tag:theconversation.com,2011:/fr/topics/animal-models-13262/articlesAnimal models – The Conversation2023-08-07T12:43:56Ztag:theconversation.com,2011:article/2051102023-08-07T12:43:56Z2023-08-07T12:43:56ZZebrafish are a scientist’s favorite for early-stage research – especially to study human blood disorders<figure><img src="https://images.theconversation.com/files/540000/original/file-20230728-23-tbljsp.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C1299&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">As an animal model, the zebrafish offers many advantages that save researchers time and money.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/wBu5Uz">Uri Manor/NICHD via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Scientists have <a href="https://doi.org/10.7554/eLife.05959">relied on animal models</a> as an alternative to testing on human tissues and cells for decades. But not just any organism can adequately model how human cells behave. Researchers take into account how quickly the organism can mature, how many offspring it can produce and how often it can reproduce. When studying genetics and developmental biology, one of the most important qualities to consider is how similar the model organism’s genes are to human genes.</p>
<p>Although humans and fish certainly look very different, the zebrafish has proved to be an excellent model organism for scientists studying <a href="https://doi.org/10.1242%2Fdev.083147">hematopoiesis</a>, or the development of blood cells.</p>
<p>In the <a href="https://www.espinlab.com">Espín Lab</a> at Iowa State University, <a href="https://scholar.google.com/citations?user=O2ux60wAAAAJ&hl=en">we study</a> the early stages of blood development, particularly the birth of blood stem cells, which happens only once during embryonic development. We focus on a specific set of genes that play a significant but somewhat elusive role in the molecular pathways involved in this process. Although we want to understand how these genes work in the context of human blood development, testing on human embryos is obviously ethically impossible. To circumvent these challenges, we use zebrafish instead.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Scientist holding a small fish tank in a magenta-lit aisle of fish tanks filled with zebrafish" src="https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/540001/original/file-20230728-35025-grpb0x.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">The National Institute of Child Health and Human Development houses the largest zebrafish facility in the U.S. Each tank contains live zebrafish used in research.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/HJ4qwU">Ernesto del Aguila III/NHGRI via Flickr</a></span>
</figcaption>
</figure>
<h2>Zebrafish as a model organism</h2>
<p>Zebrafish have several traits that make them excellent model organisms.</p>
<p>For one, one female zebrafish can produce <a href="https://doi.org/10.1046/j.1365-2141.2003.04682.x">hundreds of embryos per week</a>. This is important to scientists because having larger sample numbers strengthens the accuracy of the data they collect in their experiments.</p>
<p>Zebrafish embryos are also able to develop quickly. One day of development in zebrafish is equivalent to approximately 90 days of human development. This means that researchers can save time and observe the different stages of development much sooner than with other organisms.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/BD4gqmGdFyY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">This time-lapse video shows the first 22 hours of zebrafish development after fertilization, with blood vessels labeled green. Blood has already formed at this stage of development.</span></figcaption>
</figure>
<p>Another useful quality of zebrafish is that they are <a href="https://doi.org/10.1046/j.1365-2141.2003.04682.x">translucent during early development</a>. As soon as their embryos are fertilized, scientists can observe cells and tissues form and clearly see the effects of modifying different genes.</p>
<p>Perhaps the most important feature of zebrafish for scientists is their genetic makeup. Approximately <a href="https://doi.org/10.1038/nature12111">70% of zebrafish genes</a> have similar analogs in people, allowing researchers to study how certain genes work.</p>
<h2>Studying blood disorders with zebrafish</h2>
<p>Beyond sharing a significant percentage of genes with people, zebrafish are especially useful to blood development research because they produce the <a href="https://doi.org/10.1046/j.1365-2141.2003.04682.x">same types of blood cells</a>. Just like people, zebrafish have <a href="https://doi.org/10.1016/j.bcmd.2013.07.006">erythroid</a>, <a href="https://doi.org/10.1038/nri.2017.86">lymphoid</a> and <a href="https://doi.org/10.1016/j.biocel.2004.01.020">myeloid</a> cell types that are responsible for numerous roles in the body, like circulating oxygen and regulating inflammation and immunity. Mature blood cells are derived from blood stem cells. Therefore, studying how these stem cells are made would aid in developing treatment for numerous blood disorders that rely on blood stem cell therapies, such as leukemia, lymphoma and anemia.</p>
<p>Labs like ours use zebrafish to study how specific cell signaling pathways contribute to the birth, development and maturation of these blood stem cells. This knowledge provides context for how healthy cells work and communicate, because cells rely on signals from other cells to know which genes they need to turn on to produce specific proteins and molecules. </p>
<p>For example, we have previously shown how <a href="http://dx.doi.org/10.1016/j.cell.2014.10.031">inflammatory signaling pathways</a> are needed for zebrafish to properly develop the <a href="https://doi.org/10.15283/ijsc19127">hematopoietic stem cells</a> that produce multiple kinds of blood cells. We are currently exploring how these inflammatory pathways produce human blood stem cells. While most cells receive certain signals that trigger them to express certain genes, <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 capable of developing into multiple types of cells in an organism. Stem cells are undifferentiated, meaning that they are not yet limited to expressing or following only certain parts of the DNA like more mature, differentiated cells. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of blood cells flowing through the blood vessels on the yolk of a zebrafish embryo" src="https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=473&fit=crop&dpr=1 600w, https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=473&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=473&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=594&fit=crop&dpr=1 754w, https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=594&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/540002/original/file-20230728-17-35i4pz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=594&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 blood cells (magenta) in blood vessels (yellow) on the yolk of a 2-day-old zebrafish embryo, which is roughly the size of a grain of rice.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/2j6TzAo">Daniel Castranova/National Institute of Child Health and Human Development, NIH via Flickr</a></span>
</figcaption>
</figure>
<p>For patients with blood-related disorders like leukemia, there are currently limited treatment options. <a href="https://theconversation.com/gut-bacteria-nurture-the-immune-system-for-cancer-patients-a-diverse-microbiome-can-protect-against-dangerous-treatment-complications-184427">Bone marrow transplants</a> are among these options. But there is a shortage of matching donors, and the procedure can be risky because of <a href="https://www.cancerresearchuk.org/about-cancer/coping/physically/gvhd/about">graft-versus-host disease</a>, in which the donor’s healthy immune cells attack the recipient’s body cells. </p>
<p>A possible solution is to use a special kind of stem cell called an <a href="https://doi.org/10.1038/cr.2008.309">induced pluripotent stem cell</a>. To make these cells, scientists use a special set of proteins called Yamanaka factors to turn on specific genes that revert a mature, differentiated cell into an immature, undifferentiated cell. From this point, the cells can be manipulated to express certain genes at specific times, told which part of their DNA to read or which signals to follow. </p>
<p>However, to properly direct these stem cells, researchers need a more complete understanding of the molecular signals involved and how they contribute to early blood development. To bridge these gaps, labs like ours rely on zebrafish to test their theories about the roles that certain genes and proteins play in development.</p>
<p>Model organisms like zebrafish are what allow scientists to get one step closer to solving real-world problems every day.</p><img src="https://counter.theconversation.com/content/205110/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Raquel Espín-Palazón receives funding from NIH, Carver Charitable Trust, Fundacion Seneca, American Heart Association, Iowa State University</span></em></p><p class="fine-print"><em><span>Gabrielle Dubansky 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>Of the many qualities that make the zebrafish a model organism, the fact that it shares 70% of the genes humans have makes it an ideal candidate for developmental biology research.Gabrielle Dubansky, Master's Candidate in Molecular, Cellular and Developmental Biology, Iowa State UniversityRaquel Espín-Palazón, Assistant Professor of Genetics, Development and Cell Biology, Iowa State UniversityLicensed 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/1908762022-11-23T13:19:17Z2022-11-23T13:19:17ZWhat is ethical animal research? A scientist and veterinarian explain<figure><img src="https://images.theconversation.com/files/493593/original/file-20221104-24-tgu2zn.jpg?ixlib=rb-1.1.0&rect=23%2C17%2C1972%2C1478&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Animal research's benefits are clear -- but public awareness of what it involves is not.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/woman-wearing-boiler-suit-and-mask-standing-in-room-royalty-free-image/200399533-001?phrase=%22woman%20wearing%20boiler%20suit%22&adppopup=true">Javier Pierini/DigitalVision via Getty Images</a></span></figcaption></figure><p>A <a href="https://www.reuters.com/world/europe/switzerland-vote-becoming-first-nation-ban-animal-testing-2022-02-13/">proposed measure</a> in Switzerland would have made that country the first to ban medical and scientific experimentation on animals. It failed to pass in February 2022, with only 21% of voters in favor. Yet globally, <a href="https://www.congress.gov/bill/117th-congress/house-bill/8699?s=1&r=8">including in the United States</a>, there is concern about whether animal research is ethical.</p>
<p>We are scientists who support ethical animal research that reduces suffering of humans and animals alike by helping researchers <a href="https://fbresearch.org/medical-advances/animal-research-achievements/">discover the causes of disease and how to treat it</a>. One of us is a <a href="https://scholar.google.com/citations?user=JxIoO1sAAAAJ&hl=en&oi=ao">neuroscientist</a> who studies <a href="https://www.apa.org/ptsd-guideline/treatments/prolonged-exposure">behavioral treatments</a> and <a href="https://doi.org/10.1038/s41398-022-01952-8">medications</a> for people with post-traumatic stress disorder – treatments made possible by <a href="https://doi.org/10.1016%2Fj.nlm.2013.11.014">research with dogs and rodents</a>. The other is a <a href="https://www.enprc.emory.edu/research/divisions/animal_resources/Stammen_Rachelle_L.html">veterinarian</a> who cares for laboratory animals in research studies and trains researchers on how to interact with their subjects. </p>
<p>We both place high importance on ensuring that animal research is conducted ethically and humanely. But what counts as “ethical” animal research in the first place?</p>
<h2>The 4 R’s of animal research</h2>
<p>There is no single standard definition of ethical animal research. However, it broadly means the humane care of research animals – from their acquisition and housing to the study experience itself.</p>
<p>Federal research agencies follow <a href="https://olaw.nih.gov/policies-laws/gov-principles.htm">guiding principles</a> in evaluating the use and care of animals in research. One is that the research must increase knowledge and, either directly or indirectly, have the potential to benefit the health and welfare of humans and other animals. Another is that only the minimum number of animals required to obtain valid results should be included. Researchers must use procedures that minimize pain and distress and maximize the animals’ welfare. They are also asked to consider whether they could use nonanimal alternatives instead, such as mathematical models or computer simulations.</p>
<p>These principles are summarized by the “<a href="https://flexiblelearning.auckland.ac.nz/medsci303/15/1/1/files/overview_of_3rs.pdf">3 R’s” of animal research</a>: reduction, refinement and replacement. The 3 R’s encourage scientists to develop new techniques that allow them to replace animals with appropriate alternatives. </p>
<figure class="align-center ">
<img alt="Two men bend over a microscope in an office with big glass walls overlooking water." src="https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/493596/original/file-20221104-11-6zdg0h.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">L'Oreal Brazil CEO Marcelo Zimet looks at microscope samples at the Episkin laboratory, which has developed alternative methods to animal testing.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/loreal-brazil-ceo-marcelo-zimet-looks-on-a-microscope-news-photo/1240792707?phrase=%22animal%20testing%22%20brazil&adppopup=true">Mauro Pimentel/AFP via Getty Images</a></span>
</figcaption>
</figure>
<p>Since these guidelines were first disseminated in the <a href="https://caat.jhsph.edu/principles/the-principles-of-humane-experimental-technique">early 1960s</a>, new tools have helped to <a href="https://doi.org/10.1371/journal.pone.0101638">significantly decrease</a> animal research. In fact, since 1985, the number of animals in research has been <a href="https://speakingofresearch.com/facts/statistics/">reduced by half</a>.</p>
<p>A fourth “R” was formalized in the late 1990s: <a href="https://doi.org/10.4103%2F2229-5070.113884">rehabilitation</a>, referring to care for animals after their role in research is complete.</p>
<p>These guidelines are designed to ensure that researchers and regulators consider the costs and benefits of using animals in research, focused on the good it could provide for many more animals and humans. These guidelines also ensure protection of a group – animals – that cannot consent to its own participation in research. There are a number of human groups that cannot consent to research, either, such as infants and young children, but for whom regulated research is still permitted, so that they can <a href="https://philarchive.org/archive/MARART-26">gain the potential benefits from discoveries</a>. </p>
<h2>Enforcing ethics</h2>
<p>Specific <a href="https://www.hopkinsmedicine.org/research/resources/offices-policies/animal-care/">guidelines</a> for ethical animal research are typically established by <a href="https://www.ncbi.nlm.nih.gov/books/NBK24650/">national governments</a>. <a href="https://www.aaalac.org">Independent organizations</a> also provide research standards.</p>
<p>In the U.S., the <a href="http://www.nal.usda.gov/animal-health-and-welfare/animal-welfare-act">Animal Welfare Act</a> protects all warmblooded animals except rats, mice and birds bred for research. Rats, mice and birds are protected – along with fish, reptiles and all other vertebrates – by the <a href="https://olaw.nih.gov/policies-laws/phs-policy.htm">Public Health Service Policy</a>. </p>
<p>Each institution that conducts animal research has an entity called the <a href="https://olaw.nih.gov/resources/tutorial/iacuc.htm">Institutional Animal Care and Use Committee</a>, or IACUC. The IACUC is composed of veterinarians, scientists, nonscientists and members of the public. Before researchers are allowed to start their studies, the IACUC reviews their research protocols to ensure they follow national standards. The IACUC also oversees studies after approval to continually enforce ethical research practices and animal care. It, along with the <a href="https://www.aphis.usda.gov/aphis/ourfocus/animalwelfare/SA_AWA/CT_AWA_Inspections">U.S. Department of Agriculture</a>, accreditation agencies and funding entities, may conduct unannounced inspections.</p>
<p>Laboratories that violate standards may be fined, forced to stop their studies, excluded from research funding, ordered to cease and desist, and have their licenses suspended or revoked. Allegations of misconduct are also investigated by the <a href="https://olaw.nih.gov/home.htm">National Institutes of Health’s Office of Laboratory Animal Welfare</a>.</p>
<p>Above and beyond the basic national standards for humane treatment, research institutions across 47 countries, including the U.S., may seek voluntary accreditation by a nonprofit called the <a href="https://ar.aaalac.org/about/index.cfm">Association for Assessment and Accreditation of Laboratory Animal Care</a>, or AAALAC International. <a href="https://www.unthsc.edu/research/wp-content/uploads/sites/21/Benefits-of-AAALAC-Accreditation.pdf">AAALAC accreditation</a> recognizes the maintenance of high standards of animal care and use. It can also help recruit scientists to accredited institutes, promote scientific validity and demonstrate accountability.</p>
<h2>Principles in practice</h2>
<p>So what impact do these guidelines actually have on research and animals?</p>
<p>First, they have made sure that scientists create protocols that describe the purpose of their research and why animals are necessary to answer a meaningful question that could benefit health or medical care. While computer models and cell cultures can play an important role in some research, others studies, like those on <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">Alzheimer’s disease</a>, need animal models to better capture the complexities of living organisms. The protocol must outline how animals will be housed and cared for, and who will care for and work with the animals, to ensure that they are trained to treat animals humanely. </p>
<p>During continual study oversight, inspectors look for whether animals are provided with housing specifically designed for their species’ behavioral and social needs. For example, mice are given nesting materials to create a <a href="https://med.stanford.edu/animalresearch/animal-care-and-facilities/animal-well-being-at-stanford.html">comfortable environment for living and raising pups</a>. When animals don’t have environmental stimulation, it can alter their <a href="https://doi.org/10.1016/S0166-2236(00)01718-5">brain function</a> – harming not only the animal, but also the science.</p>
<p>Monitoring agencies also consider animals’ distress. If something is known to be painful in humans, it is assumed to be painful in animals as well. Sedation, painkillers or anesthesia must be provided when animals experience more than momentary or slight pain.</p>
<p>For some research that requires assessing organs and tissues, such as the study of heart disease, animals must be euthanized. Veterinary professionals perform or oversee the euthanasia process. Methods must be in compliance with guidelines from the <a href="https://www.avma.org/resources-tools/avma-policies/avma-guidelines-euthanasia-animals">American Veterinary Medical Association</a>, which requires rapid and painless techniques in distress-free conditions. </p>
<p>Fortunately, following their time in research, some animals can be <a href="https://www.hopkinsmedicine.org/research/resources/offices-policies/animal-care/">adopted</a> into <a href="https://homesforanimalheroes.com/">loving homes</a>, and others may be retired to <a href="https://chimphaven.org">havens and sanctuaries</a> equipped with veterinary care, nutrition and enrichment.</p>
<h2>Continuing the conversation</h2>
<p>Animal research benefits both humans and animals. Numerous medical advances exist because they were initially studied in animals – from treatments for <a href="https://www.understandinganimalresearch.org.uk/application/files/7016/4380/3819/medical-advances-and.pdf">cancer</a> and <a href="https://psycnet.apa.org/doi/10.1111/j.1749-6632.1985.tb37592.x">neurodegenerative disease</a> to new techniques for surgery, <a href="https://www.ncbi.nlm.nih.gov/books/NBK218274/">organ transplants</a> and <a href="https://doi.org/10.1093/ilar.49.1.1">noninvasive imaging and diagnostics</a>. </p>
<p>These advances also benefit zoo animals, wildlife and endangered species. Animal research has allowed for the <a href="https://doi.org/10.3201%2Feid1612.100923">eradication of certain diseases in cattle</a>, for example, leading not only to reduced farm cattle deaths and human famine, but also to improved health for wild cattle. <a href="https://nap.nationalacademies.org/read/10089/chapter/7">Health care advances for pets</a> – including <a href="https://doi.org/10.1158/1535-7163.MCT-16-0637">cancer treatments</a>, effective vaccines, nutritional prescription diets and flea and tick treatments – are also available thanks to animal research.</p>
<p>People who work with animals in research have attempted to <a href="https://www.bradglobal.org/">increase public awareness</a> of <a href="https://doi.org/10.1038/s41593-022-01039-z">research standards and the positive effects</a> animal research has had on daily life. However, some have faced harassment and violence from <a href="http://www.sciencedaily.com/releases/2009/09/090915174319.htm">anti-animal research activists</a>. Some of our own colleagues have received death threats.</p>
<p>Those who work in animal research share a deep appreciation for the creatures who make this work possible. For future strides in biomedical care to be possible, we believe that research using animals must be protected, and that animal health and safety must always remain the top priority.</p>
<p><em>Editor’s note: One photo depicting a species that is highly restricted for use in biomedical research has been removed from the article.</em></p><img src="https://counter.theconversation.com/content/190876/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lana Ruvolo Grasser, Ph.D. is the 2022-2023 American College of Neuropsychopharmacology, Americans for Medical Progress Biomedical Research Awareness Day Fellow. She has previously received funding from the National Institute of Mental Health, Blue Cross Blue Shield Foundation of Michigan, and Wayne State University; none of which has supported the work described herein. She is a member of the Anxiety and Depression Association of America, International Society for Traumatic Stress Studies, International Society for Developmental Psychobiology, and Michigan Society for Neuroscience. Dr. Grasser contributed to this article in her personal capacity. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health or the United States Government. </span></em></p><p class="fine-print"><em><span>Rachelle Stammen works as a Clinical Veterinarian at the Emory National Primate Research Center. She is a member of the American Veterinary Medical Association, American Association of Laboratory Animal Science, Association of Primate Veterinarians, and a Diplomate of the American College of Laboratory Animal Medicine. This work is not affiliated with or reflect the opinions of Emory University or Emory National Primate Research Center. </span></em></p>Guidelines and regulations weigh the medical and health benefits of animal research with researchers’ ability to ensure humane care of their subjects from start to finish.Lana Ruvolo Grasser, Postdoctoral Research Fellow in Neuroscience, National Institutes of HealthRachelle Stammen, Clinical Veterinarian, Emory National Primate Research Center, Emory UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1882072022-08-31T12:27:02Z2022-08-31T12:27:02ZExpanding Alzheimer’s research with primates could overcome the problem with treatments that show promise in mice but don’t help humans<figure><img src="https://images.theconversation.com/files/481658/original/file-20220829-8371-fvt75z.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Rhesus macaques experience an aging process similar to people's.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/rhesus-macaque-royalty-free-image/993621062">Goddard Photography/E+ via Getty Images</a></span></figcaption></figure><p>As of 2022, an estimated <a href="https://doi.org/10.1002/alz.12638">6.5 million Americans</a> have Alzheimer’s disease, an illness that robs people of their memories, independence and personality, causing suffering to both patients and their families. That number may double by 2060. The U.S. has made <a href="https://doi.org/10.1126/science.361.6405.838">considerable investments</a> in Alzheimer’s research, having allocated <a href="https://www.alz.org/news/2022/increase-in-federal-alzheimers-and-dementia-resear">US$3.5 billion in federal funding</a> this year. </p>
<p>Why, then, are researchers no closer to a cure today than they were 30 years ago? </p>
<p>Back in 1995, researchers created the <a href="https://doi.org/10.1038/373523a0">first transgenic mouse model</a> of Alzheimer’s disease, which involved genetically modifying mice to carry a gene associated with early-onset Alzheimer’s. Myriad studies have since focused on mouse models that accumulate <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">abnormal proteins</a> in their brains, a hallmark of the disease. Although these studies made great strides in understanding specific mechanisms involved in the disease, they have <a href="https://doi.org/10.1002/trc2.12114">failed to translate</a> into effective treatments.</p>
<p>As <a href="https://scholar.google.com/citations?user=LWCllSsAAAAJ">research</a> <a href="https://scholar.google.com/citations?hl=en&user=0tW5idcAAAAJ">scientists</a> <a href="https://psych.wisc.edu/staff/bennett-allyson/">working</a> with nonhuman primates, we believe that part of the problem is that mice don’t reflect the full spectrum of Alzheimer’s disease. A more complementary animal model, however, could help researchers better translate the results from animal studies to humans. </p>
<h2>Why animal models?</h2>
<p>A critical aspect of understanding what goes awry in Alzheimer’s disease is the relationship between brain and behavior. Researchers rely heavily on animal models to do these types of studies because <a href="https://grants.nih.gov/grants/policy/air/why.htm">ethical and practical issues</a> make them impossible to conduct in people.</p>
<p>In recent years, researchers have developed <a href="https://doi.org/10.15252/embj.2021110002">alternative methods</a> to study Alzheimer’s, such as computer models and cell cultures. Although these options show promise for advancing Alzheimer’s research, they don’t supersede the need for animal models because of important limitations.</p>
<p>One is their inability to replicate the complexity of the human brain. The human brain has an estimated <a href="https://doi.org/10.1002/cne.21974">86 billion neurons</a> that perform highly complex computations. While computer models can simulate the workings of specific neural circuits, they are unable to fully capture these complex interactions and work best when used <a href="https://doi.org/10.1016/j.neuron.2021.07.015">in concert with animal models</a>.</p>
<p>Similarly, cell cultures and brain organoids – miniature brains derived from human stem cells – are <a href="https://doi.org/10.3389/fphar.2020.00396">unable to adequately mimic</a> the aging process and all the ways the components of the human body interact with one another.</p>
<p>As a result of these limitations, researchers turn to animal models that better reflect human biology and disease processes.</p>
<h2>The problem with mice</h2>
<p>According to the National Association for Biomedical Research, approximately <a href="https://www.science.org/content/article/how-many-mice-and-rats-are-used-us-labs-controversial-study-says-more-100-million">95% of lab research conducted in animals in the U.S.</a> is done in mice and rats. Alzheimer’s is no exception: For more than 25 years, research on Alzheimer’s has <a href="https://doi.org/10.1002/cpns.81">focused on using transgenic mice</a> to better understand the biological changes associated with the disease.</p>
<p>Because mice do not naturally get Alzheimer’s, they are genetically engineered to develop <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">abnormal proteins</a> known as amyloid plaques and neurofibrillary tau tangles to mimic Alzheimer’s in their brains. These protein accumulations impair brain function and are associated with memory impairment. While studies on <a href="https://doi.org/10.1038/35050110">treatments that remove these proteins</a> have been able to improve cognition in mice, similar interventions have failed in people.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Four white mice in a cage" src="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.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">Many Alzheimer’s studies have been conducted in transgenic mice.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/white-research-mice-royalty-free-image/170617385">filo/E+ via Getty Images</a></span>
</figcaption>
</figure>
<p>This highlights the challenge of <a href="https://doi.org/10.1002/trc2.12114">translating animal research</a> in the lab to people in the clinic. Mouse studies often mirror only a single aspect of the disease that may not be directly relevant to people. For example, most transgenic mouse models focus on amyloid protein buildup while <a href="https://mitpress.mit.edu/9780262546010/how-not-to-study-a-disease/">neglecting other crucial aspects</a> of the disease, such as overall neurodegeneration. Such limitations have led some scientists to <a href="https://doi.org/10.3390/ijms222313168">question the value of using mouse models for Alzheimer’s research</a>. </p>
<p>It is important to recognize, however, that scientific knowledge often advances in <a href="https://www.statnews.com/2015/12/02/science-groundbreaking/">incremental steps</a> through the collective results of many studies using different methods and models. Rodent studies provide the necessary foundation for animal models that better mimic the full scope of Alzheimer’s – such as nonhuman primates.</p>
<h2>Nonhuman primates offer a closer model</h2>
<p>The specific features of a species – including brain structure, cognitive ability, life span and the extent to which they show the hallmarks of Alzheimer’s – determine how suitable it is for specific research questions. Based on these factors, we believe that nonhuman primates are particularly well suited for Alzheimer’s research.</p>
<p><a href="https://primate.wisc.edu/primate-info-net/pin-factsheets/">Primates</a> are a diverse group of mammals that includes humans, apes, monkeys and prosimians. Nonhuman primates are particularly valuable for understanding <a href="https://doi.org/10.1002/ajp.23309">human aging</a> and <a href="https://doi.org/10.1073/pnas.1912954116">Alzheimer’s disease</a> because their genetic makeup, brain, behavior, physiology and aging process closely resemble those of people. Aging monkeys experience cognitive, physical and sensory decline as well as a variety of illnesses, such as cancer and cardiovascular disease, much like aging people. Perhaps most critical for Alzheimer’s research, nonhuman primates live much longer than rodents and can <a href="https://doi.org/10.1002/ajp.23299">naturally develop some of the hallmarks associated with Alzheimer’s</a> as they get older. </p>
<p>Using nonhuman primates in research <a href="https://www.nature.com/articles/d41586-021-01894-z">faces some challenges</a>. Compared to mice, nonhuman primates are more expensive to house and feed, and face a growing shortage in research facilities. Nonhuman primates are also prime targets for activists seeking to stop the use of animals in research. Yet, in light of ongoing failures with rodent models, nonhuman primates could significantly help scientists better understand and treat Alzheimer’s. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Scientist looking at brain MRIs on multiple computer screens" src="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.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">Animal models pave the way for clinical research in humans.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/female-radiologist-analysing-the-mri-image-of-the-royalty-free-image/1326240246">simonkr/E+ via Getty Images</a></span>
</figcaption>
</figure>
<p>Scientists study Alzheimer’s in nonhuman primates in a number of ways.</p>
<p>In one approach, researchers examine species with short life spans, such as <a href="https://doi.org/10.1002/ajp.23337">gray mouse lemurs</a> or <a href="https://doi.org/10.1002/ajp.23271">common marmosets</a>, to measure how brain and behavior naturally change with age and identify potential predictors of disease. Other researchers may instead accelerate the disease process by <a href="https://doi.org/10.1002/ajp.23289">inducing plaque</a> or <a href="https://doi.org/10.1002/alz.12318">tangle formation</a> in the brains of longer-lived species, like rhesus macaques. These approaches yield studies that are particularly promising for testing treatments in a short time frame.</p>
<p>A third approach takes advantage of recent advances in genomics to study marmosets <a href="https://doi.org/10.1002/alz.049952">born with genetic mutations</a> involved in Alzheimer’s. This method provides the opportunity to test preventive treatments during early life, well before any sign of the disease appears. </p>
<p>Lastly, <a href="https://doi.org/10.1002/ajp.23254">comparing Alzheimer-like patterns across primate species</a> may help reveal critical risk factors for developing the disease, which could be reduced to promote healthy aging.</p>
<p>We believe that research in nonhuman primates, when conducted with the highest <a href="https://doi.org/10.1016/j.neuroimage.2020.117700">ethical standards</a>, provides the best chance to understand how and why Alzheimer’s disease progresses, and to design treatments that are safe and effective in people.</p><img src="https://counter.theconversation.com/content/188207/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Agnès Lacreuse receives funding from NIH, serves on the American Psychological Association Committee for Animal Research and Ethics and volunteers for Speaking of Research</span></em></p><p class="fine-print"><em><span>Allyson Bennett serves on the Board of Directors for Public Responsibility for Medicine & Research and volunteers for Speaking of Research.
</span></em></p><p class="fine-print"><em><span>Amanda M. Dettmer volunteers for Speaking of Research.</span></em></p>Nonhuman primates like rhesus monkeys share certain characteristics with people that may make them better study subjects than mice for research on neurodegenerative diseases.Agnès Lacreuse, Professor of Behavioral Neuroscience, UMass AmherstAllyson J. Bennett, Professor of Psychology, University of Wisconsin-MadisonAmanda M. Dettmer, Associate Research Scientist, Yale UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1825582022-05-12T15:51:53Z2022-05-12T15:51:53ZLab-grown mini-brains could help find treatments for Alzheimer’s and other diseases<figure><img src="https://images.theconversation.com/files/462026/original/file-20220509-11-qljz0l.png?ixlib=rb-1.1.0&rect=9%2C6%2C1002%2C1016&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It is possible to grow cells from a skin sample in a Petri dish and transform them into neurons in about a month.</span> <span class="attribution"><span class="source">(Camille Pernegre)</span>, <span class="license">Author provided</span></span></figcaption></figure><p>To assess whether a compound holds promise for treating a disease, researchers usually begin by studying its use in animals. This allows us to see if the compound has a chance of curing the disease. </p>
<p>Animal models, however, rarely reproduce all aspects of a disease. The alternative is to represent the disease in cell cultures. While at first glance, Petri dishes look quite different from a person with a disease, the reality could be quite different when you look at them more closely.</p>
<hr>
<p>
<em>
<strong>
À lire aussi :
<a href="https://theconversation.com/quels-types-doublis-sont-les-plus-lies-a-la-maladie-dalzheimer-162905">Quels types d’oublis sont les plus liés à la maladie d’Alzheimer ?</a>
</strong>
</em>
</p>
<hr>
<p>Alzheimer’s has been cured more than <a href="https://doi.org/10.1002/trc2.12179">400 times in laboratories</a>. How then can we still consider Alzheimer’s to be incurable? The reason is that it has only been cured <a href="https://dx.doi.org/10.1111%2Fjoim.12191">in animals</a>. </p>
<p>A mouse does not naturally develop Alzheimer’s, it must be induced. To do this, scientists use our limited knowledge of what triggers Alzheimer’s and reproduce it in mice. In short, these mice don’t have Alzheimer’s: they have our flawed conception of Alzheimer’s.</p>
<p>As a doctoral student in psychology, I completed a research internship at the University of Montréal Health Centre (CHUM) in the laboratory of Professor Nicole Leclerc, with the goal of developing new models to study Alzheimer’s while discarding our limited theories about the disease.</p>
<p>In modern science, a new, untested compound <a href="https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research">cannot be used to treat a human disease</a> because it poses an unacceptable risk. Therefore, a disease model, which replicates our observations of the disease in humans, is used to test whether the new compound shows promise. Disease models, which often involve animals, allow researchers to develop treatments and diagnostic tools. They also give us the opportunity to better understand the <a href="https://dx.doi.org/10.1016%2FB978-0-12-811710-1.00008-2">processes behind the disease being studied</a>. Models are an essential tool in biomedical science.</p>
<h2>Disease models of the future</h2>
<p>Studying a disease would be easier if we could directly observe and act on the cells that stop functioning properly. In the case of Alzheimer’s, it is impossible to take a slice of brain from a living person to experiment on the neurons inside. </p>
<p>However, I am working on developing a technique that will come very close to replicating that process. By taking a small piece of skin from the patient, I can grow the cells in a Petri dish and turn them into neurons in about a month.</p>
<figure class="align-center ">
<img alt="Hand of a man wearing blue rubber gloves and holding a blue liquid sample in a Petri dish in a chemistry lab" src="https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/459169/original/file-20220421-23-qo7498.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">While at first glance the Petri dish looks quite different from a person with a disease, the reality could be quite different when you look at them more closely.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>The method takes advantage of the fact that all of the cells in a person’s body have the same genetic code. What differentiates a skin cell from a neuron is simply the genes the cell expresses. This means I can force a skin cell to express typical neuronal genes so that it is gradually transformed into a neuron. </p>
<p>These neurons retain the signatures of aging, which are crucial for studying age-related diseases. The advantages are clear: one can produce a colony of human neurons from a person with Alzheimer’s. The neurons from Alzheimer’s patients will then develop <a href="https://www.sciencedirect.com/science/article/pii/S1934590921001612">Alzheimer’s characteristics</a>, making it easier to study the disease.</p>
<p>However, the neuron does not function in a vacuum; other cell types interact with it. To improve a neuronal culture, researchers can push the concept even further by producing <a href="https://www.frontiersin.org/articles/10.3389/fcell.2020.579659/full">organoids</a>. These are cell cultures comprising several types of cells. A brain organoid could more accurately re-create brain function, and be a better model of nervous system diseases.</p>
<h2>Versatile disease models</h2>
<p>If a cell functions abnormally in a person with a particular disease, we will try to understand its behaviour. By observing a model of the disease, we can find out if this abnormal functioning is similar to that observed in the brains of actual patients. If it is, we can try to modify the cell function in our model to see if there is a beneficial effect.</p>
<p>The primary function of models is to make it easier to study a disease. A good model must represent the disease as reliably as possible. When a model is considered sufficiently representative of the disease, it can be used in preclinical studies to verify whether a compound has the potential to cure it without being harmful. </p>
<p>When the disease is well reproduced by the model, researchers can assume that a treatment that works on it will be likely to work in people with the disease. Cell cultures and organoids from patients are particularly promising because of this. Even if we don’t know all the features of a disease, there is a chance that these will also be replicated in the models.</p>
<p>Because these models come from real patients, they could be used for a third unique purpose in the future: <a href="https://doi.org/10.1186/s13619-020-00059-z">personalized medicine</a>. Patients with the same disease are heterogeneous and may not respond in the same way to a treatment. When several types of therapies exist, we rely on trial and error to identify the best one for each patient.</p>
<p>In 2021, Kimberly K. Leslie’s team at the University of Iowa demonstrated that organoids might remedy this problem. They used endometrial and ovarian cancer tissues from patients to create organoids, <a href="https://www.mdpi.com/2072-6694/13/12/2901">showing their potential to evaluate different treatments</a>. In the same year, a team from Singapore and Hong Kong demonstrated that organoids could be used to <a href="https://doi.org/10.3389/fonc.2021.622244">predict the response of nasopharyngeal tumours to radiation therapy and adjust the dose</a>. </p>
<p>This method may make it possible to select the most promising treatment for an individual in a much shorter time. But it has only been tested in animal models and cell extracts, and its feasibility in humans has yet to be proven.</p>
<h2>Promising, but imperfect models</h2>
<p>A treatment that works in a disease model will not necessarily work in humans. This is precisely why Alzheimer’s, or at least its reconstruction in a laboratory animal model, has been “cured” more than 400 times but not in humans. </p>
<p>Similarly, it is possible that compounds that slow the progression of Alzheimer’s have failed to cure these animals, and have been discarded. For neurodegenerative diseases like Alzheimer’s, creating a representative model is particularly complex since the disease does not have a single cause. We know of <a href="https://pubs.rsc.org/en/content/chapterhtml/2022/bk9781839162305-00001?isbn=978-1-83916-230-5&sercode=bk">hundreds of processes that are thought to be deregulated by Alzheimer’s</a>, involving the nervous, cardiovascular and immune systems.</p>
<p>It is not yet possible to reproduce these interactions in cell cultures. Even if future models allow researchers to better represent the disease, and perhaps discover treatments, they will always be imperfect. So, finding a cure in a model will never be the same as identifying a cure for a disease.</p><img src="https://counter.theconversation.com/content/182558/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Étienne Aumont has received a scholarship from the Canadian Institutes of Health Research</span></em></p>Cell cultures have shown promise in representing diseases. The Petri dish is not as different from a sick person as one might think.Étienne Aumont, Étudiant au doctorat en psychologie, Université du Québec à Montréal (UQAM)Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1627432021-07-21T12:16:19Z2021-07-21T12:16:19ZInsulin was discovered 100 years ago – but it took a lot more than one scientific breakthrough to get a diabetes treatment to patients<figure><img src="https://images.theconversation.com/files/412304/original/file-20210720-15-sb91vs.jpg?ixlib=rb-1.1.0&rect=0%2C91%2C2902%2C2241&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A single brilliant insight is only part of the story of how diabetes became a manageable disease.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/diabetic-girl-injecting-her-arm-with-insulin-news-photo/3324678">Douglas Grundy/Three Lions via Getty Images</a></span></figcaption></figure><p>Diabetes was a fatal disease before insulin was discovered on July 27, 1921. A century ago, people diagnosed with this <a href="https://www.niddk.nih.gov/-/media/Files/Strategic-Plans/Diabetes-in-America-2nd-Edition/chapter10.pdf">metabolic disorder usually survived only a few years</a>. Physicians had no way to treat their diabetic patients’ dangerously high blood sugar levels, which were due to a lack of the hormone insulin. Today, though, nearly <a href="https://www.diabetes.org/resources/statistics/statistics-about-diabetes">1.6 million</a> Americans are living normal lives with Type 1 diabetes thanks to the discovery of insulin.</p>
<p>This medical breakthrough is usually attributed to one person, Frederick Banting, who was searching for a cure for diabetes. But getting a reliable diabetes treatment depended on the research of two other scientists, Oskar Minkowski and Søren Sørensen, who had done earlier research on seemingly unrelated topics. </p>
<p><a href="https://scholar.google.com/citations?user=Itgu0QwAAAAJ&hl=en&oi=ao">I’m a biomedical engineer</a>, and I teach a course on the history of the treatment of diabetes. With my students, I emphasize the importance of unrelated basic research in the development of medical treatments. The story of insulin illustrates the point that medical innovations build on a foundation of basic science and then require skilled engineers to get a treatment out of the lab and to the people who need it.</p>
<h2>Basic research pointed to the pancreas</h2>
<p><a href="https://doi.org/10.4239/wjd.v7.i1.1">Diabetes had been known since antiquity</a>. The first symptoms were often a prodigious thirst and urination. Within weeks the patient would be losing weight. Within months, the patient would enter a coma, then die. For centuries, no one had any clue about what caused diabetes.</p>
<p>People had, though, been aware of the pancreas for centuries. The <a href="https://doi.org/10.1016/0002-9610(83)90286-6">Greek anatomist Herophilos</a> first described it around 300 B.C. Based on its anatomical location, people suspected it was involved in the digestive system. But no one knew whether the pancreas was an essential organ, like the stomach, or extraneous, like the appendix.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Portrait of a bearded man with glasses" src="https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=855&fit=crop&dpr=1 600w, https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=855&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=855&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1075&fit=crop&dpr=1 754w, https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1075&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/412040/original/file-20210720-25-1i67eeo.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1075&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Oskar Minkowski discovered the pancreatic origin of diabetes almost by accident.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Minkowski.JPG">Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>In 1889, <a href="https://doi.org/10.1007/BF00271257">Oskar Minkowski</a>, a pathologist at the University of Strassburg, in what was then Germany, was one of the most talented surgeons of his time. As part of a study, he performed a surgical feat that was thought to be impossible: keeping an animal alive after totally removing its pancreas.</p>
<p>The dog he operated on survived the surgery, but to Minkowski’s surprise, it began exhibiting all the symptoms of diabetes. Minkowski had discovered that removing the pancreas caused diabetes. Today, this is known as an animal model of the disease. Once an animal model of a disease is established, researchers can experiment with different cures in the animal in hopes they’ll find something that will then work in people.</p>
<p>Can you grind up a pancreas and feed it to a diabetic animal to cure or alleviate the symptoms of diabetes? No, that didn’t work. The problem, understood in today’s terms, is that the pancreas has two functions: producing enzymes for the digestive system and producing insulin. Mixed together, the digestive enzymes destroyed the insulin.</p>
<h2>Isolating the insulin</h2>
<p>In 1920, Fred Banting, a small-town doctor in London, Ontario, had an idea. He thought that he could surgically tie off the ducts between the pancreas and the digestive system in an animal. Wait for a few weeks, while the part of the pancreas that produces those digestive enzymes decays, then remove the pancreas completely. This decayed pancreas, he thought, would contain the insulin, but not the destructive enzymes.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="two men in early 20th C clothes standing with a dog between them" src="https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=816&fit=crop&dpr=1 600w, https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=816&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=816&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1025&fit=crop&dpr=1 754w, https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1025&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/412303/original/file-20210720-27-tr5jkz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1025&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Charles Best (left) and Frederick Banting with one of the first dogs to be kept alive with insulin.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/discoverers-of-insulin-charles-best-and-frederick-banting-news-photo/2667496">Hulton Archive via Getty Images</a></span>
</figcaption>
</figure>
<p>On July 27, 1921, he concluded this experiment <a href="https://insulin.library.utoronto.ca/">in the laboratory of J.J.R. Macleod</a> at the University of Toronto. Banting, working with a Toronto student named Charles Best, prepared an extract from the atrophied pancreas of a dog. Then he injected the extract into another dog that had induced diabetes, due to the removal of its pancreas. The animal’s diabetes symptoms began to disappear.</p>
<p>Although Banting’s experiment was successful, his method of insulin purification was impractical. J.J.R. Macleod assigned the biochemist James Collip the task of coming up with a practical method of purifying insulin from a pancreas.</p>
<p>Collip developed a method based on alcohol purification. The concept was simple: He’d mash up a fresh pig pancreas, readily available from butcher shops, and mix it into a solution of alcohol and water. Collip slowly increased the percentage of alcohol in the solution. He found that the insulin would stay dissolved in the solution until he reached a critical concentration of alcohol, then it would suddenly fall out of solution, no longer dissolved in the liquid. By collecting that solid precipitate at the bottom of a flask, he had a purified form of insulin.</p>
<p>Collip’s extraction of insulin allowed Banting and others at the University of Toronto Hospital to <a href="https://insulin100.utoronto.ca/">begin treating patients</a>. The first injections took place in January 1922. Within weeks, the results were miraculous. These injections of insulin helped dozens of patients who were close to dying regain normal activities. Word spread. Demand for insulin increased.</p>
<h2>Insight from a brewery</h2>
<p>But disaster struck when Collip failed to purify larger batches of insulin. He was puzzled why, following the exact same recipe as he’d used before, his preparations lacked insulin. J.J.R. Macleod now turned to Eli Lilly and Company, a commercial firm in Indiana that made medicinal capsules, for help.</p>
<p>At Eli Lilly, <a href="https://doi.org/10.1093/clinchem/48.12.2270">the purification problem fell to George Walden</a>, a 27-year-old chemist. Walden thought of a measure that Danish chemist <a href="https://doi.org/10.1038/143629a0">Søren Sørensen</a> had introduced a dozen years before. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="beer with analysis tools at a brewery" src="https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/412305/original/file-20210720-19-ejtxrh.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">The equipment has changed, but breweries still monitor the pH of their beers.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/still-life-analyze-still-life-beer-brewery-analysis-ph-news-photo/883613366">Stanzel\ullstein bild via Getty Images</a></span>
</figcaption>
</figure>
<p>Sørensen was the director in the early 1900s of the Carlsberg Laboratory, set up by the beer company to advance the science of brewing. He introduced the concept of pH as a way to quantify the acidity of a solution. A higher pH during the brewing stage leads to a more bitter-tasting beer.</p>
<p>When Walden measured the pH of the pancreas solution, he discovered that the acidity was far more important to the solubility of insulin than the alcohol concentration. He set up a purification procedure like Collip’s but based on pH rather than alcohol concentration. Collip’s failure to scale up purification of insulin was probably because he neglected to control the pH of the solution carefully.</p>
<p>This insight allowed for mass production of insulin.</p>
<h2>Vanquishing a human disease</h2>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="ampules of commercial insulin from the 1920s" src="https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=652&fit=crop&dpr=1 600w, https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=652&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=652&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=820&fit=crop&dpr=1 754w, https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=820&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/412306/original/file-20210720-23-181jgrc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=820&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Insulin samples from the 1920s.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/still-life-analyze-still-life-beer-brewery-analysis-ph-news-photo/883613366">Science & Society Picture Library via Getty Images</a></span>
</figcaption>
</figure>
<p>By May 1924, diabetes was no longer a fatal disease. Physician Joseph Collins, writing in The New York Times, described it this way: “One by one the implacable enemies of man, the diseases which seek his destruction, are overcome by Science. <a href="https://www.nytimes.com/1923/05/06/archives/diabetes-dreaded-disease-yields-to-new-gland-cure-previous-claims.html">Diabetes, one of the most dreaded, is the latest to succumb</a>.”</p>
<p>Today, the implacable enemies of man include cancer, Alzheimer’s disease and schizophrenia. The cures for each will likely be built from advances made by basic research.</p>
<p>[<em>Get our best science, health and technology stories.</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-best">Sign up for The Conversation’s science newsletter</a>]</p><img src="https://counter.theconversation.com/content/162743/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>James P. Brody has in the past received funding from the National Science Foundation, the National Institutes of Health and the US Department of Defense.</span></em></p>A biomedical engineer explains the basic research that led to the discovery of insulin and its transformation into a lifesaving treatment for millions of people with diabetes.James P. Brody, Professor of Biomedical Engineering, University of California, IrvineLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/928332018-06-07T20:28:00Z2018-06-07T20:28:00ZTraffic is complex, but modelling using deceptively simple rules can help unravel what’s going on<p><em>This is the fourth article in our series, <a href="https://theconversation.com/au/topics/moving-the-masses-54500">Moving the Masses</a>, about managing the flow of crowds of individuals, be they drivers or pedestrians, shoppers or commuters, birds or ants.</em></p>
<hr>
<p>Scientists, engineers and economists have used equations to solve real-world problems since the invention of basic addition and subtraction. Not sure how to price your apple harvest? Use a supply-and-demand equation to find the ideal price. It seems there’s an equation for everything in life. </p>
<p>Equations are great for modelling well-defined problems where the rules do not change, and as such have been the backbone of pure science. But in today’s ever-growing, fast-shifting society, many problems are too complex to model with a single equation. So how do we deal with complex phenomena such as traffic, the subject of this Conversation series? To that end, <a href="https://en.wikiquote.org/wiki/Discourse_on_the_Method">Descartes gave us a hint</a> many years ago:</p>
<blockquote>
<p>Divide each difficulty into as many parts as feasible and necessary to resolve it.</p>
</blockquote>
<p><a href="http://www.agent-based-models.com/blog/2010/03/30/agent-based-modeling/">Agent-based modelling</a> (ABM) is an approach that encapsulates this philosophy and has been gaining in popularity for the past decade. Instead of treating the problem as one entity, ABM looks at modelling the behaviour of each of the smaller elements (agents) within the system.</p>
<p>It is a bottom-up approach where macro outcomes are derived from the activities of individual micro actors. As the agents interact, you gain a better understanding of the system as a whole. </p>
<h2>So how does this work for traffic?</h2>
<p>Let’s take the example of a <a href="https://www.citylab.com/transportation/2013/09/fantastically-clear-concise-explanation-why-traffic-happens/6962/">traffic jam</a>. Conventionally, scientists have used sophisticated analytical approaches, such as <a href="https://www.wired.com/2010/06/st_equation_traffic/">equations</a>, that treat traffic like a flow of liquid. Interestingly, we can replicate the same traffic phenomena by modelling individual cars with two simple rules:</p>
<ol>
<li><p>If there’s a car in front of you, slow down.</p></li>
<li><p>If there aren’t any cars in front of you, speed up (while obeying the speed limit).</p></li>
</ol>
<p>These rules are essentially descriptions of what a rational person would do while driving. One could presume that to cause a traffic jam we would need an additional factor such as police checks or traffic accidents. Traffic jams do not just happen by themselves – or do they?</p>
<p>It turns out that those two rules are enough to naturally cause a traffic jam. A traffic jam can occur purely out of internal interactions between cars, and not because of any external factor. In this phenomenon, a <a href="https://www.newscientist.com/article/dn13402-shockwave-traffic-jam-recreated-for-first-time/">congestion “shockwave”</a> travels in the direction opposite to the direction of the cars. </p>
<p>Researchers from several Japanese universities recreated this phenomenon with real cars back in 2008, as shown in the video below.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Suugn-p5C1M?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">A shockwave traffic jam recreated.</span></figcaption>
</figure>
<p>When an unexpected phenomenon results from the interactions between individuals (agents), this is called emergent behaviour. It is this unique property of agent-based modelling that gives it an advantage over conventional models.</p>
<p>Another benefit is that it is very intuitive to develop an agent-based model. Instead of having to understand the mechanics of traffic jams, all you need to do is define the rules that govern the behaviour of individual cars. It shouldn’t be too surprising that two high school students from Boston originally built the earlier traffic jam model more than 20 years ago. </p>
<p>A good example that demonstrates ABM’s intuitive nature is the modelling of flocking behaviour in birds. It’s <a href="https://www.sciencenews.org/article/birds-turns-match-math-quantum-matter">fantastically difficult</a> to model mathematically, but flocking behaviour can be replicated in agent-based modelling using <a href="http://www.cs.toronto.edu/%7Edt/siggraph97-course/cwr87/">three simple governing rules</a>: </p>
<p><strong>1. Separation:</strong> steer to avoid crowding local flockmates </p>
<p><img src="https://cdn.theconversation.com/static_files/files/155/01-Separation-v2.gif?1528257919" width="100%">
</p><figure><figcaption>Adapted from <a href="https://www.red3d.com/cwr/boids/" target="_blank">original graphic</a> by Craig Reynolds.</figcaption></figure><p></p>
<p><strong>2. Alignment:</strong> steer towards the average heading of local flockmates</p>
<p><img src="https://cdn.theconversation.com/static_files/files/157/02-Alignment-v2.gif?1528257919" width="100%">
</p><figure><figcaption>Adapted from <a href="https://www.red3d.com/cwr/boids/" target="_blank">original graphic</a> by Craig Reynolds.</figcaption></figure><p></p>
<p><strong>3. Cohesion:</strong> steer to move towards the average position of local flockmates.</p>
<p><img src="https://cdn.theconversation.com/static_files/files/156/03-Cohesion-v2.gif?1528257919" width="100%">
</p><figure><figcaption>Adapted from <a href="https://www.red3d.com/cwr/boids/" target="_blank">original graphic</a> by Craig Reynolds.</figcaption></figure><p></p>
<p>The resulting model is remarkably similar to real life. The three rules successfully bring out the emergent phenomenon of flocking behaviour.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/MvmN5o6dZ8s?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Daniel Shiffman’s implementation of Craig Reynold’s Boids program to simulate flocking. Each bird steers itself based on rules of avoidance, alignment and cohesion.</span></figcaption>
</figure>
<h2>From playful toy to policy tool</h2>
<p>In addition to traffic management, agent-based modelling has practical applications in other fields. For example, to understand how infectious diseases such as MERS spread through a city, the author has developed a large-scale <a href="https://www.informs-sim.org/wsc17papers/includes/files/233.pdf">ABM simulation</a> that models each individual living in his home town, Suwon, in South Korea. </p>
<p>The governing rules are simple: </p>
<ol>
<li>In the daytime, individuals go to work (or school, depending on their age) and interact with their colleagues (or classmates).</li>
<li>At night, individuals return home to spend time with their family.</li>
<li>Individuals can become infected when interacting with a sick person. </li>
</ol>
<p>Through this simple set of interactions, a vast network of secondary contacts is formed, through which a disease can spread. To ensure that the results represent the city accurately, we carefully selected each individual’s age, gender, family members, and home and work locations, to ensure that they matched regional census statistics on housing, labour and education. </p>
<p>The results revealed that prevention efforts should focus on key schools, where most of the disease spread takes place.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=254&fit=crop&dpr=1 600w, https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=254&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=254&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=319&fit=crop&dpr=1 754w, https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=319&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/213063/original/file-20180404-189801-w2wpb.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=319&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Close-up of Suwon city showing all residential buildings. Individuals spend their time with their family within each house, and interact with neighbours from nearby.</span>
<span class="attribution"><span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Beyond the above examples, ABM has practical applications in <a href="https://www.anylogic.com/a-pharmaceutical-company-used-agent-based-modeling-to-decide-on-a-marketing-strategy/">marketing</a>, <a href="https://ops.fhwa.dot.gov/trafficanalysistools/index.htm">traffic management</a>, and <a href="http://biomedicalcomputationreview.org/content/biology-interacting-things-intuitive-power-agent-based-models">biomedical</a> fields. As computational power increases, this modelling approach is limited only by imagination in its implementation and use. </p>
<hr>
<p><em>You can find other articles in the series <a href="https://theconversation.com/au/topics/moving-the-masses-54500">here</a>.</em></p><img src="https://counter.theconversation.com/content/92833/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Yohan Kim have received funding from National Research Foundation of Korea for his research on Suwon city.</span></em></p><p class="fine-print"><em><span>Jay Falletta and Scott Kelly 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>By identifying and applying the key rules governing the behaviour of each individual, agent-based modelling offers insights into complex phenomena like traffic jams and flocking.Yohan Kim, Research Principal, Institute for Sustainable Futures, University of Technology SydneyJay Falletta, Research Assistant, Institute for Sustainable Futures, University of Technology SydneyScott Kelly, Research Principal, University of Technology SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/931832018-03-14T10:49:47Z2018-03-14T10:49:47ZControversial brain study has scientists rethinking neuron research<figure><img src="https://images.theconversation.com/files/210020/original/file-20180313-30954-l9is0w.jpg?ixlib=rb-1.1.0&rect=289%2C0%2C3156%2C1922&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Could it be that a baby has all the brain cells she ever will?</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/2Lb835v61Qo">Jv Garcia on Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Scientists have known for about two decades that some neurons – the fundamental cells in the brain that transmit signals – are <a href="http://www.jneurosci.org/content/22/3/614">generated throughout life</a>. But now a controversial new study from the University of California, San Francisco, casts doubt on whether many <a href="https://doi.org/10.1038/nature25975">neurons are added to the human brain after birth</a>.</p>
<p><a href="https://scholar.google.com/citations?user=J8IBQ_8AAAAJ&hl=en">As a translational neuroscientist</a>, this work immediately piqued my interest. It has direct implications for the <a href="http://naegelelab.research.wesleyan.edu">research my lab does</a>: We transplant young neurons into damaged brain areas in mice in an attempt to treat epileptic seizures and the damage they’ve caused. Like many labs, part of our work is based on a foundational belief that the hippocampus is a brain region where new neurons are born throughout life.</p>
<p>If the new study is right, and human brains for the most part don’t add new neurons after infancy, researchers like me need to reconsider the validity of the animal models we use to understand various brain conditions – in my case temporal lobe epilepsy. And I suspect other labs that focus on conditions including drug addiction, depression and post-traumatic stress disorder are thinking about what the UCSF study means for their investigations, too. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=473&fit=crop&dpr=1 600w, https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=473&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=473&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=595&fit=crop&dpr=1 754w, https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=595&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/210098/original/file-20180313-30983-17040k8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=595&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">In the brain of a baby who died soon after birth, there are many new neurons (green in this image) in the hippocampus.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/nature25975">Sorrells et al</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>When and where are new neurons born?</h2>
<p>No doubt, the adult human brain is able to learn throughout life and to change and adapt – a capability brain scientists call neuroplasticity, the <a href="https://theconversation.com/what-is-brain-plasticity-and-why-is-it-so-important-55967">brain’s ability to reorganize itself by rewiring connections</a>. Yet, a central dogma in the field of neuroscience for nearly 100 years had been that a child is <a href="https://doi.org/10.1093/acprof:oso/9780195065169.001.0001">born with all the neurons she will ever have</a> because the adult brain cannot regenerate neurons. </p>
<p>Just over half a century ago, researchers devised a way to study proliferation of cells in the mature brain, based on <a href="https://doi.org/10.1038/35036235">techniques to incorporate a radioactive label</a> into new cells as they divide. This approach led to the startling discovery in the 1960s that <a href="https://doi.org/10.1002/cne.901370404">rodent brains actually could generate new neurons</a>. </p>
<p>Neurogenesis – the production of new neurons – was previously thought to only occur during embryonic life, a time of extremely rapid brain growth and expansion, and the rodent findings were met with considerable skepticism. Then researchers discovered that new neurons are also <a href="http://www.pnas.org/content/80/8/2390.short">born throughout life in the songbird brain</a>, a species scientists use as a model for studying vocal learning. It started to look like neurogenesis plays a key role in learning and neuroplasticity – at least in some brain regions in a few animal species. </p>
<p>Even so, neuroscientists were skeptical that many nerve cells could be renewed in the adult brain; evidence was scant that dividing cells in mammalian brains produced new neurons, as opposed to other cell types. It wasn’t until researchers extracted neural stem cells from adult mouse brains and grew them in cell culture that scientists showed these precursor cells could <a href="https://doi.org/10.1073/pnas.90.5.2074">divide and differentiate into new neurons</a>. Now it is generally well accepted that neurogenesis takes place in two areas of the adult rodent brain: the olfactory bulbs, which process smell information, and the hippocampus, a region characterized by neuroplasticity that is required for forming new declarative memories.</p>
<p>Adult neural stem cells cluster together in what scientists call niches – <a href="https://doi.org/10.1016/j.devcel.2015.01.010">hotbeds for cultivating the birth and growth of new neurons</a>, recognizable by their distinctive architecture. Despite the mounting evidence for regional growth of new neurons, these studies underscored the point that the adult brain harbors only a few stem cell niches and their capacity to produce neurons is limited to just a few types of cells. </p>
<p>With this knowledge, and new tools for labeling proliferating cells and identifying maturing neurons, scientists began to look for postnatal neurogenesis in primate and human brains.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/210140/original/file-20180313-30989-51senu.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">A mouse neural stem cell (blue and green) grows in a lab dish. Can human brain cells do what rodent brain cells do?</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/nihgov/34021671492">Mark McClendon, Zaida Alvarez Pinto, Samuel I. Stupp, Northwestern University, Evanston, IL</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<h2>What’s happening in adult human brains?</h2>
<p>Many neuroscientists believe that by understanding the process of adult neurogenesis we’ll gain insights into the causes of some human neurological disorders. Then the next logical step would be trying to develop new treatments harnessing neurogenesis for conditions such as Alzheimer’s disease or trauma-induced epilepsy. And stimulating resident stem cells in the brain to generate new neurons is an exciting prospect for treating neurodegenerative diseases.</p>
<p>Because neurogenesis and learning in rodents <a href="https://doi.org/10.1523/JNEUROSCI.1731-05.2005">increases with voluntary exercise</a> and <a href="https://doi.org/10.1159/000368575">decreases with age</a> and <a href="https://doi.org/10.1101/cshperspect.a021303">early life stress</a>, some workers in the field became convinced that older people might be able to enhance their memory as they age by maintaining a program of <a href="https://doi.org/10.1073/pnas.1015950108">regular aerobic exercise</a>.</p>
<p>However, obtaining rigorous proof for adult neurogenesis in the human and primate brain has been technically challenging – both due to the limited experimental approaches and the larger sizes of the brains, compared to reptiles, songbirds and rodents.</p>
<p>Researchers injected a compound found in DNA, nicknamed BrdU to <a href="https://doi.org/10.1038/3305">identify brand new neurons in human adult hippocampus</a> – but the labeled cells were extremely rare. Other groups demonstrated that adult human brain tissue obtained during neurosurgery contained stem cell niches that housed progenitor cells that <a href="https://doi.org/10.1038/nature02301">could generate new neurons in the lab</a>, showing that these cells had an inborn neurogenic capacity, even in adults.</p>
<p>But even when scientists saw evidence for new neurons in the brain, they tended to be scarce. Some neurogenesis experts were skeptical that evidence based on incorporating BrdU into DNA was a reliable method for proving that new cells were actually being born through cell division, rather than just serving as a <a href="http://www.jneurosci.org/content/22/3/614.long">marker for other normal cell functions</a>.</p>
<p>Further questions about how long human brains retain the capacity for neurogenesis arose in 2011, with a study that compared numbers of <a href="https://doi.org/10.1038/nature10487">newborn neurons migrating</a> in the olfactory bulbs of infants versus older individuals up to 84 years of age. Strikingly, in the first six months of life, the baby brains contained lots of chains of young neurons <a href="https://doi.org/10.1126/science.aaf7073">migrating into the frontal lobes</a>, regions that guide executive function, long-range planning and social interactions. These areas of the human cortex are hugely increased in size and complexity compared to rodents and other species. But between 6 to 18 months of age, the migrating chains dwindled to a thin stream. Then, a very different pattern emerged: Where the migrating chains of neurons had been in the infant brain, a cell-free gap appeared, suggesting that neural stem cells become depleted during the first six months of life. </p>
<p>Questions still lingered about the human hippocampus and adult neurogenesis as a source for its neuroplasticity. One group came up with a clever approach based on radiocarbon dating. They measured how much atmospheric ¹⁴C – a radioactive isotope derived from nuclear bomb tests – was incorporated into people’s DNA. This method suggested that as many as <a href="https://doi.org/10.1016/j.cell.2013.05.002">700 new cells are added to the adult human hippocampus every day</a>. But these findings were contradicted by a 2016 study that found that the neurogenic cells in the adult hippocampus <a href="https://doi.org/10.1111/nan.12337">could only produce non-neuronal brain cells called microglia</a>. </p>
<h2>Rethinking neurogenesis research</h2>
<p>Now the largest and most comprehensive study conducted to date <a href="https://theconversation.com/adult-human-brains-dont-grow-new-neurons-in-hippocampus-contrary-to-prevailing-view-93123">presents even stronger evidence</a> that robust neurogenesis doesn’t continue throughout adulthood in the human hippocampus – or if it does persist, it is extremely rare. This work is controversial and not universally accepted. Critics have been <a href="https://www.statnews.com/2018/03/07/adult-brains-neurogenesis/">quick to cast doubt on the results</a>, but the finding isn’t totally out of the blue. </p>
<p>So where does this leave the field of neuroscience? If the UCSF scientists are correct, what does that mean for ongoing research in labs around the world?</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=385&fit=crop&dpr=1 600w, https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=385&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=385&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=483&fit=crop&dpr=1 754w, https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=483&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/210092/original/file-20180313-30983-74xzrf.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=483&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">It’s much easier to work with rodent brains than human ones. This is a stained image of the hippocampus and neurons of a mouse with neurodegenerative disease.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/nichd/22028646372">NICHD/I. Williams</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Because lots of studies of neurological diseases are done in mice and rats, many scientists are invested in the possibility that adult neurogenesis persists in the human brain, just as it does in rodents. If it doesn’t, how valid is it to think that the mechanisms of learning and neuroplasticity in our model animals are comparable to those in the human brain? How relevant are our models of neurological disorders for understanding how changes in the hippocampus contribute to disorders such as the type of epilepsy I study? </p>
<p>In my lab, we transplant embryonic mouse or human neurons <a href="https://doi.org/10.1523/JNEUROSCI.0005-14.2014">into the adult hippocampus in mice, after damage caused by epileptic seizures</a>. We aim to repair this damage and suppress seizures by seeding the mouse hippocampus with neural stem cells that will mature and form new connections. In temporal lobe epilepsy, studies in adult rodents suggest that naturally occurring hippocampal neurogenesis is problematic. It seems that the newborn hippocampal neurons become highly excitable and contribute to seizures. We’re trying to inhibit these newborn hyperexcitable neurons with the transplants. But if humans don’t generate new hippocampal neurons, then maybe we’re developing a treatment in mice for a problem that has a different mechanism in people.</p>
<p>Perhaps our species has evolved separate mechanisms for neuroplasticity, distinct from those used by species such as rats and mice. One possibility is that there are other sites in the human brain where neurogenesis occurs - its a big structure and more exploration will be necessary. If it turns out to be true that the human brain has a diminished capacity for neurogenesis after birth, the finding will have important implications for how neuroscientists like me think about tackling brain disorders.</p>
<p>Perhaps most importantly, this work underscores how crucial it is to learn how to increase the longevity of the neurons we do have, born early in life, and how we might replace or repair neurons that become damaged.</p><img src="https://counter.theconversation.com/content/93183/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Janice R. Naegele receives funding from the National Institutes of Health, Connecticut Regenerative Medicine Fund and CURE Epilepsy.</span></em></p>Neuroscience labs around the world may need to reevaluate some of their assumptions about whether what works in animals will really produce meaningful treatments for people.Janice R. Naegele, Alan M Dachs Professor of Science, Professor of Biology, Neuroscience and Behavior, Wesleyan UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/581832016-05-04T12:53:17Z2016-05-04T12:53:17ZTesting drugs on animals could soon be a thing of the past<figure><img src="https://images.theconversation.com/files/119962/original/image-20160425-22378-68rq6i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Rats are commonly used in animal testing</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-68440837/stock-photo-rat-in-laboratory-tests-on-animal-experiments.html?src=9XOxfxI_HlUB--6P27QedA-1-25">FikMik</a></span></figcaption></figure><p>Before a drug can be tested on humans, it has to be tested on animals. The drugs regulators <a href="http://www.efpia.eu/topics/innovation/animal-welfare">demand it</a>. Nobody – including researchers – likes testing on animals, which is why the race is on to find <a href="http://www.neavs.org/alternatives/in-testing">alternatives</a>. </p>
<p>For this reason – as well as the fact that animal models are often unable to correctly predict how a drug will react in humans – scientists are actively considering alternatives. Fortunately, rapid progress is being made in a number of areas which may soon, hopefully, render animal testing obsolete.</p>
<p>One promising alternative to animal testing is computer models. This “<a href="http://www.oapublishinglondon.com/article/1119"><em>in silico</em></a>” technique simulates the workings of human biology to predict how a new drug will behave in the body, where it will end up – and even what side effects might occur. </p>
<p>This helps researchers refine drug structures before they are tested in animals. It can reduce the number of animals that are tested on by weeding out compounds that are overly toxic or not likely to be effective. Almost all pharmaceutical companies now routinely use computer models in drug development as the database of background knowledge of how drugs interact with biological systems has expanded significantly in recent years. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/119964/original/image-20160425-22383-1f49c7c.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">It can take up to 12 years and £1.15 billion for a drug to be ready for use.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/en/pic.mhtml?irgwc=1&utm_campaign=Pixabay&tpl=44814-43068&utm_medium=Affiliate&id=298303490&utm_source=44814">VonaUA</a></span>
</figcaption>
</figure>
<p>Another alternative to animal testing is <a href="http://mpkb.org/home/patients/assessing_literature/in_vitro_studies">“<em>in vitro</em>” testing</a>. These are biological and chemical mimics that recreate particular parts of the body. They include mimics of the <a href="http://www.scientificamerican.com/article/brain-in-a-dish-could-replace-toxic-animal-tests/">brain</a>, heart, lungs and a variety of other body systems. Although these systems may look nothing like the original organ, they will consist of cells or molecules that have been made in the lab and behave in a similar way to those found in actual biological systems. For example, the surface of the skin can be recreated to measure how fast drugs get through and how much can be delivered by this route. </p>
<p>These in vitro studies have become so advanced that it’s now possible to predict how drugs will behave in almost any part of the body or any disease state. This has been achieved through an accumulation of knowledge about the science behind each disease, from how the body behaves in a healthy situation to how it changes when unwell and then how drugs can cure the disease. </p>
<p>Using clinical data available for existing drugs allows scientists to compare real-life results with their mimics to prove their suitability before they are validated as a potential alternative.</p>
<p>Once the test system has been validated using known drugs, it can be used to analyse potential new drugs. Basically, once a new test method has proven effective it can begin the process of approval as a legal alternative for testing a specific property of a drug. In the EU these test methods are organised through EURL-ECVAM (the European Union Reference Laboratory for alternatives to animal testing), an organisation based in northern Italy.</p>
<h2>We’re getting there</h2>
<p>These alternatives to animal studies still need refining. Although they are used in some laboratories today, they can only help narrow down potential drug candidates or confirm results already obtained from animals. Unfortunately, at this time it is not possible to recreate all of the intricacies of the human body. The models we use are often overly simplified. This can sometimes make it hard to predict everything we need to know about a drug and we can miss out on noticing the more subtle biological interactions. </p>
<p>In some situations these simplified systems can work well, especially when ranking a series of potential drugs against each other, or looking for one particular interaction.</p>
<p>We are now in an incredibly exciting period of scientific progress. It is imaginable that all the information needed to understand how drugs behave can be determined without the need for animal testing. And it’s entirely plausible that in the next decade or two, animal testing will no longer be needed in the pharmaceutical industry.</p><img src="https://counter.theconversation.com/content/58183/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Laura Waters 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>Why are animals still being used in drug development and what are the alternatives that could end their use altogether?Laura Waters, Principal Enterprise Fellow, University of HuddersfieldLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/478202015-12-02T11:05:25Z2015-12-02T11:05:25ZWhat clues does your dog’s drool hold for human mental health?<figure><img src="https://images.theconversation.com/files/103945/original/image-20151201-26568-1ld7n8o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">There goes some precious DNA....</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/graemebird/2478467142">Graeme Bird</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>Dogs were the <a href="https://theconversation.com/new-dna-analysis-says-your-poochs-ancestors-were-central-asian-wolves-49271">first animals people domesticated</a>, long before the earliest human civilizations appeared. Today, tens of thousands of years later, dogs have an unusually close relationship with us. They share our homes and steal our hearts – and have even evolved <a href="http://barkpost.com/dogs-love-us-like-family/">to love us back</a>. Sadly, they also suffer from many of the same difficult-to-treat psychiatric and neurological diseases we do.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=733&fit=crop&dpr=1 600w, https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=733&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=733&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=921&fit=crop&dpr=1 754w, https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=921&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/103939/original/image-20151201-26582-1tcleck.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=921&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Beskow, in fine spirits.</span>
<span class="attribution"><span class="source">Elinor Karlsson</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>I learned this firsthand about six years ago, when my sister Adria adopted Beskow, a beautiful, boisterous, black and white mutt. Beskow became my constant companion on my morning runs along the Charles River. Her joy in running was obvious to everyone we passed, and she kept me going mile after mile. </p>
<p>When not running, though, Beskow suffered from constant anxiety that left her stressed and unhappy – on edge around other dogs and prone to aggressive behavior. Beskow had trouble even playing outdoors, since she was compelled to attend to every sound and movement. Working one-on-one with skilled behaviorists and trainers helped immensely, but poor Beskow still never seemed able to relax. Eventually, Adria combined the intensive training with medication, which finally seemed to give Beskow some relief. </p>
<p>Beskow’s personality – her intelligence, her focus and her anxiety – was shaped not only by her own life experiences, but by thousands of years of evolution. Have you ever known a dog who would retrieve the same ball over and over again, for hours on end? Or just wouldn’t stay out of the water? Or wasn’t interested in balls, or water, but just wanted to follow her nose? These dogs are the result of hundreds of generations of artificial selection by human beings. By favoring useful behaviors when breeding dogs, we made the genetic changes responsible more common in their gene pool.</p>
<p>When a particular genetic change rapidly rises in prevalence in a population, it leaves a “signature of selection” that we can detect by sequencing the DNA of <a href="http://genomesunzipped.org/2010/09/detecting-positive-natural-selection-from-genetic-data.php">many individuals from the population</a>. Essentially, around a selected gene, we find a region of the genome where one particular pattern of DNA – the variant linked to the favored version of the gene – is far more common than any of the alternative patterns. The stronger the selection, the bigger this region, and the easier it is to detect this signature of selection. </p>
<p>In dogs, genes shaping behaviors purposely bred by humans are marked with large signatures of selection. It’s a bit like evolution is shining a spotlight on parts of the dog genome and saying, “Look here for interesting stuff!” To figure out exactly how a particular gene influences a dog’s behavior or health, though, we need lots more information. </p>
<p>To try to unravel these connections, my colleagues and I are launching a new citizen science research project we’re calling <a href="http://darwinsdogs.org/">Darwin’s Dogs</a>. <a href="http://iaabc.org/">Together with animal behavior experts</a>, we’ve put together a series of short surveys about everything from diet (does your dog eat grass?) to behavior (is your dog a foot sitter?) to personality (is your dog aloof or friendly?). </p>
<p>Any dog can participate in <a href="http://darwinsdogs.org/">Darwin’s Dogs</a>, including purebred dogs, mixed breed dogs, and mutts of no particular breed – our study’s participants will be very genetically diverse. We’re combining <a href="http://doi.org/10.1016/j.cell.2013.09.006">new DNA sequencing technology</a>, which can give us much more genetic information from each dog, with powerful new <a href="http://doi.org/10.1038/nrg3382">analysis methods that can control for diverse ancestry</a>. By including all dogs, we hope to be able to do much larger studies, and home in quickly on the important genes and genetic variants. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/103941/original/image-20151201-26574-6ny0rs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A beagle considers making the saliva donation.</span>
<span class="attribution"><span class="source">Stephen Schaffner</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>Once an owner has filled out the survey, there’s a second, crucial step. We send an easy-to-use kit to collect a small dog saliva sample we can use for DNA analysis. There’s no cost, and we’ll share any information we find.</p>
<p>Our plan is to combine the genetic data from many dogs and look for changes in DNA that correlate with particular behaviors. It won’t be easy to match up DNA with an obsession with tennis balls, for instance. Behavior is a complex trait that relies on many genes. Simple <a href="http://www.nature.com/scitable/topicpage/gregor-mendel-and-the-principles-of-inheritance-593">Mendelian traits</a>, like Beskow’s black and white coat, are controlled by a single gene which determines the observable characteristic. This kind of inherited trait is comparatively easy to map. Complex traits, on the other hand, may be shaped by tens or even hundreds of different genetic changes, each of which on its own only slightly alters the individual carrying it. </p>
<p>Adding to the complexity, environment often plays a big role. For example, Beskow may not have been as anxious if she’d lived with Adria from puppyhood, even though her genetics would be unchanged. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=648&fit=crop&dpr=1 600w, https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=648&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=648&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=814&fit=crop&dpr=1 754w, https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=814&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/103946/original/image-20151201-26546-hlyirx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=814&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Darwin’s Dogs team member Jesse McClure extracts DNA from a sample.</span>
<span class="attribution"><span class="source">Elinor Karlsson</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>To succeed, we need a lot of dogs to sign up. Initially, we’re aiming to enroll 5,000 dogs. If successful, we’ll keep growing. With bigger sample sizes, we’ll be able to tackle even more complex biological puzzles. </p>
<p>This is a huge effort, but could offer huge rewards. By figuring out how a genetic change leads to a change in behavior, we can decipher neural pathways involved in psychiatric and neurological diseases <a href="http://doi.org/10.1016/S0278-5846(00)00104-4">shared between people and dogs</a>. We already know these include not just anxiety, but also <a href="http://www.nytimes.com/2011/12/02/us/more-military-dogs-show-signs-of-combat-stress.html">PTSD</a>, <a href="http://doi.org/10.1186/gb-2014-15-3-r25">OCD</a>, <a href="http://doi.org/10.1038/tp.2014.106">autism spectrum disorders</a>, <a href="http://doi.org/10.2460/javma.2001.219.467">phobias</a>, <a href="http://doi.org/10.1016/S0092-8674(00)81965-0">narcolepsia</a>, <a href="http://doi.org/10.1111/epi.12138">epilepsy</a>, <a href="http://doi.org/10.1016/0197-4580(95)02060-8">dementia and Alzheimer’s disease</a>.</p>
<p>Understanding the biology underlying a disease is the first step in developing more effective treatments – of both the canine and human variety. For example, <a href="http://doi.org/10.1016/S0092-8674(00)81965-0">genetic studies of narcolepsy in Doberman pinschers</a> found the gene mutation causing the disease – but only in this one dog population. Researching the gene’s function, though, led to critical new insights into the molecular biology of sleep, and, eventually, to <a href="http://dx.doi.org/10.2147/NSS.S56077">new treatment options for people</a> suffering from this debilitating disease. </p>
<p><a href="http://darwinsdogs.org">Darwin’s Dogs</a> is investigating normal canine behaviors as well as diseases. We hypothesize that finding the small genetic changes that led to complex behaviors, like retrieving, or even personality characteristics, like playfulness, will help us figure out how brains work. We need this mechanistic understanding to design new, safe and more effective therapies for psychiatric diseases. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/103943/original/image-20151201-26582-7fy2k.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">Beskow with one of her loving family members.</span>
<span class="attribution"><span class="source">Adria Karlsson</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>And Beskow? Six years later, she is as wonderful as ever. While still anxious some of the time, the medication and training have paid off, and she enjoys her daily walks, training and playtime. She still gets very nervous around other dogs, but is a gentle, playful companion for my sister’s three young children.</p>
<p>We are now sequencing her genome. In the next few months, we should have our first glimpse into Beskow’s ancestry. We know she is a natural herder, so we’re curious to find out how much her genome matches up to herding breeds, and which genes are in that part of the genome.</p>
<p>Of course, we can’t figure out much from just one dog – if you are a dog owner, please <a href="http://darwinsdogs.org">enroll your dog today</a>!</p><img src="https://counter.theconversation.com/content/47820/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Elinor Karlsson receives funding from the NIH and the Worcester Foundation.</span></em></p>Researchers want your canine’s DNA to help unravel the connections between genes and behavior – for dogs and human beings.Elinor Karlsson, Assistant Professor of Bioinformatics and Integrative Biology, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/336582014-10-30T21:54:29Z2014-10-30T21:54:29ZDo our genes determine whether we survive Ebola?<figure><img src="https://images.theconversation.com/files/63425/original/h7xbypfm-1414820778.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">What is Ebola?</span> <span class="attribution"><span class="source">Emilia Stasiak</span></span></figcaption></figure><p>Despite killing a majority of people it infects, some patients survive the onslaught of Ebola virus. What gives them this resistance, ask Michael Katze, professor of microbiology, and colleagues from the University of Washington in a study published in the journal <a href="http://dx.doi.org/10.1126/science.1259595">Science</a> They used mice to answer this question because despite being infected with Ebola virus, they don’t show the symptoms seen in Ebola-infected humans. </p>
<p>Mice tend to be a good animal model for scientists to understand human diseases, because they are easy to handle in labs and have been studied extensively. However, in the case of Ebola, it is their apparent resistance which may give us more useful answers.</p>
<p>Katze and his colleagues cross-bred different genetic varieties of lab-bred mice to produce a strain that did fall victim to Ebola. Although the virus grows in both susceptible and disease-resistant mice, it grows to lower levels in resistant mice. The pattern of infection differs too. For example, virus infection of the liver is restricted to only certain types of cells in resistant mice rather than infecting most liver cells as seen in the susceptible mice. </p>
<p>Analysis of the mouse strains showed that the resistance was linked with differences in the expression of a number of mouse genes. If virus resistance is genetic in mice, could our susceptibility to fatal virus infections, such as Ebola, be determined by a genetic predisposition? What about viruses that only rarely cause fatal infections? Does a difference in genetic susceptibility also explain why some people get regular respiratory virus infections, while others rarely complain of infection?</p>
<p>The answer is a qualified yes, but it is not as startling as it first appears. Katze and colleagues show for the first time that resistance to Ebola is due to differences in gene expression. This will come as no great surprise to most virologists, who have long accepted that animals are not simply passive victims of infection but can actually contribute to diseases when infected. This has been seen in many different kinds of animals.</p>
<p>It is clear that the first line of defence following infection – the innate immune response that is present in all cells of the body – is key to the outcome. In Katze’s study, many of the genes they identify are implicated in the generation and maintenance of the integrity of blood vessels. Disruption of these gene functions correlate with the known symptoms of Ebola, such as haemmorhage, and presumably reflect differences in the way that the genes are expressed and regulated in different genetic backgrounds.</p>
<p>However, caution is needed in reading too much into the results. The fact that cross-bred mice respond with a range of symptoms after Ebola infection – just like humans do – may not be due to a genetic cause. For example, humans are more genetically mixed than mice and the sheer number of genetic combinations are likely to produce a graded spectrum of responses rather than a distinct division as seen in the mouse strains studied. </p>
<p>Equally important – but not addressed by the study – is the potential role of environmental factors that undoubtedly also play a role in the disease process. These include factors such as the underlying health status of the at-risk population,the virus dose encountered and the route of exposure. While the data in this study suggest a genetic link with Ebola virus, more work is required to confirm the role of these genes. In particular it will be important to study animals which have defects in their genes to see if they display Ebola symptoms.</p>
<p>Despite these caveats the study does raise some intriguing and potentially valuable prospects. The wild-type virus caused no symptoms and appears not to replicate in mice. So the study used a mouse-adapted strain of Ebola virus. The genetic differences between the two types of virus will enable the molecular basis of this difference to be explored in detail. Ebola is known to infect mammals other than primates, for example <a href="https://theconversation.com/ebola-bats-get-a-bad-rap-when-it-comes-to-spreading-diseases-32785">bats</a> and duiker, and the changes in the virus required to infect these hosts can now be investigated. </p>
<p>What is perhaps most interesting is that mice with only low levels of virus production did not experience severe disease. This suggests that it may not be necessary to completely eliminate the virus from the body to provide protection against the disease. So treatments or interventions designed to reduce virus levels, rather than eradicate it, may be sufficient to alleviate the considerable suffering we see in many Ebola patients. If this proves to be the case then the hurdle to be surmounted for therapies may be lower than initially thought. This is good news for the <a href="https://theconversation.com/high-hopes-rest-on-800-vials-of-experimental-ebola-vaccine-shipped-from-canada-33201">vaccines now being tested</a>.</p><img src="https://counter.theconversation.com/content/33658/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>Despite killing a majority of people it infects, some patients survive the onslaught of Ebola virus. What gives them this resistance, ask Michael Katze, professor of microbiology, and colleagues from the…Andrew Easton, Professor of Life Sciences, University of WarwickDavid Evans, Professor, University of WarwickLicensed as Creative Commons – attribution, no derivatives.