.1038/s41565-018-0246-4">standardize the field</a> and improve the reliability of nanomedicine data.</p>
<p>Aligned with these efforts, my team and I have identified several critical but often overlooked factors that can influence the performance of a nanomedicine, such as a <a href="https://doi.org/10.1038/s41467-021-23230-9">person’s sex</a>, <a href="https://doi.org/10.1039/C4BM00131A">prior medical conditions</a> and <a href="https://doi.org/10.1039/C9NH00097F">disease type</a>. Taking these factors into account when designing studies and interpreting results could enable researchers to produce more reliable and accurate data and lead to better nanomedicine treatments.</p><img src="https://counter.theconversation.com/content/196652/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Morteza Mahmoudi receives funding from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (grant DK131417). He is affiliated with PGWC, NanoServ, and Target's Tip. He is a co-founder and director of the Academic Parity Movement (<a href="http://www.paritymovement.org">www.paritymovement.org</a>), a non-profit organization dedicated to addressing academic discrimination, violence and incivility. He receives royalties/honoraria for his published books, plenary lectures, and licensed patents. </span></em></p>The proteins that cover nanoparticles are essential to understanding how they work in the body. Across 17 proteomics facilities in the US, less than 2% of the identified proteins were identical.Morteza Mahmoudi, Assistant Professor of Radiology, Michigan State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1925902022-10-26T12:29:17Z2022-10-26T12:29:17ZDrugs – 4 essential reads on how they’re made, how they work and how context can make poison a medicine<figure><img src="https://images.theconversation.com/files/489907/original/file-20221016-16-3m74ut.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Constraining drugs to a single function in the body may be limiting their full potential.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/red-and-white-pharma-pill-pattern-on-pastel-blue-royalty-free-image/1288588418">Israel Sebastian/Moment via Getty Images</a></span></figcaption></figure><p>Pandemics and disease outbreaks put a spotlight on the hurdles researchers face to get a drug on the shelves. From finding prospective drug candidates to balancing time and financial pressures with ensuring safety and efficacy, there are many aspects of drug development that determine whether a treatment ever makes it out of the lab. </p>
<p>Broadening the definition of “medicine” and where it can be found, however, could help expand the therapeutic options available for both researchers and patients.</p>
<p>Here are four facets of how drugs are developed and how they work in the body, drawn from stories in The Conversation’s archive.</p>
<h2>1. Matching drug to target</h2>
<p>The most effective drugs are, in a sense, the product of good matchmaking – they bind to a specific disease-causing receptor in the body, elicit a desired effect and ideally ignore healthy parts of the body.</p>
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<figcaption><span class="caption">Factors such as your age, genetics and diet can affect how well your body processes a drug.</span></figcaption>
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<p>Drugs <a href="https://theconversation.com/how-do-drugs-know-where-to-go-in-the-body-a-pharmaceutical-scientist-explains-why-some-medications-are-swallowed-while-others-are-injected-182488">travel through the bloodstream</a> to reach their targets. Because of this, most drugs circulate throughout the body and can bind to unintended sites, potentially causing undesired side effects.</p>
<p>Researchers can increase the precision and effectiveness of a drug by designing different ways to take it. An inhaler, for example, delivers a drug directly to the lungs without its having to travel through the rest of the body to get there.</p>
<p>Whether patients take drugs as prescribed is also essential to ensuring the right dose gets to where it needs to be often enough to have a desired effect. “Even with all the science that goes into understanding a disease well enough to develop an effective drug, it is often up to the patient to make it all work as designed,” writes pharmaceutical scientist <a href="https://www.researchgate.net/profile/Thomas-Anchordoquy">Tom Anchordoquy</a> of the University of Colorado Anschutz.</p>
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Read more:
<a href="https://theconversation.com/how-do-drugs-know-where-to-go-in-the-body-a-pharmaceutical-scientist-explains-why-some-medications-are-swallowed-while-others-are-injected-182488">How do drugs know where to go in the body? A pharmaceutical scientist explains why some medications are swallowed while others are injected</a>
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<h2>2. Searching for drug candidates</h2>
<p>Researchers have discovered a number of drugs by chance, including <a href="https://www.pbs.org/newshour/health/the-real-story-behind-the-worlds-first-antibiotic">penicillin</a> for bacterial infections, <a href="https://www.bbc.com/future/article/20200928-how-the-first-vaccine-was-born">vaccines for smallpox</a> and <a href="https://doi.org/10.1038/nrcardio.2017.172">warfarin</a> for blood clots. While serendipity still plays a role in modern drug discovery, most drug developers take a systematic approach.</p>
<p>Scientists typically start by identifying a particular molecular target, usually receptors that trigger a specific response in the body. Then, they look for chemical compounds that react with that target. Technology called <a href="https://theconversation.com/discovering-new-drugs-is-a-long-and-expensive-process-chemical-compounds-that-dupe-screening-tools-make-it-even-harder-175972">high-throughput screening</a> allows researchers to quickly test thousands of potential drug candidates at once. Compounds that match screening criteria advance to further development and refinement. Once optimized for their intended use, compounds go on to safety and efficacy testing in animals and people.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/xnM2hTXd1vE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Scientists have been isolating medicinal compounds from natural products for centuries.</span></figcaption>
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<p>One way to ease the search for optimal drug candidates is to work with compounds that are already optimized to work in living beings. <a href="https://theconversation.com/nature-is-the-worlds-original-pharmacy-returning-to-medicines-roots-could-help-fill-drug-discovery-gaps-176963">Natural products</a>, derived from organisms like microbes, fungi, plants and animals, share similar structures and functions across species. Though not without their own development challenges, they could aid the search for related compounds that work in people.</p>
<p>“There are thousands of microorganisms in the ocean left to explore as potential sources of drug candidates, not to mention all the ones on land,” writes medical chemist <a href="https://scholar.google.com/citations?user=8_T1ueYAAAAJ&hl=en">Ashu Tripathi</a> of the University of Michigan. “In the search for new drugs to combat antibiotic resistance, natural products may still be the way to go.”</p>
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Read more:
<a href="https://theconversation.com/nature-is-the-worlds-original-pharmacy-returning-to-medicines-roots-could-help-fill-drug-discovery-gaps-176963">Nature is the world's original pharmacy – returning to medicine's roots could help fill drug discovery gaps</a>
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<h2>3. A drug by any other name may be just as effective</h2>
<p>Existing drugs can find a second (or third, fourth and fifth) life through repurposing. </p>
<p>Most drugs <a href="https://theconversation.com/many-medications-affect-more-than-one-target-in-the-body-some-drug-designers-are-embracing-the-side-effects-that-had-been-seen-as-a-drawback-184922">have many functions</a> beyond what researchers originally designed them to do. While this multifunctionality is often the cause of unwanted side effects, sometimes these results are exactly what’s needed to treat a completely unrelated condition.</p>
<p>Sildenafil, for example, failed to treat severe chest pain from coronary artery disease, but proved to be potent at inducing erections as Viagra. Similarly, thalidomide, a compound that caused birth defects in thousands of infants around the world as a morning sickness drug, found redemption as a cancer treatment. </p>
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<figcaption><span class="caption">While thalidomide was disastrous for morning sickness, it has proved effective for other diseases.</span></figcaption>
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<p>Because drugs inherently have more than one function in the body, <a href="https://theconversation.com/repurposing-generic-drugs-can-reduce-time-and-cost-to-develop-new-treatments-but-low-profitability-remains-a-barrier-174874">repurposing existing drugs</a> can help fill a gap where pharmaceutical companies and other developers cannot or will not. <a href="https://scholar.google.com/citations?user=iDKZaA4AAAAJ&hl=en">Gregory Way</a>, a researcher at the University of Colorado Anschutz, uses artificial intelligence to predict the various effects a drug can have and believes that this lack of specificity is something to explore rather than eliminate. Instead of trying to home in on one specific target, he suggests that scientists “embrace the complexity of biology and try to leverage the multifaceted effects drugs can offer.”</p>
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<p>
<em>
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Read more:
<a href="https://theconversation.com/many-medications-affect-more-than-one-target-in-the-body-some-drug-designers-are-embracing-the-side-effects-that-had-been-seen-as-a-drawback-184922">Many medications affect more than one target in the body – some drug designers are embracing the 'side effects' that had been seen as a drawback</a>
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<h2>4. Poison as medicine</h2>
<p>If so many drugs can have toxic effects in the body, be it through side effects or taking the wrong dose or for the wrong condition, what determines whether a drug is a “medicine” or a “poison”?</p>
<p>Biomedical scientists evaluate drugs based on their active ingredient, or a specific compound that has a specific effect in the body. But reducing medicines to just a single molecule ignores another important factor that determines whether a drug is therapeutic – the context in which it is used. Opioids treat intractable pain but can lead to debilitating and lethal addiction when improperly administered. Chemotherapy kills tumors but causes collateral damage to healthy tissues in the process.</p>
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<a href="https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Historical illustration of a plant with leaves and large tubers" src="https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=796&fit=crop&dpr=1 600w, https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=796&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=796&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1000&fit=crop&dpr=1 754w, https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1000&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/410863/original/file-20210712-27-cocyqt.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1000&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">Aconite is a poisonous herb that was used to treat cold symptoms in ancient Chinese medical practice.</span>
<span class="attribution"><a class="source" href="https://www.loc.gov/resource/lcnclscd.2012402216.1A010/?sp=3">Library of Congress, Asian Division, Chinese Rare Books</a></span>
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<p>Another pharmaceutical paradigm, <a href="https://theconversation.com/poison-or-cure-traditional-chinese-medicine-shows-that-context-can-make-all-the-difference-163337">traditional Chinese medicine</a>, has historically acknowledged the malleability of drugs through the use of poisons as therapeutics. </p>
<p><a href="https://scholar.google.com/citations?user=4q0hYSwAAAAJ&hl=en">Yan Liu</a>, a medical historian at University of Buffalo who studies this practice, notes that ancient texts did not distinguish between poisons and nonpoisons – rather, Chinese doctors examined drugs based on a continuum of potency, or ability to harm and heal. They used different processing and administration techniques to adjust the potency of poisons. They also took a personalized approach to treatment, aware that each drug works differently based on a number of different individual factors.</p>
<p>“The paradox of healing with poisons in traditional Chinese medicine reveals a key message: There is no essential, absolute or unchanging core that characterizes a medicine,” Liu writes. “Instead, the effect of any given drug is always relational – it is contingent on how the drug is used, how it interacts with a particular body and its intended effects.”</p>
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Read more:
<a href="https://theconversation.com/poison-or-cure-traditional-chinese-medicine-shows-that-context-can-make-all-the-difference-163337">Poison or cure? Traditional Chinese medicine shows that context can make all the difference</a>
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<p><em>Editor’s note: This story is a roundup of articles from The Conversation’s archives.</em></p><img src="https://counter.theconversation.com/content/192590/count.gif" alt="The Conversation" width="1" height="1" />
Despite technological advancements, many challenges remain in getting a drug from lab to pharmacy shelf. Reframing what is a “medicine” could expand treatment options for researchers and patients.Vivian Lam, Associate Health and Biomedicine EditorLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1865372022-10-12T12:18:11Z2022-10-12T12:18:11ZMale birth control options are in development, but a number of barriers still stand in the way<figure><img src="https://images.theconversation.com/files/488588/original/file-20221006-22-mkhlv3.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1999%2C1499&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Lack of pharmaceutical industry interest has stymied the development of new male contraception options.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/lowering-sperm-count-royalty-free-illustration/825328902">filo/DigitalVision Vectors via Getty Images</a></span></figcaption></figure><p>In the wake of the reversal of Roe v. Wade, developing more contraception options for everyone becomes even more important.</p>
<p>Women and people who can become pregnant have a <a href="https://fphandbook.org">number of effective birth control methods</a> available, including oral pills, patches, injections, implants, vaginal rings, IUDs and sterilization. But for men and people who produce sperm, options have been limited. Two options, withdrawal and condoms, both have <a href="https://doi.org/10.1363/psrh.12017">high failure rates</a>. Withdrawal has a failure rate of about 20%. Condoms have a failure rate of only 2% when used correctly, but that rate rises to 13% based on how people typically use them. Vasectomies have a failure rate of less than 1%, but they require minimally invasive surgery and are seen as a permanent method of contraception. Neither vasectomies nor withdrawal protect against sexually transmitted infections.</p>
<p>There has not been a new form of male birth control since the introduction of the “<a href="https://www.healthline.com/health/mens-health/no-scalpel-vasectomy">no-scalpel vasectomy</a>” in the 1980s. <a href="https://lundquist.org/christina-chung-lun-wang-md">I, along with my team</a>, have been developing male contraception methods since the 1970s. I believe that new safe, reversible and affordable contraception options can help men participate and share contraceptive responsibilities with their partners, and <a href="https://doi.org/10.1016/j.contraception.2017.08.015">reduce the rate of unintended pregnancies</a>.</p>
<h2>Taking responsibility for family planning</h2>
<p>A <a href="https://www.malecontraceptive.org/uploads/1/3/1/9/131958006/mci_consumerresearchstudy.pdf">2017 survey</a> of 1,500 men ages 18 to 44 found that over 80% wanted to prevent their partner from getting pregnant and felt that they had shared or sole responsibility for birth control. </p>
<p>Men who are dissatisfied with condoms are more likely to either use withdrawal as a form of birth control or never use contraception. Of those dissatisfied with condoms, however, 87% percent are interested in new methods for male contraception. This translates to an estimated <a href="https://www.malecontraceptive.org/uploads/1/3/1/9/131958006/mci_consumerresearchstudy.pdf">17 million men in the U.S.</a> who are looking for new methods of contraception to prevent unintended pregnancies.</p>
<p>Similarly, a 2002 survey of over 9,000 men in nine countries over four continents found that <a href="https://doi.org/10.1093/humrep/deh574">over 55%</a> would be willing to use a new method of male birth control. Importantly, a 2000 survey across three continents found that <a href="https://doi.org/10.1093/humrep/15.3.646">98% of women</a> would trust their partner to use a male birth control method.</p>
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<a href="https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Person displaying a variety of birth control methods." src="https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=386&fit=crop&dpr=1 600w, https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=386&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=386&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=485&fit=crop&dpr=1 754w, https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=485&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/488600/original/file-20221006-24-7c71p6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=485&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">The onus of birth control has largely fallen on women and people who can become pregnant.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/doctor-explaining-contraception-royalty-free-image/602936017">Peter Dazeley/The Image Bank via Getty Images</a></span>
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<h2>Barriers to male contraception</h2>
<p>Strong interest in a new male contraceptive raises the question of why there haven’t been any new male birth control methods since the ‘80s.</p>
<p>Male contraception development has primarily been supported by governmental and nongovernmental organizations, including the <a href="https://www.who.int/publications/m/item/global-study-men-and-women-male-contraceptive-knowledge-using-mixed-methods">World Health Organization</a> working with academic medical centers. However, these agencies frequently do not have a <a href="https://doi.org/10.3389/fendo.2022.891589">drug development infrastructure</a> comparable to pharmaceutical companies, with programs typically run by only a handful of personnel assisted by clinical research organizations. Limited financial resources further slow down development.</p>
<p><a href="https://www.bloomberg.com/news/features/2017-08-03/why-we-can-t-have-the-male-pill">Lack of interest from pharmaceutical companies</a> may also play a role in deterring male contraception development, and there are a number of possible reasons the drug industry shies away from male birth control. One reason includes weighing the cost of development with uncertainties about the potential market. Other reasons include uncertainties about who would dispense these drugs and unclear <a href="https://pharmaceutical-journal.com/article/feature/overcoming-the-challenges-in-developing-male-contraceptives">regulatory requirements</a> for male contraceptive methods to receive FDA approval. Companies may also be concerned about liability if pregnancy occurs.</p>
<h2>New methods currently in development</h2>
<p>Researchers are currently looking into several different methods of male contraception.</p>
<p><a href="https://doi.org/10.1210/clinem/dgab034">Hormonal methods</a> are usually taken as a gel applied to the skin, injection to the muscle or oral pill. These methods typically contain testosterone and a progestin. The progestin suppresses two pituitary hormones that control the testes, the organs that produce sperm. While the testes require high concentrations of testosterone to make sperm, testosterone is typically included in hormonal methods to ensure that there is an adequate level of the hormone for other bodily functions. Counterintuitively, taking testosterone may also help <a href="https://doi.org/10.5534%2Fwjmh.180036">suppress sperm production</a>, because increasing circulating testosterone levels above a certain level suppresses the same two pituitary hormones. The addition of a progestin further enhances the suppression of sperm production.</p>
<p>The hormonal contraceptive candidate furthest along in development is currently in an ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT03452111">second stage clinical study</a> that has recruited over 400 couples across four continents. I served as the principal investigator of this trial at the Lundquist Institute. The results of the study, sponsored by the <a href="https://www.nichd.nih.gov/about/org/dir/dph/officebranch/cdp">Eunice Kennedy Shriver National Institute of Child Health and Human Development</a> and the <a href="https://www.popcouncil.org/research/contraceptive-development">Population Council</a>, have so far been promising with minimal side effects, and the couples have found the gel acceptable to use.</p>
<p>My team and I are also developing drugs that function like <a href="https://doi.org/10.1210/clinem/dgab034">both testosterone and progestin</a>, but in a single compound. These drugs are currently undergoing early testing in people as a daily oral pill or a long-acting injection.</p>
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<figcaption><span class="caption">Scientists have been trying to develop male birth control pills for decades.</span></figcaption>
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<p><a href="https://doi.org/10.3389/fcell.2020.00061">Nonhormonal methods</a> typically involve drugs that specifically target sperm-producing organs to decrease sperm concentration or function. Nonhormonal drugs show efficacy in animal models, but preclinical toxicology results are needed before clinical studies to demonstrate safety, tolerability and efficacy in people can begin. <a href="https://doi.org/10.1210/clinem/dgab034">A few</a> of these methods are working toward first-stage clinical trials.</p>
<p>Another nonhormonal method involves reversibly blocking the vas deferens, an organ that transports sperm for ejaculation. Studies sponsored by the <a href="https://www.malecontraceptive.org">Male Contraceptive Initiative</a> and <a href="https://www.parsemus.org/humanhealth/male-contraceptive-research/">Parsemus Foundation</a> are testing <a href="https://doi.org/10.1210/clinem/dgab034">hydrogels</a>, a type of polymer that retains water, that block sperm from traveling through the vas deferens.</p>
<p>People are ready for new contraceptive methods. I believe that collaboration across academic, government, nonprofit and pharmaceutical sectors can help deliver new birth control methods that are safe, reversible, acceptable and accessible to all.</p><img src="https://counter.theconversation.com/content/186537/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christina Chung-Lun Wang receives funding from the Eunice Shriver Kennedy National Institute of Child Health and Human Development, National Institutes of Health, USA. She is a member of the International Committee for Contraceptive Development of the Population Council. She was a temporary consultant for the Research Group for the Study of Male Reproduction and previously named the Task Force for the Regulation of Male Infertility of the World Health Organization. She is currently an investigator at The Lundquist Institute and a Professor of Medicine in the Division of Endocrinology, Department of Medicine at the Harbor-UCLA Medical Center. </span></em></p>There hasn’t been a new form of male birth control since the 1980s. More contraception options for all partners could help reduce the rate of unintended pregnancies.Christina Chung-Lun Wang, Physician/Investigator at Lundquist Institute at Harbor-UCLA Medical Center and Professor of Medicine at David Geffen School of Medicine, University of California, Los AngelesLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1834132022-08-24T15:35:58Z2022-08-24T15:35:58ZCataracts: we’re working on eye drops to treat them so people don’t need surgery<figure><img src="https://images.theconversation.com/files/480563/original/file-20220823-25-kpi17p.jpg?ixlib=rb-1.1.0&rect=7%2C0%2C4996%2C3338&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-female-ophthalmologist-using-apparatus-632890571">Olena Yakobchuk/Shutterstock</a></span></figcaption></figure><p>Many years ago, I began my PhD with the firm resolve of finding a cure for cataracts – not in several years or decades, but within the duration of my PhD. Such was my enthusiasm and naivety. Decades later, though, that dream looks as if it might come true. </p>
<p>Cataracts are the result of a buildup of broken protein fragments within the eye lens. This buildup and clumping together of protein fragments severely reduce the transmission of light to the retina – making things appear blurry or misty. It is the cause of around <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1705965/?report=reader">43% of all blindness</a>.</p>
<p>Surgery to remove the clouded lens and replace it with an artificial one has so far been the only treatment available for cataracts. About <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1705965/">10 million cataract operations</a> are performed each year, globally. The procedure can be life-changing, but who would not want to avoid surgery if a less-invasive treatment was available? This is where sterol eye drops come into the picture. (Sterols are fat-like substances that occur in nature.)</p>
<p>My colleagues and I recently <a href="https://pubmed.ncbi.nlm.nih.gov/35575904/">conducted a study in mice</a> that showed promising and dramatic effects on cataracts after we applied a sterol compound to their eyes. When the compound was applied to one eye of 26 mice with cataracts, we found that 61% of the treated lenses showed an improvement in their refractive index gradient. This gradient is a measure of optical density and a vital component of image quality. The opacity of the lenses was reduced in 46% of the mice, as well.</p>
<p>However, the effects were not universal, suggesting that the same remedy may not apply to all cataracts (there are several types). </p>
<p>The compound we used had been tested before, but not for optics. Yet the optical quality of the lens is fundamental to light travelling unimpeded to the retina and hence to maintaining vision. </p>
<p>Investigations using this sterol compound <a href="https://www.science.org/doi/10.1126/science.aac9145">reported in 2015</a> improved transparency in mouse lenses, and partially restored protein solubility both in the lenses of living mice and in human lenses in a dish.</p>
<p>But a subsequent <a href="https://www.nature.com/articles/s41598-019-44676-4">study in 2019</a> could not find evidence that this compound reverses protein buildup in rat and human samples, nor that it reverses the opacities in rat lenses with cataracts. However, the sterol compound had not been tested on whole, intact human lenses. And most importantly, the effect of this compound on the optical property of the refractive index (that is, the optical quality of the lens) had not been measured. </p>
<h2>Measuring optical quality</h2>
<p>I have spent years developing and applying methods of measuring the optical quality of the lens, and have been measuring lens optics for over a decade using the most advanced system in the world, the <a href="https://en.wikipedia.org/wiki/SPring-8">SPring-8 synchrotron</a> in Japan – a particle accelerator that produces powerful X-rays, allowing measurements to be taken with the highest accuracy yet on optical properties of the eye. </p>
<p>This technology has allowed my colleagues and me to accurately characterise the refractive index gradient in transparent lenses as well as those that have cataracts – something that could not be conducted using a visible light source. </p>
<p>The refractive index gradient is important for image quality because it provides improved focusing capacity. Cataracts disrupt this gradient because of the protein buildup. The application of X-ray measurements has been key to our latest findings. In addition, when we measure optical properties, we do this on whole lenses with the protein distributions left undisturbed in the lens. </p>
<p>The link between a lens’s optical function and the protein solubility and propensity to clump needs to be studied further. This is important for addressing whether it is possible to reverse the process of cataract formation and restore transparency to a clouded lens. </p>
<p>Scientists have long believed that a buildup of the major structural proteins of a cataract – the crystallins – is irreversible. So any possible treatment for a cataract could, at best, halt or slow its progression. </p>
<p>If this is not true and protein aggregation is reversible, then it opens up a wealth of treatment possibilities. Not only can cataracts be prevented by avoiding certain known causes, such as <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097885/">poor nutrition</a>, <a href="https://iovs.arvojournals.org/article.aspx?articleid=2128544">smoking</a> and certain drugs, <a href="https://journals.lww.com/ijo/Fulltext/2014/62020/Etiopathogenesis_of_cataract__An_appraisal.2.aspx">such as steroids</a>, it may be possible to use drugs that prevent further progression. Other drugs may even be able to reverse the process of cataract formation and restore clarity to a lens that has become clouded.</p>
<p>Further research needs to include investigations of all proteins in the lens: the major structural proteins of the lens (the crystallins and the water channel proteins) in tandem with studies of optical function. </p>
<p>We are currently looking at the optics of the lens from all aspects, from early developmental stages to adulthood, and looking at how these results map on to changes in proteins.</p>
<p>A great deal more research may be needed, but what our recent research findings have shown is that non-surgical treatment for cataracts is possible – and may be closer than we think.</p><img src="https://counter.theconversation.com/content/183413/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Barbara Pierscionek currently receives funding from EU under the Marie Skłodowska-Curie Doctoral Training Centre scheme. </span></em></p>Eye drops might one day be a safe, non-invasive and less costly alternative to cataract surgery.Barbara Pierscionek, Professor and Deputy Dean, Research and Innovation, Anglia Ruskin UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1872012022-08-17T16:20:01Z2022-08-17T16:20:01ZClinical trials without humans – why computer simulations could make drugs a lot cheaper<p>Before a drug or medical device is approved for use in humans, it must undergo a clinical trial. Clinical trials ultimately aim to answer two simple questions: is the drug or device safe? And does it do what it’s supposed to do?</p>
<p>The downside to clinical trials is that they are complex, take years to complete and are extremely expensive. However, a recent development called “in silico clinical trials” (trials conducted using <a href="https://www.ijclinicaltrials.com/index.php/ijct/article/view/105">computer simulation</a>) are beginning to show their potential for substantially speeding up trials and drastically reducing their costs. And drugs regulators are starting to pay attention.</p>
<p>Indeed, evidence from an in silico clinical trial has already been used to get approval for a new type of pacemaker. </p>
<p>About <a href="https://pubmed.ncbi.nlm.nih.gov/15826268/">75% of patients</a> fitted with a pacemaker will need an MRI scan at some stage, but these devices run the risk of overheating in an MRI machine and burning heart tissue. A novel pacemaker was developed and approved in 2011 that was safe to use in MRI machines. </p>
<p>Testing this new pacemaker using a standard clinical trial would have required thousands of participants to catch those few occasions where the pacemaker overheated. Instead, the evidence from the in silico clinical trial was accepted by the US Food and Drug Administration (FDA) and the device was <a href="https://www.nejm.org/doi/full/10.1056/nejmra1512592#">approved</a>.</p>
<p>In silico trials have also been used to reduce the amount of animal testing. In 2008, the FDA approved one such trial to replace the use of dogs when testing insulin control loops in type 1 diabetes (a device that lets an insulin pump communicate with a continuous glucose monitor). Since then, more than 140 control loops have been tested in this way, avoiding <a href="https://pubmed.ncbi.nlm.nih.gov/28427321/">experimentation on hundreds of dogs</a>.</p>
<figure class="align-center ">
<img alt="A beagle looking out of its cage." src="https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/479417/original/file-20220816-1453-edol3i.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">In silico trials have saved on the use of dogs in clinical trials.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/dog-behind-cage-304277162">TONG4130/Shutterstock</a></span>
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<p>There has since been a flurry of attempts to develop in silico clinical trials in conditions ranging from <a href="https://www.frontiersin.org/articles/10.3389/fneur.2020.558125/full">stroke</a>, to <a href="https://pubmed.ncbi.nlm.nih.gov/29237680/">atrial fibrillation</a> (a potentially life-threatening irregular heartbeat), to assessing the <a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00668/full">toxicity of drugs</a>. Although none of these recent computer trials have attempted to get regulatory approval, they are paving the way for future in silico clinical trials to be used in regulatory approval of the drug or device.</p>
<p>These simulations have the potential to reduce the estimated <a href="https://theconversation.com/90-of-drugs-fail-clinical-trials-heres-one-way-researchers-can-select-better-drug-candidates-174152">failure rate of 90%</a> of new drugs in getting to market. Changes to the design or dosing of the medicine may improve clinical trial outcomes and reduce failure rates, but these are often not explored because of the huge costs of rerunning the clinical trials. But they can be explored cheaply using in silico trials.</p>
<h2>Widely used in other industries</h2>
<p>Manufacturing industries have long used computer simulations. Cars, planes and nuclear reactors are all designed and tested on a computer before building begins. What is new is the use of these simulations to predict disease, and the effect of a drug or medical device on that disease, for a general population.</p>
<p>Medical regulators such as the FDA are increasingly interested in assessing in silico clinical trials as they can reduce the cost, time and failure rate when developing a new treatment. Estimates of drug or medical device development costs range from <a href="https://bmjopen.bmj.com/content/10/6/e038863">US$50 million</a> (£41 million) to over <a href="https://jamanetwork.com/journals/jama/fullarticle/2762311">US$1 billion</a> (£828 million). Any reduction in these costs should result in cheaper medicines.</p>
<p>Research has reached a point where computational power and understanding of biology allow highly specific predictions to be made on how a medicine will affect the human body. However, this in no way means that these in silico clinical trials will fully replace human trials. There are too many “unknown unknowns” in understanding medical interventions, which means 100% accuracy at simulating reality is never guaranteed.</p>
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Read more:
<a href="https://theconversation.com/the-human-body-has-37-trillion-cells-if-we-can-work-out-what-they-all-do-the-results-could-revolutionise-healthcare-185654">The human body has 37 trillion cells. If we can work out what they all do, the results could revolutionise healthcare</a>
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<p>Regulatory acceptance is another hurdle that must be overcome. While there are promising signs from the FDA that in silico trials can be accepted as evidence, there is still a need for clear regulatory guidance for this to become the norm. As more successful in silico trials are developed, regulators around the world will probably accept them as valid evidence.</p>
<p>While in silico clinical trials will never completely replace real-world clinical trials, the two questions – is the medicine safe, and does it do what it’s supposed to do? – will increasingly be answered by a combination of humans and computer simulations of humans.</p><img src="https://counter.theconversation.com/content/187201/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Wahbi El-Bouri receives funding from The Royal Society and EPSRC. He is affiliated with the Avicenna Alliance and InSilico UK communities that seek to drive adoption of in silico clinical trials for patient safety and benefit. </span></em></p>In silico clinicial trials have the potential to speed up trials and cut costs.Wahbi K. El-Bouri, Research Fellow, University of LiverpoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1869752022-08-03T12:09:46Z2022-08-03T12:09:46ZMany drugs have mirror image chemical structures – while one may be helpful, the other may be harmful<figure><img src="https://images.theconversation.com/files/477203/original/file-20220802-11469-xcg7eb.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C1732%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Drugs can convert between different isomers in the body, leading to unexpected effects.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/pill-bipolar-disorder-opposites-royalty-free-illustration/1370292588">Dmitrii Guzhanin/iStock via Getty Images</a></span></figcaption></figure><p>The effects a drug or chemical compound have on the body depend on how its atoms are arranged in space. Some compounds have a dark twin with the same molecular formula but different 3D structure – and this can have consequences for what they do or don’t do in the body.</p>
<p>Consider the tragic story of <a href="https://www.nytimes.com/2013/09/23/booming/the-death-and-afterlife-of-thalidomide.html">thalidomide</a>, a morning sickness drug that caused thousands of birth defects and miscarriages. While <a href="https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/thalidomide.html">one form</a>, or isomer, of thalidomide has a sedative effect, the other is thought to cause abnormal physiological development. Because the two versions can <a href="https://doi.org/10.1073/pnas.1417832112">convert back and forth in the body</a>, it’s dangerous to take either form of thalidomide while pregnant.</p>
<p><a href="https://scholar.google.com/citations?user=dChGtb0AAAAJ&hl=en">My research</a> has focused on one such compound found in red grapes and peanuts, resveratrol. It has been a scientific mystery why clinical trials on using resveratrol to treat Alzheimer’s disease have had inconsistent results. Turns out, it may be because <a href="https://doi.org/10.1038/s41467-022-30785-8">two different forms were used</a> – while one may help with cognition and memory, the other may be toxic to the nervous system.</p>
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<figcaption><span class="caption">Thalidomide has since been repurposed to treat other conditions, including cancer.</span></figcaption>
</figure>
<h2>Isomers and amino acids</h2>
<p>Many drugs have the same atoms and bonds but are arranged differently in space. These drugs are called <a href="https://www.khanacademy.org/test-prep/mcat/chemical-processes/stereochemistry/a/chiral-drugs">chiral</a> compounds – meaning they exist as two nonsuperimposable mirror images. For example, your hands are also nonsuperimposable mirror images of each other. Although they look the same, they don’t overlap when you put one on top of the other. </p>
<p>Usually these mirror-image versions have very similar properties because they share the same elements and bonds. But the way they are arranged in space can drastically change the effects they have in the body. Just as you wouldn’t be able to fit a left-handed glove on your right hand, a left-handed version of a drug wouldn’t be able to fit into a target in the body shaped to fit a right-handed molecule.</p>
<p>Chiral molecules come in two versions, or isomers, defined by their <a href="https://www.khanacademy.org/test-prep/mcat/chemical-processes/stereochemistry/a/chiral-drugs">optical activity</a>. This means that if you shine polarized light on a chiral molecule, one will rotate the light to the left (indicated by the prefix L-, or levorotatory) while the other will rotate it to the right (indicated by the prefix D, or dextrorotatory).</p>
<p><a href="https://www.nature.com/scitable/topicpage/an-evolutionary-perspective-on-amino-acids-14568445/">Amino acids</a>, the building blocks of proteins, are chiral molecules. Living organisms primarily make proteins from <a href="https://atlasofscience.org/l-amino-acids-key-for-the-evolution-of-life-came-from-extraterrestrial-space/">amino acids with L configurations</a>. The D configuration, however, has many other functions in nature. <a href="https://doi.org/10.3389/fmicb.2018.00683">Bacteria</a>, for example, use D configuration amino acids to make their cell walls. <a href="https://doi.org/10.1007/s00726-020-02892-7">Mammals</a> use D configuration amino acids as messengers in their nervous and endocrine systems. </p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/Bw_cetheReo?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The structure of a compound matters just as much as its individual atoms and bonds.</span></figcaption>
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<p>The amino acid tyrosine is one important exception to the L configuration rule. Unlike other amino acids, both the L and D configurations of tyrosine can be activated for protein synthesis by an enzyme called <a href="https://doi.org/10.1016/0022-2836(67)90259-8">tyrosyl-tRNA synthetase (TyrRS)</a>. </p>
<p>The presence of D-tyrosine can make it difficult for cells to synthesize proteins that only use L-tyrosine. However, cells have evolved enzymes that can discriminate between both versions and ensure that only L-tyrosine is used. When tyrosine-consuming enzymes are absent, the resulting increased levels of tyrosine in the body can have <a href="https://medlineplus.gov/genetics/condition/tyrosinemia/">toxic effects</a>, including <a href="https://doi.org/10.1056/NEJM199002153220704">damage to the nervous system</a>. </p>
<p><a href="https://doi.org/10.1038/s41467-022-30785-8">Recently published work</a> from my lab suggests a potential reason why too much tyrosine can be neurotoxic. When we added increasing amounts of L-tyrosine to rat brain cells in a petri dish, we found that it decreased levels of TyrRS, the enzyme that activates tyrosine to make proteins without causing damage to the body. Surprisingly, adding D-tyrosine not only caused TyrRS levels to drop, but also killed the neurons.</p>
<p>When we looked at the brains of Alzheimer’s patients who show increased tyrosine levels, we also found that TyrRS enzyme levels are depleted. Our hypothesis is that as tyrosine levels in the brain increase, TyrRS enzyme levels drop and cause damaging effects on the brains of those with Alzheimer’s. These findings indicate the potentially important role TyrRS may play in the synthesis of proteins essential for cognition and memory.</p>
<h2>Grapes, peanuts and Alzheimer’s</h2>
<p>These findings have implications for studies on <a href="https://doi.org/10.3390%2Fbiomedicines6030091">resveratrol</a>, a compound found in red wine that researchers have been examining for potential health benefits. While <a href="https://doi.org/10.1016/j.trci.2018.09.009">some clinical trials</a> found that resveratrol can improve cognitive function in people with Alzheimer’s disease, <a href="https://doi.org/10.1212/WNL.0000000000002035">others found it had the opposite effect</a> and made the disease more severe. Why resveratrol can have such varying effects has remained a scientific enigma.</p>
<p>Resveratrol comes in two forms, cis-resveratrol and trans-resveratrol. The <a href="https://courses.lumenlearning.com/suny-mcc-organicchemistry/chapter/geometric-stereoisomers-cistrans/">“cis-” and “trans-” prefixes</a>, much like L- and D-, describe how the same atoms in two isomers are arranged differently in space. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Isomerization of trans- to cis-resveratrol" src="https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=201&fit=crop&dpr=1 600w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=201&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=201&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=253&fit=crop&dpr=1 754w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=253&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=253&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">At low concentrations, the trans form of resveratrol, left, can switch to the cis form, right.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Rasveratrol_isomerization.png">V8rik/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>My colleagues and I found that because the two forms of resveratrol <a href="https://doi.org/10.1007/s11357-020-00295-w">bind to TyrRS in different ways</a>, they can result in <a href="https://doi.org/10.1038/s41467-022-30785-8">opposite effects in neurons</a>. While cis-resveratrol was able to increase TyrRS levels in rat neurons in a petri dish, high concentrations of trans-resveratrol depleted TyrRS and caused neural damage. However, low concentrations of trans-resveratrol can <a href="https://doi.org/10.1038/nature14028">convert into cis-resveratrol</a> in the body. This result leads to an increase in TyrRS levels and its associated benefits.</p>
<p>We hypothesize that many clinical trials on resveratrol failed because none tested cis-resveratrol alone. We believe that this may also explain why trials that used high doses of trans-resveratrol saw harmful effects, while trials that used low doses of trans-resveratrol that were then converted into cis-resveratrol in the body saw beneficial effects.</p>
<p>Beyond the individual atoms and bonds of molecules, the body also cares about how they’re arranged in space. Paying attention to the different forms a drug takes could help lead to more effective treatments.</p><img src="https://counter.theconversation.com/content/186975/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sajish Mathew receives funding from NIH COBRE grant (P20GM109091). </span></em></p>From thalidomide to resveratrol, molecules with the exact same chemical properties can have drastically different effects in the body depending on how they’re arranged in space.Sajish Mathew, Assistant Professor of Drug Discovery and Biomedical Sciences, University of South CarolinaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1769632022-07-27T12:00:00Z2022-07-27T12:00:00ZNature is the world’s original pharmacy – returning to medicine’s roots could help fill drug discovery gaps<figure><img src="https://images.theconversation.com/files/475941/original/file-20220725-19-fgfrya.jpg?ixlib=rb-1.1.0&rect=98%2C165%2C1986%2C1237&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Around 75% of antibiotics, including penicillin and amphotericin B, are derived from natural products.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/directly-above-shot-of-pills-on-leaf-royalty-free-image/1004440852">Aphiwat Chuangchoem/EyeEm via Getty Images</a></span></figcaption></figure><p>While humans evolved over a period of approximately <a href="https://humanorigins.si.edu/education/introduction-human-evolution">6 million years</a>, breakthroughs in modern medicine as we know it today got going only in the <a href="https://www.medicalnewstoday.com/articles/323538">19th and 20th centuries</a>. So how did humans successfully survive through millions of years of diseases and illnesses without modern drugs and treatments?</p>
<p>This was a question I came to wonder about when the COVID-19 pandemic reached my family in India in April 2020, when there was very limited access to vaccines and treatments. All of my years working as a <a href="https://scholar.google.com/citations?user=8_T1ueYAAAAJ&hl=en">biomedical scientist</a>, requiring empirical evidence and formal safety testing before using a treatment, took a back seat as I scrambled for potential therapies from any sources I could find, be it scientific papers or folklore. I was ready to try any experimental or traditional medicine that might have a chance at helping my dad.</p>
<p>Luckily, my dad recovered. I can’t say for sure if any of the traditional medicines we used actually helped him recover. But as someone whose entire scientific career has focused on discovering new drugs from chemical compounds found in nature, I wondered if there was a molecule in the traditional medicines we used that could be isolated and optimized to treat COVID-19.</p>
<p>Scientists like me have been looking for new drugs for various diseases by purifying existing compounds in nature instead of synthesizing completely new ones in the lab. From <a href="https://doi.org/10.1021/acs.jnatprod.0c00968">COVID-19</a> to <a href="https://doi.org/10.1007/978-3-319-78538-7_17">antibiotic resistance</a>, I believe that past successes and new technologies point to the tremendous potential of developing new drugs from natural products.</p>
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<figcaption><span class="caption">Early drug development involved searching for plants with medicinal properties. Scientists have since been able to isolate the active ingredients bestowing medicinal properties on natural products, such as the morphine in poppies.</span></figcaption>
</figure>
<h2>The natural product advantage</h2>
<p>Humans have coevolved with the rest of nature over time, and obtaining medicine is perhaps one of the most important interactions people continue to have with the natural world. DNA analyses have shown that <a href="https://doi.org/10.1038/nature21674">early humans may have treated dental abscesses</a> with poplar, containing the active ingredient of aspirin, and <em>Penicillium</em> mold, containing the antibiotic penicillin.</p>
<p>Researchers call the molecules like the ones that give poplar and <em>Penicillium</em> their biological effects <a href="https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3A_Basic_Principles_of_Organic_Chemistry_(Roberts_and_Caserio)/30%3A_Natural_Products_and_Biosynthesis">natural products</a> because they are produced by living organisms such as microbes, fungi, corals and plants. These natural products have evolved to be <a href="https://doi.org/10.1002/1521-3773(20020816)41:16%3C2878::AID-ANIE2878%3E3.0.CO;2-B">structurally “optimized</a>” to serve particular biological functions, primarily to <a href="https://pubs.rsc.org/en/content/articlelanding/2015/np/c4np00150h">deter predators or gain a survival advantage</a> in a particular environment and over other competitors.</p>
<p>Because natural products are already made to function in living creatures, this makes them especially attractive as a source for drug discovery. While proteins may look different in different organisms, many have <a href="https://doi.org/10.1073/pnas.95.18.10396">similar structural features and functions</a> across species. This can help ease the search for related proteins that work in people.</p>
<h2>Natural product hall of fame</h2>
<p>Natural products derived from microbes and plants are the biggest resource for drug discovery for modern medicine. Case in point, the discovery of the antibiotic <a href="https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html">penicillin</a> in 1940 from <em>Penicillium</em> mold allowed doctors to treat previously fatal infections and started the era of antibiotics. </p>
<p>As of September 2019, <a href="https://doi.org/10.1021/acs.jnatprod.9b01285">over 50%</a> of currently available FDA-approved drugs are either directly or indirectly derived from natural products. One of the best-selling drugs of the past two decades, atorvastatin (Lipitor), an anti-cholesterol drug, is derived from a compound produced by the fungus <a href="https://doi.org/10.1038/nm1008-1050"><em>Penicillium citrinum</em></a>. From 1992 to 2017, atorvastatin sales in the U.S. totaled <a href="https://www.fiercepharma.com/pharma/from-old-behemoth-lipitor-to-new-king-humira-u-s-best-selling-drugs-over-25-years">US$94.67 billion</a>.</p>
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<figcaption><span class="caption">Penicillin revolutionized medicine.</span></figcaption>
</figure>
<p>Other prominent examples of drugs derived from natural products currently used today include the anti-fungal <a href="https://doi.org/10.1378/chest.54.Supplement_1.296">amphotericin B</a>, isolated from the soil bacteria <em>Streptomyces nodosus</em>, the chemotherapy <a href="https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/camptothecintaxol.html">taxol</a>, isolated from the bark of the Pacific yew tree, and the immunosuppressant <a href="https://doi.org/10.1016/S0269-915X(98)80100-6">cyclosporin</a>, isolated from the fungus <em>Tolypocladium inflatum</em>.</p>
<p>I believe that undiscovered treatments for a wide range of diseases are lying right under our noses in natural products. In January 2021, the FDA approved <a href="https://www.lupus.org/resources/lupkynis-voclosporin-what-you-need-to-know">voclosporin (Lupkynis)</a>, isolated from the fungus <a href="https://mycocosm.jgi.doe.gov/Tolinf1/Tolinf1.home.html"><em>Tolypocladium inflatum</em></a>, to treat lupus. Recently, researchers have been looking into <a href="https://doi.org/10.1126/sciadv.abi6110">cannabidiol</a> and other <a href="https://doi.org/10.1021/acs.jnatprod.1c00946">cannabinoid compounds</a> as a potential way to prevent or treat COVID-19. The FDA has not authorized any drug containing CBD for COVID-19 yet.</p>
<h2>Challenges in natural product discovery</h2>
<p>Researchers are increasingly able to use new <a href="https://doi.org/10.1038/s41573-020-00114-z">screening technologies and methods</a> to isolate previously unidentified natural products. Screening for natural products typically involves looking through a large library of extracts from natural sources. The <a href="https://www.lsi.umich.edu/science/centers-technologies/natural-products-discovery-core">Natural Product Drug Discovery Core</a>, which I co-founded with my colleague <a href="https://scholar.google.com/citations?user=g9dFOKIAAAAJ&hl=en">David Sherman</a> at the University of Michigan, for example, searches for potential drug targets in a library containing around 50,000 natural product extracts that each contain 30 to 50 molecules to test.</p>
<p>However, discovering natural product-based drugs is not without challenges. <a href="https://doi.org/10.1073/pnas.1614680114">Since the 1980s</a>, natural products have fallen out of favor because of a number of challenges. These include difficulty accessing expensive screening methods, and limitations in technology that isn’t able to fully analyze the complexity of natural products. There are also <a href="https://doi.org/10.1007/s11101-014-9367-z">ecological and legal considerations</a>, such as accessing samples sustainably and maintaining biodiversity. Pharmaceutical companies have <a href="https://doi.org/10.1002/0471141755.ph0911s46">reduced their natural product-based drug discovery programs</a>, and <a href="https://doi.org/10.1093/ofid/ofaa001">federal funding</a> is also in short supply due to limited profitability.</p>
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<figcaption><span class="caption">As antibiotic resistance grows, developing new drugs and using current ones more responsibly becomes even more imperative.</span></figcaption>
</figure>
<h2>Finding new drugs in nature</h2>
<p>New drugs are often necessary for unprecedented health emergencies like COVID-19. They are also needed for a health emergency that began long before the pandemic – antibiotic resistance. </p>
<p>A <a href="https://apps.who.int/iris/handle/10665/258965">September 2017 report</a> from the World Health Organization reaffirmed that antibiotic resistance is a global health emergency that will seriously jeopardize progress in modern medicine. If current antibiotics lose their effectiveness, <a href="https://www.cdc.gov/drugresistance/about.html">common medical interventions</a> such as cesarean sections and cancer treatments may become incredibly risky. Transplantation could become virtually impossible. Antibiotic-resistant microbes were the direct cause of roughly <a href="https://doi.org/10.1016/S0140-6736(21)02724-0">1.27 million deaths in 2019</a>. Treating just six of the 18 microbes that pose an antibiotic resistance threat is estimated to cost <a href="https://www.cdc.gov/drugresistance/solutions-initiative/stories/partnership-estimates-healthcare-cost.html">over $4.6 billion annually</a> in the U.S. alone. The <a href="https://www.cdc.gov/media/releases/2022/s0712-Antimicrobial-Resistance.html">COVID-19 pandemic has reversed prior progress addressing this issue</a>, with a 15% increase in antimicrobial-resistant infections from 2019 to 2020. In contrast, antimicrobial-resistant infections had fallen by 27% from 2012 to 2017. Among the likely causes of this backslide were increases in antibiotic use, difficulty following infection control guidelines and longer hospital stays.</p>
<p>As of recent estimates, <a href="https://doi.org/10.1038/ja.2017.30">roughly 75%</a> of approved antibiotics are derived from natural products. There are <a href="https://doi.org/10.1038/s41586-022-04862-3">thousands of microorganisms in the ocean</a> left to explore as potential sources of drug candidates, not to mention all the ones on land. In the search for new drugs to combat antibiotic resistance, natural products may still be the way to go.</p><img src="https://counter.theconversation.com/content/176963/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ashu Tripathi receives funding from the National Institute of Health and UM Biological Sciences Initiative. He is affiliated with the American Society of Pharmacognosy, Association of Biomolecular Resources Facilities, and Society of Industrial Microbiology and Biotechnology. </span></em></p>With the dual threats of antibiotic resistance and emerging pandemics, finding new drugs becomes even more urgent. A trove of medicines may be lying under our nose.Ashu Tripathi, Director, Natural Product Discovery Core; Assistant Professor/ Research of Medicinal Chemistry, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1849222022-07-11T12:29:55Z2022-07-11T12:29:55ZMany medications affect more than one target in the body – some drug designers are embracing the ‘side effects’ that had been seen as a drawback<figure><img src="https://images.theconversation.com/files/473235/original/file-20220708-14-kbl694.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2035%2C1471&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Depending on how you look at it, drugs that can act on multiple targets could be a boon instead of a challenge.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/multi-exposure-photogram-of-molecular-structure-of-royalty-free-image/886907874">Andrew Brookes/Image Source via Getty Images</a></span></figcaption></figure><p>Drugs don’t always behave exactly as expected. While researchers may develop a drug to perform one specific function that’s perhaps tailored to work for a specific genetic profile, sometimes the drug might perform several other functions outside of its intended purpose. </p>
<p>This concept of drugs having multiple functions, called <a href="https://doi.org/10.1021/acs.jmedchem.8b00760">polypharmacology</a>, may lead to unintended consequences. This is a common occurrence for <a href="https://doi.org/10.1126/scitranslmed.aaw8412">cancer drugs in clinical trials</a> that can have <a href="https://doi.org/10.1586/ecp.12.74">harmful side effects and treatment toxity</a>. </p>
<p>But polypharmacology may in fact be the norm for most drugs, not the exception. So rather than seeing a drug’s ability to perform many functions as a flaw, <a href="https://scholar.google.com/citations?user=iDKZaA4AAAAJ&hl=en">biomedical data scientists like me</a> and my <a href="https://www.waysciencelab.com/">lab colleagues</a> believe that it can be used to our advantage in designing drugs that address the full complexity of biology.</p>
<h2>Drugs often multitask in cells</h2>
<p>When scientists talk about drugs, they like to refer to its <a href="https://www.verywellmind.com/meaning-of-mechanism-of-action-in-health-care-425245">mechanism of action, or MOA</a> – essentially, exactly what a drug does when it enters the body. A drug’s official MOA, however, may not actually include all the ways it can affect cells.</p>
<p>For example, the mechanism of action of a drug labeled as a <a href="https://www.drugs.com/drug-class/vegf-vegfr-inhibitors.html">VEGF inhibitor</a> is to block the activity of a protein called VEGF, or vascular endothelial growth factor, in a cell. While VEGF plays an important role making new blood vessels, a process that’s integral to healthy tissue development, it can also be a <a href="https://doi.org/10.1016/j.cell.2011.02.013">hallmark of cancer</a>. <a href="https://www.webmd.com/cancer/cancer-angiogenesis-inhibitors">Blocking VEGF</a> can stop the formation of new blood vessels that supply nutrients to tumors and prevent the growth and spread of many types of cancers.</p>
<p>There are currently <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet">14 drugs inhibiting new blood vessel formation</a> approved in the U.S. to treat cancer, and most target VEGF. You may be wondering why there are so many different drugs available if they’re all inhibiting the same protein. The answer comes down to polypharmacology: While they all most likely work by blocking VEGF in some way, each likely has some other function that may be unique to that drug. That alternative function might cause side effects, or only work in certain conditions. </p>
<p>VEGF belongs to a larger group of proteins called <a href="https://doi.org/10.3390/cancers12030731">receptor tyrosine kinases, or RTKs</a>, that are challenging to target individually. Many drugs that target one type of RTK, like VEGF, also end up indiscriminately <a href="https://pubmed.ncbi.nlm.nih.gov/29888050/">targeting other RTKs</a> because they share a <a href="https://doi.org/10.1016/j.chembiol.2018.11.005">similar chemical structure</a>, potentially causing unwanted side effects.</p>
<p>For example, in 1999, scientists discovered that the infamous morning sickness drug thalidomide also worked as a VEGF inhibitor to <a href="https://doi.org/10.1056/nejm199911183412102">treat multiple myeloma</a>, a type of blood cancer. This was a triumph for a drug that, just 70 years prior, was banned worldwide after causing severe birth detects in an estimated <a href="https://doi.org/10.1016/s0140-6736(04)16308-3">10,000 infants</a>, not including miscarriages and stillbirths.</p>
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<figcaption><span class="caption">As in the case of thalidomide, a slight difference in chemical structure can make a huge difference in how a drug affects the body.</span></figcaption>
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<p>Like thalidomide, many chemicals affect the body in many different ways, and their full mechanism of action still isn’t fully understood. Even some approved drugs like lithium, acetaminophen and many antidepressants still have an <a href="https://doi.org/10.1016/j.isci.2020.101487">unclear MOA</a>.</p>
<p>Perhaps the most famous example of the serendipity of polypharmacology is <a href="https://www.history.com/this-day-in-history/fda-approves-viagra">Viagra</a>, a drug that was originally developed for cardiovascular problems but was later approved for erectile dysfunction. Interestingly, there is emerging evidence that Viagra also works as a <a href="https://doi.org/10.1111%2Fj.1582-4934.2008.00319.x">VEGF activator</a>, which may help treat stroke or heart attack. </p>
<h2>Taking advantage of polypharmacology</h2>
<p>The problem is that when you take a drug with multiple functions, you can’t isolate one desired effect from all the others – you get all of them all at once. Researchers can react to polypharmacology in two ways. Scientists can try to design better drugs that home in on just one specific target. Alternatively, scientists can instead embrace the complexity of biology and try to leverage the multifaceted effects drugs can offer.</p>
<p>Many existing drugs have unknown mechanisms that can be harnessed as a strength, rather than a weakness. Researchers can use polypharmacology to <a href="https://theconversation.com/repurposing-generic-drugs-can-reduce-time-and-cost-to-develop-new-treatments-but-low-profitability-remains-a-barrier-174874">repurpose existing drugs</a> to use for other conditions, reducing the time and cost of developing new treatments. There is an entire industry of doctors and scientists currently trying to do exactly that. Chemists and drug designers are also purposefully <a href="https://doi.org/10.1021/acs.jmedchem.8b00760">designing drugs with multiple functions</a> to combat complex diseases like cancer and type 2 diabetes, which may have multiple targets that can escape single-function treatments.</p>
<p>But in order to take advantage of the polypharmacology of existing drugs, researchers require a way to measure it. Typically, chemists study drug mechanisms through laborious experiments that test drugs one at a time and don’t always lead to conclusive answers. However, new experimental approaches, like <a href="https://doi.org/10.1038/s41573-022-00472-w">phenotypic drug screening</a>, that measure the overall effect of the drug instead of trying to narrow down its mechanism of action, allow researchers to measure thousands of different drugs in a single experiment.</p>
<p>My colleagues and I <a href="https://doi.org/10.1371/journal.pcbi.1009888">used this approach</a> to predict all the effects of specific drugs, using nothing but images of cells. We collected 159 million snapshots of cells reacting to over 1,300 different drugs, then applied a machine learning algorithm to identify important patterns in the images. Instead of teaching the algorithm to look for specific details, we allowed it to search for pieces of data in the pictures that allowed it to better predict how a cell would react to different types of drugs. </p>
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<figcaption><span class="caption">Machine learning can help predict how the chemical structure of any particular drug might affect the body.</span></figcaption>
</figure>
<p>Our model repurposed an approach called <a href="http://dx.doi.org/10.48550/arXiv.1511.06434">latent space arithmetic</a>, originally developed using pictures of human faces, to predict drugs with polypharmacology. Just as the original algorithm could simulate a picture of a man wearing glasses, we could simulate what a cell looks like when treated with a drug that has multiple mechanisms of action.</p>
<p>Our model was far from perfect, though. Many drug mechanisms of action could not be simulated well, and we were limited by existing, likely incomplete, knowledge about how different drugs worked. Additional work to demystify how different drug mechanisms affect cells in a wider context could help improve predicting all of a drug’s potential functions, leading to more treatment possibilities for each compound. </p>
<p>I believe that embracing polypharmacology as an unavoidable consequence of using drugs to treat diseases can help researchers reimagine the drug discovery process. Could we design a drug that targets all the receptors going haywire in a specific patient’s tumor? Could we use artificial intelligence to simulate how such a potential drug compound might look and behave in the body? Could polypharmacology actually be the answer to precision medicine instead of one of its biggest challenges? A shift in mindset might be the first step to answering these questions.</p><img src="https://counter.theconversation.com/content/184922/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gregory Way does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Many approved drugs work on the body in ways that researchers still aren’t entirely clear about. Seeing this as an opportunity instead of a flaw may lead to better treatments for complex conditions.Gregory Way, Assistant Professor of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1834212022-06-29T12:04:48Z2022-06-29T12:04:48ZMany drugs can’t withstand stomach acid – a new delivery method could lead to more convenient medications<figure><img src="https://images.theconversation.com/files/470674/original/file-20220623-60671-hmb5da.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2000%2C1500&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A new polymer could help the medicine go down easier.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/stomach-shaped-with-medication-royalty-free-image/1206781656">Hiroshi Watanabe/DigitalVision via Getty Images</a></span></figcaption></figure><p>For patients and physicians, taking medications orally is often the most desirable way to administer drugs. Among other <a href="https://www.merckmanuals.com/home/drugs/administration-and-kinetics-of-drugs/drug-administration#">advantages</a>, swallowing a pill is safer, more convenient and less invasive compared to injections or other ways to take a drug. </p>
<p>But one of the challenges oral pills face is getting digested by the stomach before they can deliver their payloads and carry out their intended effects. Because drugs that are degraded in the stomach are <a href="https://doi.org/10.3390%2Fpharmaceutics11030129">less effective</a>, many treatments are currently unable to be taken by mouth.</p>
<p>As researchers in <a href="https://scholar.google.com/citations?user=azZT0AkAAAAJ&hl=en">polymer science</a> and <a href="https://scholar.google.com/citations?user=d8rx9j8AAAAJ&hl=en">bioengineering</a>, we wanted to figure out a way to deliver drugs so that they could withstand stomach acid but still dissolve at the right place. In our <a href="https://doi.org/10.1038/s41467-022-29851-y">recently published paper</a>, we believe we have developed a new material that can help drugs do just that.</p>
<h2>Oral drug challenges</h2>
<p>Oral drugs are primarily <a href="https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-absorption#">absorbed in the small intestine</a>, where they subsequently enter the bloodstream and travel to the rest of the body. In order for a drug to get to the small intestine, however, it must first get past the <a href="https://www.healthline.com/health/how-strong-is-stomach-acid#strength">highly acidic environment</a> of the stomach, which can deteriorate medications before they can be absorbed. </p>
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<figcaption><span class="caption">This is what pills look like when they dissolve in water.</span></figcaption>
</figure>
<p>To compensate for degradation in the stomach, oral medications typically come in doses that are <a href="https://doi.org/10.1016/j.ejps.2021.105812">higher than necessary</a>. This strategy works for many common <a href="https://scholarblogs.emory.edu/techtransfer/2021/02/the-differences-between-small-molecule-drugs-and-biological-drugs/">small-molecule drugs</a> that have a low mass. They are often more stable and can more easily enter cells compared to other types of drugs. However, increasing dosage is not a viable approach for treatments that easily build up to toxic levels, are too sensitive to the acidity of the stomach or are very costly.</p>
<h2>A stomach acid-resistant material</h2>
<p>To help drugs withstand the harsh environment of the stomach, our research team developed a new type of material called <a href="https://doi.org/10.1038/s41467-022-29851-y">polyzwitterionic complexes, or pZCs</a>. pZCs are composed of two types of <a href="https://www.britannica.com/science/polymer">polymers</a>, or large molecules made of a string of repeating smaller molecules. As the name suggests, pZCs are made of <a href="https://doi.org/10.1021/acsapm.9b00897">polyzwitterions</a>, which are both positively and negatively charged, and <a href="https://doi.org/10.1021/acs.macromol.7b01929">polyelectrolytes</a>, which are exclusively positive or negative. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram comparing monomers, dimers, trimers and oligomers with polymers" src="https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/470676/original/file-20220623-51620-pjglx7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=471&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Polymers are made of individual units that repeat and combine in different ways.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/vector-scientific-illustration-of-monomer-royalty-free-illustration/1299060265">petrroudny/iStock via Getty Images</a></span>
</figcaption>
</figure>
<p>Through a process called <a href="https://doi.org/10.1002/9781119290971.ch7">complex coavcervation</a> that joins oppositely charged molecules, these two polymers self-assemble to form pZC droplets that are sensitive to acidity. In principle, these droplets could encapsulate and protect a therapeutic cargo as it travels through the highly acidic stomach, but disassemble and release the drug upon reaching the <a href="https://doi.org/10.1136%2Fgut.29.8.1035">more neutral environment</a> of the small intestine.</p>
<p>We first tested whether the pZC droplets were able to encapsulate a protein as a test cargo. Once we were successfully able to place the cargo in the droplet, we then measured how much protein cargo was released in varying levels of acidity through <a href="https://www.nist.gov/programs-projects/spectrophotometry">spectrophotometry</a>, a method that uses light absorption to measure the amount of substance present in a sample. We found that the pZC droplets retained their protein cargo in acidic conditions and steadily released it as acidity decreased.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting pZC associating at low pH levels and dissociating at high pH levels as it travels through the gastrointestinal tract" src="https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=445&fit=crop&dpr=1 600w, https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=445&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=445&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=559&fit=crop&dpr=1 754w, https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=559&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/470828/original/file-20220624-24-xso94d.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=559&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">pZC is designed to stay enveloped around its drug cargo in highly acidic environments, as in the stomach, and disassemble in less acidic environments, as in the small intestine.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41467-022-29851-y">Khatcher Margossian</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>Making drugs more convenient</h2>
<p>We believe that our pZC system can enable researchers to develop new and improved ways to deliver drugs through the gastrointestinal tract. Our future work will focus on better understanding how pZCs behave as their chemical properties change in different conditions. We are also experimenting with different types of polymers and drug cargoes.</p>
<p>Our hope is that our methods and conceptual framework will one day increase the number and variety of drugs that can be taken orally, making it more convenient to take your medicine and improving the lives of patients.</p><img src="https://counter.theconversation.com/content/183421/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Khatcher O. Margossian has received funding from the National Science Foundation. No additional conflicts of interest are declared.</span></em></p><p class="fine-print"><em><span>Murugappan Muthukumar receives funding from the National Science Foundation and the Air Force Office of Scientific Research.</span></em></p>While pills are more practical than injections or infusions, digestion in the stomach prevents many drugs from being taken orally. Better drug design could change this.Khatcher O. Margossian, MD/PhD Candidate in Polymer Science and Engineering, UMass AmherstMurugappan Muthukumar, Professor in Polymer Science and Engineering, UMass AmherstLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1824882022-06-17T12:33:45Z2022-06-17T12:33:45ZHow do drugs know where to go in the body? A pharmaceutical scientist explains why some medications are swallowed while others are injected<figure><img src="https://images.theconversation.com/files/469333/original/file-20220616-24-uw9qbz.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">While pills come in many shapes and sizes, they all eventually reach your bloodstream and travel throughout your body.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/pop-art-medicine-pill-or-tablet-icon-royalty-free-illustration/1264546155">Vadim Sazhniev/iStock via Getty Images</a></span></figcaption></figure><p>When you take aspirin for a headache, how does the aspirin know to travel to your head and alleviate the pain?</p>
<p>The short answer is, it doesn’t: Molecules can’t transport themselves through the body, and they don’t have control over where they eventually end up. But researchers can chemically modify drug molecules to make sure that they bind strongly to the places we want them and weakly to the places we don’t.</p>
<p>Pharmaceutical products contain more than just the active drug that directly affects the body. Medications also include “inactive ingredients,” or molecules that enhance the stability, absorption, flavor and other qualities that are critical to allowing the drug to do its job. For example, the aspirin you swallow also has ingredients that both prevent the tablet from fracturing during shipping and help it break apart in your body.</p>
<p>As a <a href="https://www.researchgate.net/profile/Thomas-Anchordoquy">pharmaceutical scientist</a>, I’ve been studying <a href="https://www.nibib.nih.gov/science-education/science-topics/drug-delivery-systems-getting-drugs-their-targets-controlled-manner">drug delivery</a> for the past 30 years. That is, developing methods and designing nondrug components that help get a medication where it needs to go in the body. To better understand the thought process behind how different drugs are designed, let’s follow a drug from when it first enters the body to where it eventually ends up.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Shelves of orange pill bottles" src="https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/469339/original/file-20220616-20-4bvdhf.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">Drugs aren’t sentient, but good design can help them get where doctors and patients want them to go.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/rows-of-pill-bottles-on-shelves-in-pharmacy-royalty-free-image/73092126">Andersen Ross/DigitalVision via Getty Images</a></span>
</figcaption>
</figure>
<h2>How drugs are absorbed in the body</h2>
<p>When you swallow a tablet, it will initially dissolve in your stomach and intestines before the drug molecules are <a href="https://www.britannica.com/science/drug-chemical-agent/Types-of-drugs">absorbed into your bloodstream</a>. Once in the blood, it can circulate throughout the body to access different organs and tissues.</p>
<p>Drug molecules affect the body by <a href="https://open.lib.umn.edu/pharmacology/chapter/introduction-to-drug-receptor-interactions-and-pharmacodynamics/">binding to different receptors</a> on cells that can trigger a particular response. Even though drugs are designed to target specific receptors to produce a desired effect, it is impossible to keep them from continuing to circulate in the blood and binding to nontarget sites that potentially cause unwanted side effects.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/uOcpsXMJcJk?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Many factors, like your age, genetics and diet, can affect how well your body processes a drug.</span></figcaption>
</figure>
<p>Drug molecules circulating in the blood also degrade over time and eventually leave the body in your urine. A classic example is the strong smell your urine might have after you eat asparagus because of how quickly your kidney clears <a href="https://theconversation.com/that-distinctive-springtime-smell-asparagus-pee-94696">asparagusic acid</a>. Similarly, <a href="https://www.getthegloss.com/article/ask-the-doctor-why-do-vitamins-make-my-pee-yellow">multivitamins</a> typically contain riboflavin, or vitamin B2, which causes your urine to turn bright yellow when it is cleared. Because how efficiently drug molecules can cross the intestinal lining can vary depending on the drug’s chemical properties, some of the drugs you swallow never get absorbed and are removed in your feces.</p>
<p>Because not all of the drug is absorbed, this is why some medications, like those used to treat high blood pressure and allergies, are <a href="https://www.healthymepa.com/2018/07/23/important-take-medications-time/">taken repeatedly</a> to replace eliminated drug molecules and maintain a high enough level of drug in the blood to sustain its effects on the body. </p>
<h2>Getting drugs to the right place</h2>
<p>Compared with pills and tablets, a more efficient way of getting drug into the blood is to inject it directly into a vein. This way, all the drug gets circulated throughout the body and avoids degradation in the stomach. </p>
<p>Many drugs that are given intravenously are “<a href="https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers">biologics” or “biotechnology drugs</a>,” which include substances derived from other organisms. The most common of these are a type of cancer drug called <a href="https://my.clevelandclinic.org/health/treatments/22774-monoclonal-antibody-therapy">monoclonal antibodies</a>, proteins that bind to and kill tumor cells. These drugs are injected directly into a vein because your stomach can’t tell the difference between digesting a therapeutic protein and digesting the proteins in a cheeseburger.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Nurse checking infusion bag hanging on IV pole" src="https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/469317/original/file-20220616-24-tpqvb8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Sometimes the most effective way to deliver a drug is through an infusion.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/professional-black-head-nurse-wearing-face-mask-royalty-free-image/1321691597">gorodenkoff/iStock via Getty Images</a></span>
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<p>In other cases, drugs that need very high concentrations to be effective, such as <a href="https://health.ucsd.edu/news/features/pages/2017-05-01-intravenous-antibiotics-q-and-a-ritter.aspx">antibiotics for severe infections</a>, can be delivered only through infusion. While increasing drug concentration can help make sure enough molecules are binding to the correct sites to have a therapeutic effect, it also increases binding to nontarget sites and the risk of side effects.</p>
<p>One way to get a high drug concentration in the right location is to apply the drug right where it’s needed, like rubbing an ointment onto a skin rash or using <a href="https://www.webmd.com/allergies/allergy-eye-drops">eyedrops for allergies</a>. While some drug molecules will eventually get absorbed into the bloodstream, they will be <a href="https://doi.org/10.1007/978-1-4471-3625-5_24">diluted enough</a> that the amount of drug that reaches other sites is very low and unlikely to cause side effects. Similarly, an inhaler delivers the drug directly to the lungs and avoids affecting the rest of the body.</p>
<h2>Patient compliance</h2>
<p>Finally, a key aspect in all drug design is to simply get patients to take medications in the right amounts at the right time. </p>
<p>Because remembering to take a drug several times a day is difficult for many people, researchers try to design drug formulations so they need to be <a href="http://dx.doi.org/10.1201/9781315111896-12">taken only once a day or less</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Person taking out pills from pill box" src="https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/469327/original/file-20220616-15-393l9w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Taking medications as instructed can help increase their effectiveness and reduce the risk of side effects.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/senior-woman-took-out-the-pills-from-pill-container-royalty-free-image/1289013876">violetphoto/Moment via Getty Images</a></span>
</figcaption>
</figure>
<p>Similarly, pills, inhalers or nasal sprays are more convenient than an infusion that requires traveling to a clinic for a trained clinician to inject it into your arm. The less troublesome and expensive it is to administer a drug, the more likely it is that patients will take their medication when they need it. However, sometimes infusions or injections are the only effective way that certain drugs can be administered. </p>
<p>Even with all the science that goes into understanding a disease well enough to develop an effective drug, it is often up to the patient to make it all work as designed.</p><img src="https://counter.theconversation.com/content/182488/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Tom Anchordoquy receives funding from the National Institutes of Health. </span></em></p>From tablets and patches to ointments and infusions, the best way to deliver a drug is the one that gets the right amount to the right place.Tom Anchordoquy, Professor of Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.