tag:theconversation.com,2011:/au/topics/genetic-disease-2244/articlesGenetic disease – The Conversation2023-07-26T12:15:25Ztag:theconversation.com,2011:article/2100362023-07-26T12:15:25Z2023-07-26T12:15:25ZFragile X syndrome often results from improperly processed genetic material – correctly cutting RNA offers a potential treatment<figure><img src="https://images.theconversation.com/files/538608/original/file-20230720-23-yssm44.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2308%2C1298&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">For many people with fragile X, the mutated gene that causes symptoms is active rather than silenced.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/fragile-x-chromosome-illustration-royalty-free-illustration/1407268269">Thom Leach/Science Photo Library</a></span></figcaption></figure><p><a href="https://www.cdc.gov/ncbddd/fxs/features/fragile-x-five-things.html">Fragile X syndrome</a> is a genetic disorder caused by a mutation in a gene that lies at the tip of the X chromosome. It is linked to autism spectrum disorders. People with fragile X experience a range of symptoms that include cognitive impairment, developmental and speech delays and hyperactivity. They may also have some physical features such as large ears and foreheads, flabby muscles and poor coordination.</p>
<p>Along with our colleagues <a href="https://scholar.google.com/citations?user=fbDXtcUAAAAJ&hl=en">Jonathan Watts</a> and <a href="https://www.rushu.rush.edu/faculty/elizabeth-m-berry-kravis-md-phd">Elizabeth Berry-Kravis</a>, <a href="https://profiles.umassmed.edu/display/133116">we are</a> <a href="https://scholar.google.com/citations?user=syYm8JMAAAAJ&hl=en">a team</a> of scientists with expertise in molecular biology, nucleic acid chemistry and pediatric neurology. We recently discovered that the mutated gene responsible for fragile X syndrome is active in most people with the disorder, not silenced as previously thought. But the affected gene on the X chromosome is still unable to produce the protein it codes for because the <a href="https://doi.org/10.1073/pnas.2302534120">genetic material isn’t properly processed</a>. Correcting this processing error suggests that a potential treatment for symptoms of fragile X may one day be available.</p>
<h2>Repairing faulty RNA splicing</h2>
<p>The <a href="https://doi.org/10.1038/s41583-021-00432-0">FMR1 gene encodes a protein</a> that regulates protein synthesis. A lack of this protein leads to overall excessive protein synthesis in the brain that results in many of the symptoms of fragile X. </p>
<p>The mutation that causes fragile X results in extra copies of a DNA sequence called a <a href="https://doi.org/10.1038/s41583-021-00432-0">CGG repeat</a>. Everyone has CGG repeats in their FMR1 gene, but typically fewer than 55 copies. Having 200 or more CGG repeats silences the FMR1 gene and results in fragile X syndrome. However, we found that <a href="https://doi.org/10.1073/pnas.2302534120">around 70% of people</a> with fragile X still have an active FMR1 gene their cellular machinery can read. But it is mutated enough that it is unable to direct the cell to produce the protein it encodes.</p>
<p>Genes are transcribed into another form of genetic material called RNA that cells use to make proteins. Normally, genes are processed before transcription in order to make a readable strand of RNA. This involves removing the <a href="https://www.genome.gov/genetics-glossary/Intron">noncoding sequences</a> that interrupt genes and splicing the genetic material back together. For people with fragile X, the cellular machinery that does this cutting incorrectly splices the genetic material, such that the protein the FMR1 gene codes for is not produced.</p>
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<figcaption><span class="caption">Fragile X syndrome is the most common inherited form of intellectual disability.</span></figcaption>
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<p>Using cell cultures in the lab, we found that <a href="https://doi.org/10.1073/pnas.2302534120">correcting this missplice</a> can restore proper RNA function and produce the FMR1 gene’s protein. We did this by using short bits of DNA called <a href="https://doi.org/10.3390%2Fjcm9062004">antisense oligonucleotides, or ASOs</a>. When these bits of genetic material bind to RNA molecules, they change the way the cell can read it. That can have effects on which proteins the cell can successfully produce.</p>
<p>ASOs have been used with spectacular success to treat other childhood disorders, such as <a href="https://doi.org/10.1016/j.tins.2020.11.009">spinal muscular atrophy</a>, and are now being used to treat <a href="https://doi.org/10.1146/annurev-pharmtox-010919-023738">a variety of neurological diseases</a>.</p>
<h2>Beyond mice models</h2>
<p>Notably, fragile X syndrome is most often <a href="https://doi.org/10.1242/dmm.049485">studied using mouse models</a>. However, because these mice have been genetically engineered to lack a functional FMR1 gene, they are quite different from people with fragile X. In people, it is not a missing gene that causes fragile X but mutations that lead the existing gene to lose function. </p>
<p>Because the mouse model of fragile X lacks the FMR1 gene, the RNA is not made and so cannot be misspliced. Our discovery would not have been possible if we used mice.</p>
<p>With further research, future studies in people may one day include injecting ASOs into the cerebrospinal fluid of fragile X patients, where it will travel to the brain and hopefully restore proper function of the FMR1 gene and improve their cognitive function.</p><img src="https://counter.theconversation.com/content/210036/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Joel Richter receives funding from NIH and FRAXA. </span></em></p><p class="fine-print"><em><span>Sneha Shah receives funding from the FRAXA Research Foundation.</span></em></p>Fragile X syndrome is the most common inherited form of intellectual disability. Using short bits of DNA to fix improperly transcribed genes may one day be a potential treatment option.Joel Richter, Professor of Neuroscience, UMass Chan Medical SchoolSneha Shah, Assistant Professor of Molecular Medicine, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2005262023-05-12T12:19:21Z2023-05-12T12:19:21ZGene therapy helps combat some forms of blindness – and ongoing clinical trials are looking to extend these treatments to other diseases<figure><img src="https://images.theconversation.com/files/517754/original/file-20230327-14-rcucem.jpg?ixlib=rb-1.1.0&rect=24%2C18%2C997%2C490&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">New gene therapies are helping to treat certain forms of inherited blindness.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/view-of-a-blind-man-assisted-by-a-friend-as-he-walks-on-a-news-photo/1299277661?phrase=blind%20person%20walking&adppopup=true">GettyImages</a></span></figcaption></figure><p><em><a href="https://www.orbis.org/en/news/2021/new-global-blindness-data#">An estimated 295 million people</a> suffer from visual impairment globally. Around 43 million of those people are living with blindness. While not every form of blindness can be cured, <a href="https://pubmed.ncbi.nlm.nih.gov/33278565/">recent scientific breakthroughs</a> have uncovered new ways to treat some forms of inherited blindness through gene therapy.</em></p>
<p><em><a href="https://www.med.upenn.edu/apps/faculty/index.php/g275/p11214">Jean Bennett</a> is a gene therapy expert and a professor emeritus of ophthalmology at the University of Pennsylvania. She and her laboratory developed the first gene therapy drug for a genetic disease to be approved in the U.S. The drug, <a href="https://luxturna.com/">Luxturna</a>, treats patients with biallelic RPE65 mutation-associated retinal dystrophy, a rare genetic disorder that causes visual impairments and blindness in patients early in life.</em></p>
<p><em>In March, Bennett spoke at the 2023 <a href="https://www.imaginesolutionsconference.com/">Imagine Solutions Conference</a> in Naples, Florida, about what gene therapy is, why it matters and the success she and her team have had helping the blind to see. The Conversation caught up with Bennett after the conference. Her edited answers are below.</em></p>
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<figcaption><span class="caption">Jean Bennett speaks at the 2023 Imagine Solutions Conference.</span></figcaption>
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<h2>What is gene therapy and how does it work?</h2>
<p><a href="https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy">Gene therapy</a> is a set of techniques that harness <a href="https://medlineplus.gov/genetics/understanding/basics/dna/">DNA</a> or <a href="https://www.umassmed.edu/rti/biology/what-is-rna/">RNA</a> to treat or prevent disease. Gene therapy treats disease in <a href="https://www.childrenshospital.org/treatments/gene-therapy#">three primary ways</a>: by substituting a disease-causing gene with a healthy new or modified copy of that gene; turning genes on or off; and injecting a new or modified gene into the body.</p>
<h2>How has gene therapy changed how doctors treat genetic eye diseases and blindness?</h2>
<p>In the past, many doctors did not think it necessary to identify the genetic basis of eye disease because treatment was not yet available. However, a few specialists, including <a href="https://www.med.upenn.edu/carot/">me and my collaborators</a>, identified these defects in our research, convinced that someday treatment would be made possible. Over time, we were able to create a treatment designed for individuals with particular gene defects that lead to congenital blindness.</p>
<p>This development of gene therapy for inherited disease has <a href="https://www.eye-tuebingen.de/wissingerlab/projects/rd-cure/">inspired</a> <a href="https://atsenatx.com/">other</a> <a href="https://www.medicalnewstoday.com/articles/gene-therapy-for-macular-degeneration">groups</a> around the world to initiate clinical trials targeting other genetic forms of blindness, such as <a href="https://medlineplus.gov/genetics/condition/choroideremia/">choroideremia</a>, <a href="https://medlineplus.gov/genetics/condition/achromatopsia/">achromatopsia</a>, <a href="https://medlineplus.gov/genetics/condition/retinitis-pigmentosa/">retinitis pigmentosa</a> and even <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/agerelated-macular-degeneration-amd">age-related macular degeneration</a>, all of which lead to vision loss. There are at least <a href="https://www.clinicaltrials.gov/">40 clinical trials</a> enrolling patients with other genetic forms of blinding disease. </p>
<p>Gene therapy treatments are now available in pharmacies and operating rooms all over the world. </p>
<p>Gene therapy is even being used to restore vision to people whose photoreceptors – the cells in the retina that respond to light – have completely degenerated. This approach uses <a href="https://pubmed.ncbi.nlm.nih.gov/36499371/">optogenetic therapy</a>, which aims to revive those degenerated photoreceptors by adding light-sensing molecules to cells, thereby drastically improving a person’s vision.</p>
<h2>You created one of the first gene therapies approved in the US. What is the current state of the clinical use of gene therapy?</h2>
<p>There are now many approved gene therapies in the U.S., but the majority are combined with cell therapies in which a cell is modified in a dish and then injected back into the patient. </p>
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<img alt="Woman in lab coat, face mask, goggles and gloves squeezes syringe into petri dish" src="https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Many forms of gene therapy are helping to treat blindness.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/asian-female-doctor-is-working-in-laboratory-royalty-free-image/1363580438?phrase=laboratory%20technician&adppopup=true">GettyImages</a></span>
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<p>The majority of those therapies target different forms of cancer, although there are several for devastating inherited diseases. The drug <a href="https://www.fda.gov/vaccines-blood-biologics/skysona">Skysona</a> is a new injectable gene therapy medication that treats boys ages 4 to 17 with <a href="https://www.childrenshospital.org/conditions/adrenoleukodystrophy-ald">cerebral adrenoleukodystrophy</a>, a genetic disease in which a buildup of very-long-chain fatty acids in the brain can lead to death.</p>
<p>The gene therapy that my team and I developed was the first FDA-approved project involving injection of a gene therapy directly into a person – in this case, into the retina. Only one other <a href="https://www.fda.gov/vaccines-blood-biologics/zolgensma">FDA-approved gene therapy</a> is directly administered to the body – one that targets <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/spinal-muscular-atrophy-sma#">spinal muscular atrophy</a>, a disease that causes progressive muscle weakness and eventually death. The drug, Zolgensma, is injected intravenously into babies and children diagnosed with the disease, allowing them to live as healthy, active children. </p>
<p>There are now more than two dozen FDA-approved cell and gene therapies, including <a href="https://theconversation.com/anti-cancer-car-t-therapy-reengineers-t-cells-to-kill-tumors-and-researchers-are-expanding-the-limited-types-of-cancer-it-can-target-196471">CAR T-cell therapies</a> – in which T cells, a type of immune system cells, are modified in the laboratory to better attack cancer cells in the body – and therapies for various blood diseases.</p>
<h2>What are you currently working on that you’re most excited about?</h2>
<p>I am very excited about some <a href="https://clinicaltrials.gov/ct2/show/NCT05616793?cond=LCA5&draw=2&rank=1">upcoming clinical trials</a> that my team will soon initiate to target some other devastating blinding diseases. We will incorporate a new test of functional vision – how your eyes, brain and the visual pathways between them work together to help a person move in the world. This test utilizes a virtual reality game that is not only fun for the user but promises to provide an objective measure of the person’s functional vision. I hope that our virtual reality test will inform us of any potential benefits from the treatments and also serve as a useful outcome measure for other gene and cell therapy clinical trials involving vision.</p>
<h2>What are the biggest challenges gene therapy faces?</h2>
<p>The biggest challenges involve systemic diseases, or diseases affecting the entire body rather than a single organ or body part. For those diseases, super-high doses of gene therapy reagents must be delivered. Such diseases involve not only technical challenges – such as how to manufacture enormous amounts of gene therapy compounds without contaminating them – but also difficulties ensuring that the treatment targets diseased tissues without causing toxic immune side effects. That level of a problem does not exist with the eye, where relatively small doses are used and exposure to the rest of the body is limited.</p>
<p>Another challenge is how to address diseases in which the target gene is very large. Current approaches to delivering treatments into cells lack the capacity to hold large genes.</p>
<p>Cost remains a key issue in this effort – gene therapy drugs are <a href="https://www.nytimes.com/2017/09/11/health/cost-gene-therapy-drugs.html">enormously expensive</a>. As drug manufacturers are able to refine this technique, gene therapy drugs may become more commonplace, causing their price to drop as a result.</p><img src="https://counter.theconversation.com/content/200526/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jean Bennett was a founder of GenSight Biologics and Opus Genetics and was a scientific (non-equity holding) founder of Spark Therapeutics. She and her husband waived any potential financial gain from Luxturna in 2002 so that they could conduct the clinical trials. Her team received funds from the Children's Hospital of Philadelphia, Foundation Fighting Blindness and Spark Therapeutics to run those trials. She is a co-author on a number of gene therapy patents, including one on LCA5 gene therapy that was licensed to Opus Genetics. She also is a co-author of intellectual property relating to use of virtual reality for vision assessment. She also serves on Scientific Advisory Boards for several groups and serves on Boards of two companies (Opus Genetics and REGENXBIO) and a private Foundations (RDFund).</span></em></p>Genetics expert Jean Bennett explains how gene therapy is being used to treat certain forms of inherited blindness.Jean Bennett, Professor Emeritus of Ophthalmology; Cell and Developmental Biology, University of PennsylvaniaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1830872022-05-19T19:15:52Z2022-05-19T19:15:52ZAbortion and inherited disease: Genetic disorders complicate the view that abortion is a choice<figure><img src="https://images.theconversation.com/files/464309/original/file-20220519-20-kfauht.jpg?ixlib=rb-1.1.0&rect=143%2C19%2C3884%2C2844&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Incidence of birth defects is about one in 25 pregnancies.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/abortion-and-inherited-disease--genetic-disorders-complicate-the-view-that-abortion-is-a-choice" width="100%" height="400"></iframe>
<p>With the rising spectre of the <a href="https://www.theglobeandmail.com/canada/article-roe-v-wade-abortion-supreme-court-leak/">loss of women’s reproductive autonomy in the United States</a>, it’s timely to consider why abortion is an important and necessary part of pregnancy and fetal care. More consideration needs to be given to women and their partners who have a need for abortion due to serious fetal problems that will lead to early death or profound disability in their children.</p>
<p>Few enter into pregnancy with the idea that something could go wrong with fetal development, but approximately <a href="https://doi.org/10.24095/hpcdp.35.1.04">one in 25 infants are born with a birth defect</a>. And as a medical geneticist, I would like to focus on the much higher risk (often one in four) of recurrence of an inherited disease.</p>
<p>Statistically, each of us is more likely than not to be carriers for <a href="https://doi.org/10.1534/genetics.114.173351">a disorder that would be lethal before adulthood</a>. As carriers, we are not affected by disease, but are at risk of transmitting the disease to children if a partner is also a carrier. At present, any of us could be at risk, but we just don’t know.</p>
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<a href="https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram illustrating 25 per cent odds of inheriting a recessive genetic disease" src="https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=335&fit=crop&dpr=1 600w, https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=335&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=335&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=420&fit=crop&dpr=1 754w, https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=420&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/464311/original/file-20220519-18-iu1zrz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=420&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Two carriers of the same recessive genetic disease have a 25 per cent chance of conceiving a child who will inherit two recessive genes and have the disease, even though neither parent is affected.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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<p>To put it into human terms, consider as an example my least favourite genetic disorder, <a href="https://doi.org/10.1002/ana.26260">SURF1 deficiency</a>, which occurs in about one in 40,000 births. Affected fetuses develop normally, have an unremarkable birth and early infancy, learn to walk and speak and then begin quite literally to stumble. They typically come to medical attention at around 18 months of age, are diagnosed at age two, and half of them die by the age of five years. </p>
<p>It’s a horror for sure, but now consider that these children retain normal cognition as their body fails. Looking into the eyes of a four-year-old who understands that they are dying is hard for me when I see them in clinic every few months, but their mothers must do this every day.</p>
<h2>Abortion is a critical option</h2>
<p>For families that have experienced a serious inherited disorder, subsequent pregnancies are traumatic. Abortion is a critical option, a security feature that allows them to consider having children again. Entering into a pregnancy with the intent to terminate one-quarter of the time may be hard for most people to understand, but for affected families it is a safe option when the alternatives are devastating. </p>
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<img alt="People holding signs reading 'There's nothing pro-life about this' and 'Abortion is healthcare'" src="https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=411&fit=crop&dpr=1 600w, https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=411&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=411&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=517&fit=crop&dpr=1 754w, https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=517&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/464227/original/file-20220519-6976-hxtdx8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=517&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Demonstrators protest outside of the U.S. Supreme Court in Washington, D.C., on May 6, 2022, after the leak of a draft opinion suggesting the U.S. Supreme Court could be poised to overturn Roe vs. Wade, the case that legalized abortion nationwide.</span>
<span class="attribution"><span class="source">(AP Photo/Mariam Zuhaib)</span></span>
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<p>It is true that there are other options. Families can consider the use of donor sperm or egg. They can attempt the <a href="http://doi.org/10.1016/j.jogc.2018.08.001">pre-implantation diagnosis of embryos</a> created by <em>in vitro</em> fertilization. They can adopt. But all of these options may create financial, social or moral burdens that some women find impossible. </p>
<p>The important principle is that women and their families have all options available. We, as a society at large, are not relevant and should have no interest or opinion in the decisions they make.</p>
<h2>Gestational age and diagnostic timelines</h2>
<p>Abortion should remain legal, and it should not be limited by gestational age. I won’t hide my personal belief that abortion should be available without exception up until the time of delivery. This view has largely been formed by watching children die of untreatable disease. </p>
<p>The discovery of serious problems in a pregnancy can’t be subjected to a tidy timeline. Many diagnostic procedures that identify serious problems occur later than we would like them to, but this is what biology allows us. </p>
<p>Efforts to limit access to abortion late in pregnancy are particular in their cruelty to women carrying fetuses with congenital defects. These restrictions are often used as a <a href="https://www.jstor.org/stable/41054184">gateway to eliminate women’s reproductive freedom</a>, and will be in the United States.</p>
<p>It could be argued that the number of people affected by this problem is small. However, their exceptional voices risk being drowned out by a noisy debate about abortion. I am bothered by abortion debates being framed wholly in terms of the word “choice.” These women never asked to be put into this situation, and their rights, options and dreams must also be considered.</p><img src="https://counter.theconversation.com/content/183087/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Neal Sondheimer is a member of the board of directors of the MitoCanada Foundation, a non-profit supporting patients and families with mitochondrial disease and research into therapy. He serves on advisory boards for Jaguar Gene Therapy and Moderna. </span></em></p>For women with a family history of serious genetic disorders, abortion is a critical option: a security feature that allows them to consider having children.Neal Sondheimer, Associate Professor of Paediatrics and Molecular Genetics, University of TorontoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1649902021-08-31T12:28:57Z2021-08-31T12:28:57ZNew gene therapies may soon treat dozens of rare diseases, but million-dollar price tags will put them out of reach for many<figure><img src="https://images.theconversation.com/files/418515/original/file-20210830-22-1fltn8m.jpg?ixlib=rb-1.1.0&rect=248%2C144%2C8488%2C4217&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gene therapy uses our genomic makeup to treat or prevent disease. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/biotechnology-molecular-engineering-dna-genetic-royalty-free-image/1310024666">ktsimape/iStock via Getty Images</a></span></figcaption></figure><p><a href="https://theconversation.com/the-most-expensive-drug-in-the-world-how-it-works-and-the-devastating-disease-it-treats-164535">Zolgensma</a> – which treats <a href="https://www.mda.org/disease/spinal-muscular-atrophy">spinal muscular atrophy</a>, a rare genetic disease that damages nerve cells, leading to muscle decay – is currently the most expensive drug in the world. A one-time treatment of the life-saving drug for a young child <a href="https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever">costs US$2.1 million</a>.</p>
<p>While Zolgensma’s exorbitant price is an outlier today, by the end of the decade there’ll be dozens of cell and gene therapies, costing hundreds of thousands to millions of dollars for a single dose. The Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics">predicts that by 2025 it will be approving 10 to 20 cell and gene therapies</a> every year.</p>
<p>I’m a <a href="https://www.kevindoxzen.com/">biotechnology and policy expert</a> focused on improving access to cell and gene therapies. While these forthcoming treatments have the potential to save many lives and ease much suffering, health care systems around the world aren’t equipped to handle them. Creative new payment systems will be necessary to ensure everyone has equal access to these therapies. </p>
<h2>The rise of gene therapies</h2>
<p>Currently, only <a href="https://globalgenes.org/rare-facts/">5% of the roughly 7,000 rare diseases</a> have an FDA-approved drug, leaving thousands of conditions without a cure.</p>
<p>But over the past few years, genetic engineering technology has made <a href="https://www.genengnews.com/insights/the-outlook-for-2020-and-beyond/">impressive strides</a> toward the ultimate goal of curing disease by <a href="https://www.npr.org/sections/health-shots/2019/10/21/771266879/scientists-create-new-more-powerful-technique-to-edit-genes">changing a cell’s genetic instructions</a>.</p>
<p>The resulting <a href="https://theconversation.com/boyer-lectures-gene-therapy-is-still-in-its-infancy-but-the-future-looks-promising-104558">gene therapies</a> will be able to treat many diseases at the DNA level in a single dose. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786935/#:%7E:text=There%20are%205%2C000%E2%80%938%2C000%20monogenic,mutations%20on%20a%20single%20gene.">Thousands of diseases</a> are the result of DNA errors, which prevent cells from functioning normally. By directly correcting disease-causing mutations or altering a cell’s DNA to give the cell new tools to fight disease, <a href="https://theconversation.com/explainer-what-is-gene-therapy-19883">gene therapy</a> offers a powerful new approach to medicine.</p>
<p>There are <a href="https://asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-july-20.aspx?_zs=sisac&_zl=Uu4h2">1,745 gene therapies</a> in development around the world. A large fraction of this research focuses on rare genetic diseases, which affect <a href="https://globalgenes.org/rare-facts/">400 million people worldwide</a>. </p>
<p>We may soon see cures for rare diseases like <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2031054">sickle cell disease</a>, <a href="https://www.pnas.org/content/118/22/e2004840117">muscular dystrophy</a> and <a href="https://www.sciencemag.org/news/2021/01/incredible-gene-editing-result-mice-inspires-plans-treat-premature-aging-syndrome">progeria</a>, a rare and progressive genetic disorder that causes children to age rapidly. </p>
<p>Further into the future, gene therapies may help treat more common conditions, like <a href="https://www.nature.com/articles/d41586-018-02482-4">heart disease</a> and <a href="https://www.wsj.com/articles/crisprs-next-frontier-treating-common-conditions-11620226832">chronic pain</a>. </p>
<h2>Sky-high price tags</h2>
<p>The problem is these therapies will carry enormous price tags. </p>
<p>Gene therapies are the result of years of research and development totaling hundreds of millions to <a href="https://fortune.com/2020/02/07/zolgensma-high-drug-prices/">billions of dollars</a>. Sophisticated manufacturing facilities, highly trained personnel and complex biological materials set gene therapies apart from other drugs.</p>
<p>Pharmaceutical companies say recouping costs, especially for drugs with <a href="https://www.technologyreview.com/2017/10/24/148183/tracking-the-cost-of-gene-therapy/">small numbers of potential patients</a>, means higher prices.</p>
<p>The toll of high prices on health care systems will not be trivial. Consider a gene therapy cure for sickle cell disease, which is expected to be available in the next few years. The estimated price of this treatment is $1.85 million per patient. As a result, economists predict that it could cost a single state Medicare program <a href="https://www.doi.org/10.1001/jamapediatrics.2020.7140">almost $30 million per year</a>, even assuming only 7% of the eligible population received the treatment. </p>
<p>And that’s just one drug. Introducing dozens of similar therapies into the market would <a href="https://www.valueinhealthjournal.com/article/S1098-3015(19)30188-3/fulltext">strain health care systems</a> and create <a href="https://www.insurancejournal.com/news/national/2019/09/13/539591.htm">difficult financial decisions for private insurers</a>.</p>
<p>[<em>Over 110,000 readers rely on The Conversation’s newsletter to understand the world.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=100Ksignup">Sign up today</a>.]</p>
<h2>Lowering costs, finding new ways to pay</h2>
<p>One solution for improving patient access to gene therapies would be to simply demand drugmakers charge less money, a <a href="https://www.statnews.com/2021/04/22/bluebirds-withdrawal-of-therapy-from-germany-could-chill-talks-over-gene-therapy-prices-across-europe/">tactic recently taken in Germany</a>. </p>
<p>But this comes with a lot of challenges and may mean that companies <a href="https://www.fiercepharma.com/pharma/situation-untenable-bluebird-will-wind-down-its-operations-broken-europe">simply refuse to offer the treatment</a> in certain places.</p>
<p>I think a more balanced and sustainable approach is two-fold. In the short term, it’ll be important to develop new payment methods that entice insurance companies to cover high-cost therapies and distribute risks across patients, insurance companies and drugmakers. In the long run, improved gene therapy technology will inevitably help lower costs.</p>
<p>For innovative payment models, one tested approach is tying coverage to patient health outcomes. Since these therapies are still experimental and relatively new, there isn’t much data to help insurers make the risky decision of whether to cover them. If an insurance company is paying $1 million for a therapy, it had better work. </p>
<p>In <a href="https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/unlocking-market-access-for-gene-therapies-in-the-united-states">outcomes-based models</a>, insurers will either pay for some of the therapy upfront and the rest only if the patient improves, or cover the entire cost upfront and receive a reimbursement if the patient doesn’t get better. These models help insurers share financial risk with the drug developers.</p>
<p>Another model is known as the “<a href="https://www.doi.org/10.1377/hblog20190924.559225">Netflix model</a>” and would act as a subscription-based service. Under this model, a state Medicaid program would pay a pharmaceutical company a flat fee for access to unlimited treatments. This would allow a state to <a href="https://www.cnbc.com/2019/05/20/commentary-new-drug-cures-risk-widening-income-gap-for-the-poor.html">provide the treatment to residents who qualify</a>, helping governments balance their budget books while giving drugmakers money upfront. </p>
<p>This model has worked well for <a href="https://www.biopharmadive.com/news/cms-approves-louisianas-netflix-model-with-gilead-for-hepatitis-c-drugs/557708/">improving access to hepatitis C drugs in Louisiana</a>.</p>
<p>On the cost front, the key to improving access will be investing in new technologies that simplify medical procedures. For example, the costly sickle cell gene therapies currently in clinical trials require a series of expensive steps, including a stem cell transplant. </p>
<p>The <a href="https://www.gatesfoundation.org/ideas/articles/gene-therapy-mike-mccune">Bill & Melinda Gates Foundation</a>, the <a href="https://www.nih.gov/news-events/news-releases/nih-launches-new-collaboration-develop-gene-based-cures-sickle-cell-disease-hiv-global-scale">National Institute of Health</a> and <a href="https://www.novartis.com/news/media-releases/novartis-and-bill-melinda-gates-foundation-collaborate-discover-and-develop-accessible-vivo-gene-therapy-sickle-cell-disease">Novartis</a> are partnering to develop an alternative approach that would involve a simple injection of gene therapy molecules. The goal of their collaboration is to help bring an affordable sickle cell treatment to <a href="https://www.statnews.com/2019/10/23/nih-gates-foundation-genetic-cures-hiv-sickle-cell/">patients in Africa</a> and other low-resource settings. </p>
<p>Improving access to gene therapies requires collaboration and compromise across governments, nonprofits, pharmaceutical companies and insurers. Taking proactive steps now to develop innovative payment models and invest in new technologies will help ensure that health care systems are ready to deliver on the promise of gene therapies.</p>
<p><em>The Bill & Melinda Gates Foundation has provided funding for The Conversation US and provides funding for The Conversation internationally.</em></p><img src="https://counter.theconversation.com/content/164990/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kevin Doxzen is affiliated with Arizona State University and the World Economic Forum</span></em></p>New payment models may mean more of the people who need these treatments can get them.Kevin Doxzen, Hoffmann Postdoctoral Fellow, Arizona State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1644592021-08-05T12:48:25Z2021-08-05T12:48:25ZFrom CRISPR to glowing proteins to optogenetics – scientists’ most powerful technologies have been borrowed from nature<figure><img src="https://images.theconversation.com/files/414624/original/file-20210804-15-1fuewod.jpg?ixlib=rb-1.1.0&rect=391%2C30%2C3002%2C1822&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Crystal jellyfish contain glowing proteins that scientists repurpose for an endless array of studies.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/crystal-jellyfish-royalty-free-image/1013185852?adppopup=true">Weili Li/Moment via Getty Images</a></span></figcaption></figure><p><a href="https://www.nature.com/scitable/topicpage/discovery-of-dna-structure-and-function-watson-397/">Watson and Crick</a>, <a href="https://www.nobelprize.org/prizes/physics/1933/schrodinger/biographical/">Schrödinger</a> and <a href="https://www.nobelprize.org/prizes/physics/1921/einstein/biographical/">Einstein</a> all made theoretical breakthroughs that have changed the world’s understanding of science. </p>
<p>Today big, game-changing ideas are less common. New and improved techniques are the <a href="https://doi.org/10.1038/nmeth1004-1">driving force behind modern scientific research and discoveries</a>. They allow scientists – <a href="https://scholar.google.com/citations?user=RpiSPiwAAAAJ&hl=en&oi=ao">including chemists like me</a> – to do our experiments faster than before, and they shine light on areas of science hidden to our predecessors. </p>
<p>Three cutting-edge techniques – the gene-editing tool <a href="https://www.newscientist.com/definition/what-is-crispr/">CRISPR</a>, <a href="https://doi.org/10.1242/jcs.072744">fluorescent proteins</a> and <a href="https://www.scientificamerican.com/article/optogenetics-controlling/">optogenetics</a> – were all inspired by nature. Biomolecular tools that have worked for bacteria, jellyfish and algae for millions of years are now being used in medicine and biological research. Directly or indirectly, they will change the lives of everyday people.</p>
<h2>Bacterial defense systems as genetic editors</h2>
<p>Bacteria and viruses battle themselves and one another. They are at constant biochemical war, <a href="https://doi.org/10.1016/j.cub.2019.04.024">competing for scarce resources</a>. </p>
<p>One of the weapons that bacteria have in their arsenal is the <a href="https://www.livescience.com/58790-crispr-explained.html">CRISPR-Cas system</a>. It is a genetic library consisting of short repeats of DNA gathered over time from hostile viruses, paired with a protein called Cas that can cut viral DNA as if with scissors. In the natural world, when bacteria are attacked by viruses whose DNA has been stored in the CRISPR archive, the CRISPR-Cas system hunts down, cuts and destroys the viral DNA.</p>
<p>Scientists have repurposed these weapons for their own use, with groundbreaking effect. Jennifer Doudna, a biochemist based at the University of California, Berkeley, and French microbiologist Emmanuelle Charpentier shared the <a href="https://theconversation.com/nobel-prize-for-chemistry-honors-exquisitely-precise-gene-editing-technique-crispr-a-gene-engineer-explains-how-it-works-147701">2020 Nobel Prize in chemistry</a> for <a href="https://www.nobelprize.org/prizes/chemistry/2020/doudna/lecture/">the development of</a> <a href="https://theconversation.com/nobel-prize-for-crispr-honors-two-great-scientists-and-leaves-out-many-others-147730">CRISPR-Cas as a gene-editing technique</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="French researcher Emmanuelle Charpentier (left) and U.S. biochemist Jennifer Doudna (right)" src="https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=365&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=365&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=365&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=459&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=459&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414580/original/file-20210804-21-1k8hfpd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=459&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">French microbiologist Emmanuelle Charpentier (left) and U.S. biochemist Jennifer Doudna shared the 2020 Nobel Prize in Chemistry for development of the CRISPR-Cas gene editing technique.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/french-researcher-in-microbiology-genetics-and-biochemistry-news-photo/493945408?adppopup=true">Miguel Riopa/AFP via Getty Images</a></span>
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</figure>
<p>The <a href="https://www.genome.gov/human-genome-project">Human Genome Project</a> has provided a nearly complete genetic sequence for humans and given scientists a template to sequence all other organisms. However, before CRISPR-Cas, we researchers didn’t have the tools to easily access and edit the genes in living organisms. Today, thanks to CRISPR-Cas, lab work that used to take months and years and cost hundreds of thousands of dollars can be done in less than a week for just a few hundred dollars. </p>
<p>There are more than 10,000 genetic disorders caused by mutations that occur on only one gene, the <a href="http://hihg.med.miami.edu/thromboticstorm/genetics-overview/single-gene-disorders">so-called single-gene disorders</a>. They affect millions of people. <a href="https://www.genome.gov/Genetic-Disorders/Sickle-Cell-Disease">Sickle cell anemia</a>, <a href="https://www.cff.org/What-is-CF/Genetics/CF-Genetics-The-Basics/">cystic fibrosis</a> and <a href="https://doi.org/10.31887/DCNS.2016.18.1/pnopoulos">Huntington’s disease</a> are among the most well-known of these disorders. These are all obvious targets for CRISPR therapy because it is much simpler to fix or replace just one defective gene rather than needing to correct errors on multiple genes. </p>
<p>For example, in preclinical studies, <a href="https://doi.org/10.1056/NEJMoa2107454">researchers injected</a> an encapsuled CRISPR system into patients born with a rare genetic disease, <a href="https://rarediseases.info.nih.gov/diseases/656/familial-transthyretin-amyloidosis">transthyretin amyloidosis</a>, that causes fatal nerve and heart conditions. Preliminary results from the study demonstrated <a href="https://www.nature.com/articles/d41586-021-01776-4">that CRISPR-Cas can be injected</a> directly into patients in such a way that it can find and edit the faulty genes associated with a disease. In the six patients included in this landmark work, the encapsuled CRISPR-Cas minimissiles reached their target genes and did their job, causing a significant drop in a <a href="https://www.nature.com/scitable/topicpage/protein-misfolding-and-degenerative-diseases-14434929/">misfolded protein</a> associated with the disease. </p>
<h2>Jellyfish light up the microscopic world</h2>
<p>The <a href="https://faculty.washington.edu/cemills/Aequorea.html">crystal jellyfish, <em>Aequorea victoria</em></a>, which drifts aimlessly in the northern Pacific, has no brain, no anus and no poisonous stingers. It is an unlikely candidate to ignite a revolution in biotechnology. Yet on the periphery of its umbrella, it has about 300 photo-organs that give off pinpricks of green light that have changed the way science is conducted.</p>
<p>This bioluminescent light in the jellyfish stems from a luminescent protein called aequorin and a fluorescent molecule called <a href="https://doi.org/10.1242/jcs.072744">green fluorescent protein</a>, or GFP. In modern biotechnology GFP acts as a molecular lightbulb that can be fused to other proteins, allowing researchers to track them and to see when and where proteins are being made in the cells of living organisms. Fluorescent protein technology is used in thousands of labs every day and has resulted in the awarding of two Nobel Prizes, <a href="https://www.nobelprize.org/prizes/chemistry/2008/popular-information/">one in 2008</a> and the <a href="https://www.nobelprize.org/prizes/chemistry/2014/summary/">other in 2014</a>. And fluorescent proteins have now been found in <a href="https://doi.org/10.1242/jcs.072744">many more species</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Fluorescent bacteria in petri dish and test tube" src="https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414422/original/file-20210803-13-vphczn.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">Fluorescent proteins, shown here glowing inside <em>E. coli</em> bacteria, allow researchers to visualize biological structures and processes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/red-and-green-fluorescent-proteins-in-escherichia-royalty-free-image/124368916?adppopup=true">Fernan Federici/Moment via Getty Images</a></span>
</figcaption>
</figure>
<p>This technology proved its utility once again when researchers created genetically modified <a href="https://doi.org/10.1016/j.cell.2020.05.042">COVID-19 viruses that express GFP</a>. The resulting fluorescence makes it possible to follow the path of the viruses as they enter the respiratory system and bind to surface cells with hairlike structures. </p>
<h2>Algae let us play the brain neuron by neuron</h2>
<p>When algae, which depend on sunlight for growth, are placed in a large aquarium in a darkened room, they swim around aimlessly. But if a lamp is turned on, the algae will swim toward the light. The single-celled <a href="https://www.britannica.com/science/flagellate">flagellates</a> – so named for the whiplike appendages they use to move around – don’t have eyes. Instead, they have a structure called an eyespot that distinguishes between light and darkness. The eyespot is studded with <a href="https://doi.org/10.1073/pnas.1525538113">light-sensitive proteins called channelrhodopsins</a>. </p>
<p>In the early 2000s, <a href="https://doi.org/10.1038/nn1525">researchers discovered</a> that when they genetically inserted these channelrhodopsins into the nerve cells of any organism, illuminating the channelrhodopsins with blue light caused neurons to fire. This technique, known as optogenetics, involves inserting the algae gene that makes channelrhodopsin into neurons. When a pinpoint beam of blue light is shined on these neurons, the channelrhodopsins open up, calcium ions flood through the neurons and the neurons fire. </p>
<p>Using this tool, scientists can stimulate groups of neurons selectively and repeatedly, thereby gaining a more precise understanding of which neurons to target to treat specific disorders and diseases. Optogenetics might hold the key to treating debilitating and deadly brain diseases, such as Alzheimer’s and Parkinson’s. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of amyloid plaque buildup on cells" src="https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/414426/original/file-20210803-25-1p9rv2y.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Optogenetics could help treat Alzheimer’s disease, which is characterized by the buildup of misfolded proteins called amyloid plaques.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/illustration-of-alzheimers-disease-royalty-free-illustration/1124681623?adppopup=true">Sciepro/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>But optogenetics isn’t only useful for understanding the brain. Researchers have used optogenetic techniques <a href="https://doi.org/10.1038/s41591-021-01351-4">to partially reverse blindness</a> and have found promising results in clinical trials using optogenetics on patients with <a href="https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/retinitis-pigmentosa">retinitis pigmentosa</a>, a group of genetic disorders that break down retinal cells. And in mouse studies, the technique has been used to <a href="https://doi.org/10.1016/j.pbiomolbio.2019.08.013">manipulate heartbeat</a> and <a href="https://doi.org/10.1016/j.autneu.2020.102733">regulate bowel movements of constipated mice</a>. </p>
<h2>What else lies within nature’s toolbox?</h2>
<p>What undiscovered techniques does nature still hold for us? </p>
<p>According to <a href="https://doi.org/10.1073/pnas.1711842115">a 2018 study</a>, people represent just 0.01% of all living things by mass but have caused the loss of 83% of all wild mammals and half of all plants in our brief time on Earth. By annihilating nature, humankind might be losing out on new, powerful and life-altering techniques without having even imagined them.</p>
<p>[<em>Over 100,000 readers rely on The Conversation’s newsletter to understand the world.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=100Ksignup">Sign up today</a>.]</p>
<p>After all, no one could have foreseen that the discovery of three groundbreaking processes derived from nature could change the way science is done.</p><img src="https://counter.theconversation.com/content/164459/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marc Zimmer received funding from NIH for his fluorescent protein research. </span></em></p>Three pioneering technologies have forever altered how researchers do their work and promise to revolutionize medicine, from correcting genetic disorders to treating degenerative brain diseases.Marc Zimmer, Professor of Chemistry, Connecticut CollegeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1536412021-02-01T18:58:20Z2021-02-01T18:58:20ZNew CRISPR technology could revolutionise gene therapy, offering new hope to people with genetic diseases<figure><img src="https://images.theconversation.com/files/381591/original/file-20210201-13-qr3zh4.jpg?ixlib=rb-1.1.0&rect=47%2C4%2C3147%2C1571&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>The day a muddled mob stormed the US Capitol building, a team of American researchers published a paper <a href="https://www.nature.com/articles/s41586-020-03086-7">in Nature</a> that signified a landmark in gene therapy.</p>
<p>The head of the US National Institutes of Health, Francis Collins had joined forces with Harvard University professor David Liu and others to tackle progeria, a genetic disorder that causes children to age rapidly. </p>
<p>The achievement, successfully tested in mice, was made possible by Liu’s invention of a second-generation CRISPR gene-editing technology called “base editing”. With this, researchers may eventually be able to correct lifelong genetic diseases, including <a href="https://www.webmd.com/children/progeria#1">progeria</a>, in humans.</p>
<h2>A rare but devastating disease</h2>
<p>Francis Collins, former leader of the Human Genome Project, had worked on progeria for many years before the breakthrough. </p>
<p>Children carrying the mutation for progeria have normal intelligence but show early signs of general ageing, including hair loss and hearing loss. By their teenage years they appear very old. Few live past the age of 13. </p>
<p>In 2003, Collins’s lab <a href="https://directorsblog.nih.gov/tag/progeria/">discovered</a> progeria is caused by a mutation (which you can think of as a “misspelling”) in a gene that encodes a protein called Lamin A. Lamin A has a structural role in the cell’s nucleus. </p>
<p>Many of us carry mutations in various genes. But as we typically have two copies of genes (one from our mother and one from our father), we tend to have at least one good copy and that’s usually enough.</p>
<p>But the progeria mutation in Lamin A is different. While there may be a good copy present, the mutant copy generates a poisonous product that messes things up, like a spanner in the works. This type of mutation is called a “dominant negative mutation”.</p>
<p>The solution, ideally, would be to specifically correct the mutant copy using <a href="https://theconversation.com/what-is-crispr-gene-editing-and-how-does-it-work-84591">CRISPR</a>. With this gene-editing tool, scientists can direct a pair of molecular “scissors” to any part of the genome (DNA). Unfortunately, first-generation CRISPR technologies — while good at cutting genes — do not have the level of surgical precision or efficiency needed to correct the Lamin A mutation. </p>
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<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-a-gene-12951">Explainer: what is a gene?</a>
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</em>
</p>
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<h2>Complications with mass cell editing</h2>
<p>CRISPR scissors are good at finding their target and cutting, but the reconstructive surgery that comes after is left to the cell — and isn’t guaranteed to happen in every cell. </p>
<p>In the lab, researchers can usually manage by just correcting a few cells before growing them in a petri dish for further research. </p>
<p>But in humans we need to accurately correct most, if not all, cells. It would be pointless to correct the progeria mutation in five cells in a patient’s finger, while leaving the rest of the body unrepaired.</p>
<p>This is where David Liu’s work on “base editors” is critical. Liu identified the limitations of CRISPR technology very early and began developing molecular machines that could do more than operate only as targeted molecular scissors. </p>
<p>He started with naturally occurring enzymes, which can change one type of chemical base of the genetic code into another; for example, enzymes that can convert an A (adenine) to a G (guanine), or a C (cytosine) to a T (thymine).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing basic DNA structure and chemical bases." src="https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.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">The double helix shape of DNA is supported by an alternating sugar-phsophate backbone (the sides). Attached to each sugar on the backbone is one of four chemical bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The order of these bases is what determines an organism’s genetic code.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Liu then modified the enzymes to make them more precise and fused them to CRISPR to create fusion proteins called “base editors”. Since CRISPR technology is good at reading DNA and finding a target, it can effectively deliver the editors to the gene that needs to be changed.</p>
<p>It’s important to highlight Liu deliberately developed base editors so that they change letters, but no longer sever DNA like CRISPR scissors. This is crucial, as cutting DNA increases the risk of larger chromosomal deletions, which can potentially damage cells.</p>
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<strong>
Read more:
<a href="https://theconversation.com/the-resilience-project-finding-those-rare-people-with-genetic-disease-mutations-who-are-healthy-57800">The Resilience Project: finding those rare people with genetic disease mutations who are healthy</a>
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<h2>The differences of mice and men</h2>
<p>Collins, Liu and their colleagues knew they would have to get base editors into all (or at least <em>most</em>) of the cells of a mouse with progeria to cure it. For this, they relied on using hollowed-out viruses as delivery vectors. </p>
<p>They used a vector based on the Adeno Associated Virus, or AAV. As students, we joked AAV stood for “almost a virus”, as it’s one of the smallest viruses and doesn’t cause any known disease. </p>
<p>Collins and Liu packaged the AAV virus particles with genes encoding the relevant base-editing enzyme and delivered them into the mice. The treated mice essentially avoided the disease and became indistinguishable from healthy mice.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/GO306dK8m8c?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">In this video, Collins and Lui discuss their work involving treating progeria in mice.</span></figcaption>
</figure>
<p>But, of course, this all happened in mice — and humans are bigger. We don’t know how difficult it will be to upscale this gene-editing machinery to work reliably in humans. But in any case, Collins and Liu have taken an inspiring first step by showing it’s possible in mice. </p>
<p>Base-editing CRISPR tools are a dream come true for experts committed to gene therapy and for families afflicted by conditions such as progeria. Work on this front is just beginning. But in these dark pandemic times, it provides much-needed new hope.</p><img src="https://counter.theconversation.com/content/153641/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley works for UNSW as Deputy Vice-Chancellor Academic and Student Experience, and a Professor of Molecular Biology. He holds or has held Australian Research Council and National Health and Medical Research Council grants, and collaborates with biotechnology companies, such as CSL and various international labs doing CRISPR-gene editing. He is on the Board of The Conversation, and Chair of the Editorial Board, Chair of UNSW Press, Deputy Director of the Australian Science Media Centre, and is an Honorary Associate of the Australian Museum. </span></em></p>Using ‘base editing’, researchers have cured progeria in mice. This genetic syndrome causes premature ageing in humans – those with the disease usually don’t live past the age of 13.Merlin Crossley, Deputy Vice-Chancellor Academic and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1286962020-02-10T05:01:54Z2020-02-10T05:01:54ZWhat is autoinflammatory disease, the rare immune condition with waves of fever?<figure><img src="https://images.theconversation.com/files/313866/original/file-20200206-149802-8eqdou.jpg?ixlib=rb-1.1.0&rect=0%2C8%2C1000%2C657&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/pediatrician-taking-temperature-professional-thermometer-229346311">from www.shutterstock.com</a></span></figcaption></figure><p>Just over 20 years ago, people from three generations of an American family were referred to the <a href="https://www.nih.gov/">National Institutes of Health</a> (NIH) in Washington DC with an unknown disease. </p>
<p>They were ten to 82 years old and had symptoms including monthly episodes of unexplained high fevers (up to 41°C), lasting two to seven days. </p>
<p>They also had painful swollen <a href="https://www.healthdirect.gov.au/lymph-nodes">lymph nodes</a>, enlarged <a href="https://www.health.qld.gov.au/news-events/news/facts-about-your-spleen-splenectomy-immune-system-what-is">spleens</a> and livers, abdominal pain, mouth ulcers, joint pain, and a patchwork of other symptoms.</p>
<p>The symptoms, which they’d had since shortly after birth, seemed like an inflammatory reaction. However, doctors could not trace the episodes to an infection.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-inflammation-and-how-does-it-cause-disease-84997">Explainer: what is inflammation and how does it cause disease?</a>
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<p>We now know these symptoms are typical of <a href="https://www.wehi.edu.au/research-diseases/immune-health-and-infection/autoinflammatory-diseases">autoinflammatory diseases</a> – rare conditions with seemingly unprovoked episodes of fever and inflammation. </p>
<p>Because the inflammatory episodes occur regularly, the diseases are also known as “<a href="https://my.clevelandclinic.org/health/articles/17354-periodic-fever-syndrome">periodic fever syndromes</a>”. In addition to being painful and debilitating, some of the conditions can damage vital organs, such as the heart and lungs.</p>
<h2>What causes autoinflammatory disease?</h2>
<p>Autoinflammatory diseases are <a href="https://www.ncbi.nlm.nih.gov/pubmed/24247370">caused by</a> abnormal activation of the <a href="https://www.ncbi.nlm.nih.gov/books/NBK26846/">innate immune system</a>, the body’s first-line defence against invading pathogens.</p>
<p>The innate immune system is a hard-wired response that can quickly mobilise to fight foreign invaders. Among its many roles is the release of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785020/">cytokines</a>. </p>
<p>These are immune messengers critical for alerting and recruiting other cells to the fight, increasing blood circulation and inducing fever. More about cytokines later.</p>
<p>However, in autoinflammatory diseases, invading microbes don’t cause the fever and inflammation. Instead, genetic changes (mutations) lead to the innate immune system being activated for what appears to be no reason, causing uncontrolled inflammation.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
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<p>Autoinflammatory diseases typically begin in childhood, often from birth, and are lifelong conditions. The genetic mutations can be passed from parents to their children, leading to multiple cases of disease in an extended family. </p>
<p>Autoinflammatory diseases are different from autoimmune diseases, such as <a href="https://theconversation.com/explainer-multiple-sclerosis-32662">multiple sclerosis</a>, which are caused by defects in the adaptive immune system, a different arm of the immune response.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-are-autoimmune-diseases-22577">Explainer: what are autoimmune diseases?</a>
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<p>There are a number of different autoinflammatory diseases, often caused by different genetic mutations.</p>
<h2>How do we treat autoinflammatory disease?</h2>
<p>Autoinflammatory diseases cannot be cured, and treatment is usually to relieve symptoms during an attack. Patients are often treated with high doses of <a href="https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/corticosteroids">corticosteroids</a>, a broad-brush approach to suppress the immune system.</p>
<p>Autoinflammatory diseases are also <a href="https://ghr.nlm.nih.gov/condition/tumor-necrosis-factor-receptor-associated-periodic-syndrome#statistics">quite rare</a>, which in the past has made it difficult to develop specific treatments.</p>
<p>Because autoinflammatory diseases are typically associated with excess production of cytokines, they are sometimes treated with so-called biologics – antibodies that mop up these excess cytokines.</p>
<p>These are usually antibodies to the cytokines <a href="https://www.medicalnewstoday.com/articles/324841.php">tumour necrosis factor</a> (TNF) or <a href="https://www.rndsystems.com/resources/articles/interleukin-1">interleukin-1</a>. </p>
<p>However biologics are expensive, and can have <a href="https://jamanetwork.com/journals/jama/article-abstract/202873">significant</a> <a href="https://www.nature.com/articles/s41467-017-02466-4">side-effects</a>.</p>
<p>Without knowing the cause of an inflammatory disease, treatment is a trial and error process; a drug that works for one person may not work for another.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=541&fit=crop&dpr=1 600w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=541&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=541&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=679&fit=crop&dpr=1 754w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=679&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=679&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Antibodies against the molecule TNF (above) can be used to treat excess inflammation.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/tumor-necrosis-factor-alpha-tnf-cytokine-1246006945">from www.shutterstock.com/StudioMolekuul</a></span>
</figcaption>
</figure>
<h2>Can genetic testing help?</h2>
<p>The discovery of mutations in genes causing autoinflammatory diseases has led to the development of genetic tests to help diagnosis.</p>
<p>However, some people with autoinflammatory disease do not have a change in one of the known disease-causing genes. </p>
<p>So our researchers have established the <a href="https://www.aadry.org/">Australian Autoinflammatory Disease Registry</a> to help identify other genetic causes of autoinflammatory diseases. </p>
<h2>How we found out about the underlying mechanism</h2>
<p>While the NIH researchers were looking for a cause of the American family’s disease, another strand of the story was playing out in Australia.</p>
<p>We were looking at the role of the master cytokine TNF, which controls many aspects of the body’s inflammatory response, and its partner RIPK1.</p>
<p>Usually, the body has many checks and balances to ensure these molecules are tightly controlled. </p>
<p>But we worked with the <a href="https://www.nature.com/articles/s41586-019-1828-5_">US scientists who found</a> a critical mutation in the gene coding for RIPK1. We found this mutation, leading to changes in just one amino acid, was enough to supercharge its partner TNF into an elite killer. </p>
<p>This is what triggered the uncontrolled inflammation behind the American family’s disease.</p>
<p>Our team named this condition <a href="https://pursuit.unimelb.edu.au/articles/the-genetic-mutation-behind-a-new-autoinflammatory-disease">CRIA syndrome</a> (cleavage-resistant RIPK1-induced autoinflammatory syndrome).</p>
<h2>So what does this mean?</h2>
<p>Understanding the molecular mechanism by which CRIA syndrome causes inflammation gives us an opportunity to get to the root of the problem, and to offer an alternative to existing treatments.</p>
<p>For this American family, treatment with an agent that inhibits the faulty RIPK1 might be a tailored option.</p>
<p>Lastly, the discovery of CRIA syndrome now confirms RIPK1 can play an important role in regulating inflammation in humans. So it <a href="https://www.nature.com/articles/ni.3206">may also play</a> a role in far more common human illnesses, such as colitis (inflammation of the colon), rheumatoid arthritis and the skin condition psoriasis.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/what-is-rheumatoid-arthritis-the-condition-tennis-champion-caroline-wozniacki-lives-with-119537">What is rheumatoid arthritis, the condition tennis champion Caroline Wozniacki lives with?</a>
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<img src="https://counter.theconversation.com/content/128696/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Silke consults for Anaxis, an Australian company developing drugs to inhibit inflammatory diseases. He has a fellowship from the NHMRC and the work on RIPK1 cleavage was also funded by the NHMRC (Project #1163581).</span></em></p><p class="fine-print"><em><span>Najoua Lalaoui receives funding from the Cancer Australia and Cure Cancer Australia Foundation (Project grant 1145588) and the Victorian Cancer Agency Mid-career Fellowship 17030. </span></em></p>A rare type of inflammatory disease that causes repeated bouts of high temperatures can run in families. Here’s what we know so far.John Silke, Leader, Infection, Inflammation and Immunity theme, Walter and Eliza Hall InstituteNajoua Lalaoui, Postdoctoral research fellow, Inflammation Division, Walter and Eliza Hall InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1214412019-09-13T03:27:35Z2019-09-13T03:27:35ZPolycystic kidney disease, the most common genetic kidney disorder you’ve probably never heard of<figure><img src="https://images.theconversation.com/files/290811/original/file-20190904-175700-vq8d1k.jpg?ixlib=rb-1.1.0&rect=53%2C0%2C6000%2C3997&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">If one parent has ADPKD, their child has a one in two chance of getting it.</span> <span class="attribution"><span class="source">From shutterstock.com</span></span></figcaption></figure><p>Autosomal-dominant polycystic kidney disease (<a href="https://pkdaustralia.org/adpkd/">ADPKD</a>) is the most common genetic kidney disorder, and the <a href="https://www.anzdata.org.au/report/anzdata-41st-annual-report-2018-anzdata/">fourth most common</a> cause of kidney failure in Australian adults. It affects about <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imj.13143">one in 1,000 Australians</a>. </p>
<p>In people with ADPKD, a mutation in one or two genes leads to the development and progressive growth of cysts in the kidneys, causing a decline in kidney function.</p>
<p>Labor senator Malarndirri McCarthy, a Yanyuwa woman, recently spoke publicly about having ADPKD after <a href="https://www.smh.com.au/politics/federal/senator-reveals-kidney-disease-that-saw-her-leave-question-time-for-hospital-20190802-p52d8w.html">she became unwell</a> with a kidney infection and had to leave the Senate. </p>
<p>But a newly available treatment for ADPKD shows promise for people with the disease.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-chronic-kidney-disease-and-why-are-one-in-three-at-risk-of-this-silent-killer-81942">Explainer: what is chronic kidney disease and why are one in three at risk of this silent killer?</a>
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<h2>What is ADPKD?</h2>
<p>If one parent has ADPKD, the children have a 50% chance of inheriting the gene (though <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imj.13143">up to 10%</a> of patients don’t have a family history).</p>
<p>Where it is inherited, the age of diagnosis and rate of progression to kidney failure in the parent gives some indication of how the disease will develop in affected children. </p>
<p>The cysts are like balloons filled with water, which start small in childhood and increase in size over time.</p>
<p>Typically, the cysts don’t start to cause problems until later in life. The average age at diagnosis is <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1402685">27 years</a>. </p>
<p>As the cysts grow, normal working tissue in the kidney is replaced with enlarging cysts. So with time, the kidneys don’t work as well.</p>
<p>For about <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imj.13143">half of people with ADPKD</a>, their condition will eventually progress to kidney failure, which may be treated with dialysis or a transplant. </p>
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<img alt="" src="https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=442&fit=crop&dpr=1 600w, https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=442&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=442&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=556&fit=crop&dpr=1 754w, https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=556&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/288676/original/file-20190820-170918-1foruju.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=556&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Cysts grow on the kidneys of a person with polycystic kidney disease, often impacting kidney function.</span>
<span class="attribution"><span class="source">From shutterstock.com</span></span>
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</figure>
<p>While the loss of kidney function is paramount, the cysts may cause other symptoms and complications too. </p>
<p>Symptoms can include high blood pressure and chronic pain or heaviness in the back, sides and abdomen. The growth of cysts means the kidneys can grow to as large as <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/j.1464-410X.2007.07229.x">5-6kg in size</a>.</p>
<p>Blood in the urine, urinary tract infections, kidney stones and infections in the cysts are not uncommon in people with ADKPD, and can all impact quality of life. </p>
<p>Other organs may also be affected. People with ADPKD can develop cysts in the liver, pancreas and bowel, and about 10% will experience balloon dilations of the <a href="https://www.ncbi.nlm.nih.gov/pubmed/26260542">blood vessels in the brain</a>, called aneurysms.</p>
<h2>Treatment</h2>
<p>Until recently, treatment of ADPKD was directed towards early detection, control of blood pressure, lifestyle measures such as quitting smoking, weight control and diet, antibiotics for infections, analgesics for pain and the management of progressive kidney dysfunction via dialysis and transplantation. None of these therapies however directly slowed the growth of cysts. </p>
<p>But on January 1, 2019, tolvaptan <a href="https://pkdaustralia.org/news/">was listed</a> on the Pharmaceutical Benefits Scheme. Australia now joins the United States, the European Union, and several other countries where this drug was already available. </p>
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Read more:
<a href="https://theconversation.com/kidney-disease-in-aboriginal-australians-perpetuates-poverty-15031">Kidney disease in Aboriginal Australians perpetuates poverty</a>
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<p>Tolvaptan, which is taken in tablet form, slows the growth of cysts by <a href="https://www.ncbi.nlm.nih.gov/pubmed/28379536">blocking a hormone called vasopressin</a>. Vasopressin is critical in triggering the formation of cysts. In this way, tolvaptan prolongs the time to kidney failure.</p>
<p>In one study, three years of treatment with tolvaptan <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1205511">reduced the rate of cyst growth</a> by around 50% in comparison to a placebo treatment. The authors suggested tolvaptan may delay dialysis or the need for a transplant for six to nine years for patients with ADPKD, particularly if started early. </p>
<p>People who took tolvaptan in this study also had lower incidence of ADPKD-related complications including urinary tract infections and kidney pain.</p>
<h2>Kidney disease and Indigenous Australians</h2>
<p>ADPKD is not actually more common in Aboriginal and Torres Strait Islander communities, as other causes of <a href="https://www.menzies.edu.au/page/Research/Indigenous_Health/Diabetes_and_kidney_disease/Kidney/">chronic kidney disease</a> are. This may be because ADPKD is inherited. </p>
<p>The majority of chronic kidney disease develops as a complication of diabetes, which affects Aboriginal and Torres Strait Islander populations more commonly and typically <a href="https://www.menzies.edu.au/page/Research/Indigenous_Health/Diabetes_and_kidney_disease/Diabetes/">at a younger age</a> than the overall Australian population.</p>
<p>Kidney disease, whatever the cause, remains a significant issue for Aboriginal and Torres Strait Islander communities. People in remote Indigenous communities in particular face challenges around accessing treatments in large urban centres, and have poorer access to organ transplants.</p>
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<strong>
Read more:
<a href="https://theconversation.com/why-simple-school-sores-often-lead-to-heart-and-kidney-disease-in-indigenous-children-86066">Why simple school sores often lead to heart and kidney disease in Indigenous children</a>
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<p>There are several nationally targeted activities and proposals aimed at reducing the burden of chronic kidney disease in Indigenous Australians.</p>
<p>The <a href="https://www.menzies.edu.au/icms_docs/281923_Roundtable_Towards_Roadmap_For_Renal_Health_-_Media_Release.pdf">Renal Health RoadMap</a> is designed to support health systems in early detection and management of diabetes and chronic kidney disease. It also seeks to address the social determinants of poor health in Indigenous communities, including housing quality and availability, and health infrastructure.</p>
<p>In 2018, Minister for Indigenous Australians Ken Wyatt commissioned <a href="https://www.tsanz.com.au/TSANZ%20Performance%20Report%20-%20Improving%20Indigenous%20Transplant%20Outcomes%20(Final%20edited)-1.pdf">a report</a> detailing how access to and outcomes of kidney transplants could be improved among Indigenous Australians. He also established a <a href="https://www.anzdata.org.au/anzdata/for-information-2/tsanz/">National Indigenous Kidney Transplantation Taskforce</a> to implement the recommendations from this report. </p>
<p>Some key recommendations include improving the communication between health-care teams, patients and their families, addressing cultural bias in the delivery of health care, and improving the quality of data around transplant access and outcomes.</p>
<p>Addressing transplant and treatment inequities will benefit Indigenous Australians with kidney failure sustained from ADPKD and chronic kidney disease more broadly. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/to-close-the-health-gap-we-need-programs-that-work-here-are-three-of-them-91482">To close the health gap, we need programs that work. Here are three of them</a>
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<img src="https://counter.theconversation.com/content/121441/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jaquelyne Hughes receives funding from the National Health and Medical Research Council, is the convener of the Aboriginal and Torres Strait Islander Health Working Group of the Australia and New Zealand Dialysis and Transplantation Registry (ANZDATA), and the Deputy Chair of the TSANZ National Indigenous Kidney Transplantation Taskforce.</span></em></p><p class="fine-print"><em><span>Karen Dwyer 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>You might have heard of polycystic ovary syndrome, but what about polycystic kidney disease? This genetic disorder sees cysts growing in the kidneys.Karen Dwyer, Deputy Head, School of Medicine, Deakin UniversityJaquelyne Hughes, Senior Research Fellow, Menzies School of Health ResearchLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1076772018-11-27T12:40:11Z2018-11-27T12:40:11ZThe road to enhancement, via human gene editing, is paved with good intentions<figure><img src="https://images.theconversation.com/files/247373/original/file-20181126-140525-1pu35zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A Chinese scientist claims he edited the DNA of twin girls during an in vitro fertilization procedure. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/vitro-fertilisation-ivf-cell-under-microscope-764231488?src=ENuyRzFDhQbVzA4lEBm-Yg-1-0">CI Photos / Shutterstock.com</a></span></figcaption></figure><p>It <a href="https://apnews.com/4997bb7aa36c45449b488e19ac83e86d">appears</a> that researchers in China have facilitated the birth of the first “designer baby” – actually babies, twin girls who are supposedly genetically resistant to HIV. The scientist who created the embryos, as well as some American scientists like Harvard’s George Church, have praised the beneficent intent to producing a child who is resistant to disease. Who could argue with such good intentions? </p>
<p>But, once you can do this with one gene, you could someday do it with any gene – like those linked with <a href="https://doi.org/10.1038/mp.2016.45">educational attainment</a>. Those who praise the Chinese research have given no mechanism, or rules and regulations, that would allow human gene editing for only beneficent purposes. As the old proverb says, “The road to hell is paved with good intentions.”</p>
<p>For over 20 years I have focused my research on debates about <a href="https://www.press.uchicago.edu/ucp/books/book/chicago/P/bo3621106.html">human gene editing</a> and <a href="https://global.oup.com/academic/product/what-is-a-human-9780190608071?q=evans%2C%20john%20hyde&lang=en&cc=us">other biotechnologies</a>. I have watched these debates unfold, but I am shocked by the recent speed of developments.</p>
<p>The Chinese scientist, He Jiankui, claimed to have altered embryos for seven couples during fertility treatment in China. His goal was to disable a gene that encodes a gateway protein that allows the HIV virus to enter a cell. A woman nurtured two of those embryos and this month gave birth to non-identical twin girls who would, according to He, be resistant to HIV. </p>
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<a href="https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/247399/original/file-20181126-140525-15knyis.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Chinese scientist He Jiankui claims he helped make the world’s first genetically edited babies. He revealed the news on Monday, Nov. 26, in Hong Kong to one of the organizers of an international conference on gene editing.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Genetic-Frontiers-Gene-Edited-Babies/c5f8eb88e0e64fc3aed2b2388e0195ff/4/0">AP Photo/Mark Schiefelbein</a></span>
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<p>Given the secrecy involved, it is difficult to verify He’s claim. The research wasn’t published in a peer-reviewed journal, the parents of the twins refused to speak with the media, and no one has tested the DNA of the girls to verify what He says is true. But what is more important for now is that there are scientists trying to create these enhanced humans who could pass on this trait to their offspring.</p>
<h2>Mainline and reform eugenics</h2>
<p>Creating an “improved” human species has long been the dream of eugenicists. The mainline, old school version of eugenics assumed that superior traits were found in particular races, ethnicities, and particularly in the United Kingdom, social classes. This logic culminated in the Holocaust where the Nazis concluded that some ethnic groups are genetically superior to others, and that the “inferior” ones should be exterminated and completely erased. </p>
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<a href="https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=807&fit=crop&dpr=1 600w, https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=807&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=807&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1015&fit=crop&dpr=1 754w, https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1015&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/247409/original/file-20181126-140513-1m0g57a.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1015&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">This is a magazine published by the Office of Racial Policy of the Nazi Party while they were in power. The poster says: 60,000 Reichsmark is what this person suffering from hereditary illness costs the community in his lifetime. Fellow citizen, that is your money too.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Neues_Volk_eugenics_poster,_c._1937_(brightened).jpeg">Unknown author / Wikimedia Commons</a></span>
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<p>The revelation of the Holocaust destroyed mainline eugenics, but a <a href="http://www.hup.harvard.edu/catalog.php?isbn=9780674445574">“reform” eugenics</a> arose in its wake in the 1950s. This brand of eugenics assumed that “superior traits” could be found among all ethnic groups. All that needed to happen was to get these superior people to produce more children and discourage those with inferior traits from reproducing. This turned out to be difficult.</p>
<p>But in the early 1950s, Francis Crick and James Watson <a href="https://doi.org/10.1038/171737a0">discovered the chemical structure of DNA</a>, which suggested that the genes of humans could be improved through chemical modification of their reproductive cells. A typical response was from prominent biologist <a href="https://news.ucsc.edu/2017/04/robert-sinsheimer-in-memoriam.html">Robert Sinsheimer</a> <a href="https://www.press.uchicago.edu/ucp/books/book/chicago/P/bo3621106.html">who wrote in 1969</a> that the new genetic technologies of the time allowed for “a new eugenics.” According to Sinsheimer, the old eugenics required selecting fit individuals to breed and culling the unfit. “The new eugenics would permit in principle the conversion of all of the unfit to the highest genetic level … for we should have the potential to create new genes and new qualities yet undreamed.”</p>
<h2>The slippery slope of the gene editing debate</h2>
<p>The modern ethical debate about human gene editing can be traced back to this era. The debate was implicitly set up like a slippery slope. </p>
<p>At the top of the slope was an act of gene editing deemed indisputably virtuous – a step most people were willing to take – such as repairing sickle cell anemia. However, the slope was slippery. It is very difficult to say that changing other traits that are not deadly, like deafness, are not equally acceptable. Once you figure out how to change one gene, you can change any gene, regardless of its function. If we fix sickle cell, why not deafness, or late onset heart disease, or a lack of “normal” intelligence, or as we approach the bottom, a lack of superior intelligence?</p>
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<a href="https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=795&fit=crop&dpr=1 600w, https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=795&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=795&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=998&fit=crop&dpr=1 754w, https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=998&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/247407/original/file-20181126-140513-130f9qm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=998&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Aldous Huxley wrote about a world in which everyone was genetically engineered and all opportunity was determined by your genetic code.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Associated-Press-International-News-United-King-/c36a840762e5da11af9f0014c2589dfb/3/0">AP Photo/Eraldo Peres</a></span>
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<p>At the bottom of the slope was the dystopian world where nobody wants to end up. This is typically depicted as a society based on total genetic control of offspring where people’s lives and opportunities are determined by their genetic pedigree. Today the bottom of the slope is represented by the late 1990s movie “<a href="https://en.wikipedia.org/wiki/Gattaca">Gattaca</a>.” </p>
<h2>Stepping onto the slope</h2>
<p>In the 1970s, essentially all of the participants in the debate stepped onto the slope and approved of somatic gene therapy – a strategy for healing genetic diseases in the bodies of living people where genetic changes would not be passed to any offspring. Participants in the ethical debate about gene editing stepped onto this slope because they were confident that they had blocked any possible slide by creating a strong norm against the modification of DNA that passed to the next generation: the germline wall. (The germline means influencing not only the person modified, but their descendants.) </p>
<p>Somatic changes could be debated, but researchers would not move beyond the wall to change people’s inheritance – to change the human species as the eugenicists had long desired. Another barrier to the road to hell that turned out to be permeable was the wall between blocking disease and enhancing an individual. Scientists could try to use gene editing to avoid genetic diseases, like sickle cell disease, but not to create “improved” humans.</p>
<p>The recent actions of the Chinese scientist leap over both the germline and the enhancement walls. It is the first known act of human germline gene editing. These twin girls may pass their newfound resistance to HIV to their own children. It is also not meant to avoid a genetic disease like sickle cell anemia, but to create an enhanced human, albeit an enhancement made in the name of fighting infectious disease.</p>
<h2>Calling for a new wall</h2>
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<figcaption><span class="caption">A Chinese researcher claims that he helped create the world’s first genetically edited babies.</span></figcaption>
</figure>
<p>Unlike in earlier years of the human gene editing debate, we are given no argument for where these applications would stop. Those advocating the Chinese scientist’s use of gene editing do not point to a wall further down the slope that can be used to reassure ourselves that by allowing this presumably beneficent application we will not eventually end up at the bottom. Many scientists seem to think that a wall can be constructed with “disease” applications in the acceptable part of the slope and “enhancement” in the unacceptable part below. </p>
<p>However, how one defines “disease” is notoriously fluid, with pharmaceutical companies frequently creating new diseases to be treated in a process sociologists call <a href="https://books.google.com/books?hl=en&lr=&id=hYpZjDD67dkC&oi=fnd&pg=PR13&dq=medicalization&ots=GKrE5_HLc4&sig=u-a7FNTRQn3Slg53MSS_Rs_vmBw#v=onepage&q=medicalization&f=false">medicalization.</a> Moreover, is deafness a disease? Many deaf people do not think so. We also cannot simply rely upon the medical profession to define disease, as some practitioners are engaged in activities that are more aptly described as enhancement (think plastic surgery). A <a href="https://doi.org/10.17226/24623">recent report</a> by the National Academy of Sciences concluded that the distinction between disease and enhancement is hopelessly muddled.</p>
<p>So, while the scientists defending the first enhanced baby may be right that this is a moral good, unlike previous debaters they have given society no walls or barriers that allow us to confidently walk on to this new slippery slope. It is just dodging responsibility to say that “<a href="https://apnews.com/4997bb7aa36c45449b488e19ac83e86d">society will decide what to do next,</a>” as did He, or to say that the research “<a href="https://apnews.com/4997bb7aa36c45449b488e19ac83e86d">is justifiable,</a>” without defining a limit, as did Harvard University’s George Church. </p>
<p>For a responsible debate, participants must state not only their conclusion about this particular act of enhancement, but also where they will build a wall and, critically, how this wall will be maintained in the future.</p>
<p><em>This article was updated on November 29, 2018, to refer to He Jiankui by his last name.</em></p><img src="https://counter.theconversation.com/content/107677/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Evans does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A Chinese scientist has revealed he edited the DNA of twin girls born through in vitro fertilization. These girls are designed to be resistant to HIV. Is the edit a medical necessity or an enhancement?John Evans, Professor of Sociology, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1027772018-09-06T13:00:29Z2018-09-06T13:00:29ZHuntington’s disease may start much earlier than previously thought, before symptoms appear<figure><img src="https://images.theconversation.com/files/235224/original/file-20180906-190665-mprmwn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Grey matter.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/engraving-brain-illustration-gray-scale-monochrome-533933176?src=0qMPwIzLEtNMAGGfywpNHw-1-5">Jolygon/Shutterstock</a></span></figcaption></figure><p>Huntington’s disease is extraordinary for several reasons. It is caused by changes in a single gene – Huntingtin – and its mode of inheritance means that a child from a patient who has the disease has a 50% chance of being affected by it, too. Uncommonly for a genetic disease, the typical age when symptoms start to be experienced is in mid-adulthood, between 30 and 50 years old.</p>
<p>Huntington’s is classed as a neurodegenerative disease, which means that after onset, certain nerve cells are lost. The Huntingtin gene that is altered in the disease expresses a toxic protein – also called Huntingtin – in every cell of the body, but only a specific type of nerve cell (called medium spiny neurons) in a certain part of the brain (called the striatum) dies in Huntington’s patients. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=457&fit=crop&dpr=1 600w, https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=457&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=457&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=574&fit=crop&dpr=1 754w, https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=574&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/235234/original/file-20180906-190656-1vjpzi5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=574&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Neurons (red) and astrocytes (green) in a brain with Huntington’s disease.</span>
<span class="attribution"><span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>When these nerve cells die, it causes patients to display the disease’s characteristic involuntary movements. Those with the illness typically experience a gradual decline in motor skills, cognitive abilities and behaviour over a 20 year period. It leads to them needing 24 hour nursing care, and ultimately the disease is fatal. </p>
<p>Most previous <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.26331">research</a> into Huntington’s has focused on the course the disease takes after symptoms become apparent. But the Huntingtin protein is expressed in every cell from the earliest stages of embryonic development. So for <a href="http://www.pnas.org/content/early/2018/08/21/1807962115.short?rss=1">our recently published study</a> we wanted to better understand the effects of the mutant gene on brain cells before the onset of symptoms. </p>
<p>We chose to investigate the earliest ages at which behavioural tests can be performed – shortly after birth. We found that the mutant Huntingtin gene causes changes in mouse and rat pups long before the onset of “classical” symptoms (for example, involuntary movements). </p>
<p>We also discovered that the animals with Huntington’s have lower anxiety and show more risk-taking behaviour than their unaffected siblings. For ethical reasons, clinical studies involving juveniles or young adults affected by the Huntingtin mutation where symptoms have not yet appeared are very limited. Nevertheless, some study investigators reported anecdotally that these individuals showed more outgoing behaviour. </p>
<p>We were able to identify molecular and cellular changes that may explain these behavioural differences. For example, pathways used for communication between nerve cells that use a transmitter called dopamine were deregulated at several levels. This means that the recognition of this transmitter was lowered, compared to how it would have been if the mutant Huntingtin gene had not been present.</p>
<h2>An early phase</h2>
<p>When considering our findings together with reports from other research groups, it becomes apparent that Huntington’s disease has a previously unrecognised, early phase. During this stage – which ranges probably from development of an embryo to early adulthood – the body compensates for the changes caused by the mutant Huntingtin gene, so there are no disease-like symptoms.</p>
<p>In our study, we also tested a new drug called <a href="https://bnf.nice.org.uk/drug/panobinostat.html">Panobinostat</a> – which is being used in clinical trials for treatment of cancer. We found that it could completely restore the changes caused by Huntington’s disease. While this drug cannot alter the underlying mutation, it affects changes in gene expression that cause the altered behaviour. The mice we worked with showed less risk-taking behaviour after being treated with Panobinostat, for example. This is a promising step towards developing new therapies for Huntington’s, where the intention is to delay the onset of the disease.</p>
<p>Our research shows that the mutant Huntingtin gene causes changes on multiple levels, at an age range which has not been previously investigated. It affects gene and protein, nerve cells, and behaviour, too. The prodromal stages – before symptoms appear – in Huntington’s are a window of opportunity for therapies that aim to modify the course of the disease. </p>
<p>Currently, however, there is a lack of molecular markers – an indicator of the presence or severity of a disease – that allow researchers to monitor success of treatments. But we hope that our study provides a starting point to identify and refine such biomarkers, which in turn could be used to set up studies in other pre-symptomatic juvenile gene carriers, who could be treated and then monitored via blood gene expression and <a href="https://www.nhs.uk/conditions/mri-scan/">MRI scans</a>.</p><img src="https://counter.theconversation.com/content/102777/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Florian Siebzehnrubl receives funding from the Hereditary Disease Foundation. </span></em></p>Symptoms for Huntington’s disease typically only start to be experienced in mid-adulthood.Florian Siebzehnrubl, Research Fellow, European Cancer Stem Cell Research Institute, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1002312018-08-03T10:36:16Z2018-08-03T10:36:16ZHere’s what we know about CRISPR safety – and reports of ‘genome vandalism’<figure><img src="https://images.theconversation.com/files/229623/original/file-20180727-106505-1s3j5di.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A standee of the movie 'Rampage' at a theater in Bangkok, Thailand. Scientists in the film used CRISPR to create a monster.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/bangkok-thailand-april-28-2018-standee-1082671208?src=95RXvUed_l1X6Ob0AKOAew-1-6">By Sarunyu L/shutterstock.com</a></span></figcaption></figure><p>A movie just recently released called “Rampage” features an evil corporation using a genetic engineering technology called CRISPR, to transform a gorilla, among other animals, into a flying dragon-monster with gigantic teeth. Naturally, Dwayne “The Rock” Johnson exposes their villainy and strives to administer an antidote. Though this is science fiction, not to mention impossible, the movie captures the imagination of the public and their recent interest and fascination with CRISPR. </p>
<p>CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, was originally part of bacterial defense system that evolved to destroy foreign DNA that entered a bacterium. But this system was also capable of editing DNA – and now geneticists have honed the technology to alter the DNA sequences that we specify. This has generated enormous excitement and great expectations about the possibility of using CRISPR to alter genetic sequences to improve our health, to treat diseases, improve the quality and quantity of our food supplies, and tackle environmental pollution.</p>
<p>But a few recent scientific papers suggest that CRISPR is not without its problems. The research reveals that CRISPR can damage DNA that is far from the target DNA we are trying to correct. As a cancer biologist at the University of Pittsburgh School of Medicine, I use CRISPR in <a href="https://path.upmc.edu/personnel/Faculty/Luo.htm">my lab</a> to study human cancers and develop ways to kill cancer cells. Although the new finding appears significant, I don’t think that these revelations rule out using the technology in a clinical setting, but rather, they suggest we take additional cautionary measures as we implement these strategies. </p>
<h2>Treating human diseases</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=294&fit=crop&dpr=1 600w, https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=294&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=294&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=370&fit=crop&dpr=1 754w, https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=370&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/229694/original/file-20180728-106502-5ryti8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=370&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">CRISPR/Cas9 is being used to edit DNA in plants, animals, and in humans. But new studies are casting doubts about whether the technology is safe to use for human therapies.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/crisprcas9-targeted-genome-engineering-benefit-michelangelos-1135102187?src=6YhsMSEMXCycRKNsH6ngdQ-1-12">By TotallyMJ/shutterstock.com</a></span>
</figcaption>
</figure>
<p>Using genome editing to treat human diseases is very tantalizing. Correcting inherited genetic defects that cause human disease –just as one edits a sentence – is the obvious application. This strategy has been successful in tests on animals.</p>
<p>In the U.S. and Europe, clinical trials have been planned for several human diseases. Most notably, a gene-editing <a href="https://cen.acs.org/articles/96/i2/CRISPR-coming-clinic-year.html">phase I/II trial is planned in Europe for human β-thalassemia</a>, a hereditary blood disorder that causes anemia that requires lifelong blood transfusions. In 2018, a <a href="http://ir.crisprtx.com/phoenix.zhtml?c=254376&p=irol-newsArticle&ID=2321951">CRISPR trial for sickle cell anemia</a>, another inherited blood disorder caused by a mutation that deforms the red blood cells, is planned in the U.S. </p>
<p>For both of these trials the gene editing is done ex vivo – outside the patient’s body. Hematopoietic blood cells, the stem cells that generate red blood cells, are taken from the patient and edited in the lab. The cells are then re-introduced into the same patients after the mutations have been corrected. The expectation is that by correcting the stem cells, the cells they now produce will be normal, curing the disease. </p>
<p>The ex vivo approach has also been used in China to test treatments against an array of human cancers. There researchers take immune cells – called T cells – from cancer patients and use CRISPR to stop these cells from producing a protein called PD-1 (program cell death-1). Normally, PD-1 prevents T cells from attacking one’s own tissues. However, cancer cells exploit this protective mechanism to evade the body defense system. Removing PD-1 allows T cells to attack cancer cells vigorously. <a href="https://gizmodo.com/china-has-already-gene-edited-86-people-with-crispr-1822297524">The initial results from clinical trials using gene-edited T cells appear mixed</a>.</p>
<p><a href="https://path.upmc.edu/personnel/Faculty/Luo.htm">In my lab</a> we have recently been focusing on the chromosome rearrangement, a genetic defect where a segment of chromosome skips and joins distant parts of the same or different chromosome. A scrambled chromosome is a defining characteristic of most cancers. The most famous example of such an alteration is the “Philadelphia Chromosome” – in which chromosome 9 is connected to chromosome 22 – which causes acute myeloid leukemia. </p>
<p>My team has used CRISPR in animal models to <a href="https://doi.org/10.1038/nbt.3843">insert a suicide gene to specifically target liver and prostate cancer cells</a> that harbor such rearrangements. Since these chromosome rearrangements occur only in cancer cells but not normal cells, we can target the cancer without collateral damage to healthy cells. </p>
<h2>CRISPR concerns</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/229693/original/file-20180728-106496-gwvs61.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">
<figcaption>
<span class="caption">CRISPR is a tool for editing DNA that researchers claim is as precise as a surgeons’s scalpel. But new studies suggest it that CRISPR may cause off-target damage by slicing up the DNA far from the intended target, which could set the stage for cancer.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/hand-scientist-replacing-dna-genetic-engineering-793680727?src=6YhsMSEMXCycRKNsH6ngdQ-3-18">By andriano.cz/shutterstock.com</a></span>
</figcaption>
</figure>
<p>Despite all the excitement surrounding CRISPR editing, researchers have urged caution on moving too fast. Two recent studies have raise concerns that CRISPR may not be as effective as previously thought, and in some cases it may produce unwanted side effects. </p>
<p><a href="http://doi.org/10.1038/s41591-018-0049-z">The first study showed</a> that when the Cas9 protein – part of the CRISPR system that snips the DNA before correcting the mutation – cuts the DNA of stem cells it causes them to become stressed and stops them from being edited. While some cells can recover after their DNA has been corrected, other cells could die. </p>
<p><a href="http://doi.org/10.1038/s41591-018-0050-6">The second study</a> showed that a protein called p53, which is well known for guarding against tumors, is activated by cellular stress. The protein then inhibits CRISPR from editing. Since CRISPR activity causes stress, the editing process may be thwarted before it even accomplishes its task. </p>
<p>Another study over the past year has revealed an additional potential issue with using CRISPR in humans. Since CRISPR is a bacterial protein, a significant portion of human population may have been exposed to it during common bacterial infections. In these cases, the immune system of these people may have developed <a href="https://doi.org/10.1101/243345">immune defense against the protein</a>, which means a person’s body could attack the CRISPR machinery, just as it would attack an invading bacterium or virus, preventing the cell from the benefits of CRISPR-based therapy. </p>
<p>Additionally, like most technologies, not all editing is accurate. Occasionally CRISPR targets the wrong sites in the DNA and makes changes that researchers fear could cause disease. A recent study showed that CRISPR caused <a href="http://doi.org/10.1038/nbt.4192">large chunks of the chromosome to rearrange near the site of genome editing</a> in mouse embryonic stem cells – although this effect isn’t always observed in the other cell systems. Most published results indicate that off-target rates ranges 1-5 percent. Even if the off-target rate is relatively low, we don’t yet understand the long-term consequences. </p>
<h2>CRISPR dangers have been hyped</h2>
<p>The studies referenced above have led to a glut of media reports about the potential negative effect of CRISPR, many citing potential cancer risk. More often than not, these involve a far-fetched extrapolation of actual results. As far as I am aware, no animals treated with the CRISPR-Cas9 system have been shown to develop cancers. </p>
<p>Studies have shown CRISPR-based genome editing works more efficiently in cancer cells than normal cells. Indeed, the resistance of normal cells to CRISPR editing actually makes it more appealing for cancer treatment since there would be less potential collateral damage to normal tissues – <a href="https://www.nature.com/articles/nbt.3843">a conclusion that is supported by research in our lab</a>. </p>
<p>Looking forward, it is obvious that the technology has great potential to treat human diseases. The recent studies have revealed new aspects of how CRISPR works that may have implications for the ways in which these therapies are developed. However, the long-term effect of genome editing can only be assessed after CRISPR has been used widely to treat human diseases.</p><img src="https://counter.theconversation.com/content/100231/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jianhua Luo 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>CRISPR has been hailed as the an editing tool that can delete inherited mutations and cure disease. But recent papers suggest that the technique may be too dangerous for use in human therapies.Jianhua Luo, Professor of Pathology, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/977972018-07-09T10:37:08Z2018-07-09T10:37:08ZHuntington’s disease: how brain training games could help<figure><img src="https://images.theconversation.com/files/224814/original/file-20180626-19382-1pt5ykw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/profile-bearded-man-symbol-neurons-brain-622200797?src=D238hMs8fqT1L-d5BBVpmw-1-7">Lia Koltyrina/Shutterstock</a></span></figcaption></figure><p>In the search for new treatments, science often focuses on medication first. But drugs aren’t the only way to fight illness, particularly when looking at brain diseases. <a href="https://www.cardiff.ac.uk/people/view/225350-yhnell-emma">My research</a> looks into how playing specially designed computer games might help people who are living with Huntington’s disease. </p>
<p>Huntington’s is a brain disorder that gets progressively worse over time, leading to problems with <a href="https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117">movement and thinking</a>. We know that the disease is caused by a single faulty gene, which in itself is very unique. Often if you have particular genes, your risk of developing certain diseases might increase or decrease, but it is very rare for a disease to be caused completely by a single gene. Although research is currently ongoing, unfortunately at present there are no treatments for the underlying cause of Huntington’s, or to prevent the disease getting worse.</p>
<p>You might be wondering how brain training games can possibly help those with Huntington’s disease if there aren’t yet any effective treatments for the disease. But, as my mum always used to say to me, “practice makes perfect” – if you practice something repeatedly you will generally get better at it. </p>
<p>This principle applies to brain training, too. If you practice tasks or games that are designed to help with thinking, you will probably get better at thinking. This is sometimes referred to as the “use it or lose it” approach. If you use your thinking skills and keep them active, you will probably be able to maintain them. But if you don’t practice something regularly you may forget it and not be as good at it as you once were. This is particularly relevant if you know that your thinking ability is going to get worse.</p>
<p>Using computer games to train the brain has been studied <a href="http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001756#s4">in the healthy ageing population</a>, and also with other diseases which affect the brain such as <a href="https://www.ncbi.nlm.nih.gov/pubmed/14583963">Alzheimer’s</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/24322063">Parkinson’s</a>. These studies have generally found that brain training is beneficial for improving thinking – although there is <a href="https://www.tandfonline.com/doi/full/10.1080/09602011.2016.1186101">much debate</a> about whether brain training could improve movement problems or improve quality of life for people living with these brain diseases. </p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/224815/original/file-20180626-19396-52pdkm.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">
<figcaption>
<span class="caption">Training in progress.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/vector-illustration-girl-smartphone-using-brain-499802083?src=cIIfrxve7CRj1ucBZpcz-Q-1-0">mayrum/Shutterstock</a></span>
</figcaption>
</figure>
<p>At present, there is very little evidence about computer game training and how it might impact people with Huntington’s disease. But we are now conducting a feasability study to work out whether the research can actually be done before progressing to a bigger study. Full scale studies require lots of participants and funding, so it is important to demonstrate that the research can actually work with a small number of people first.</p>
<p>Using this initial study, we want to demonstrate that computer game brain training is acceptable for people who are impacted by Huntington’s disease. We know that lack of motivation and apathy can be characteristic symptoms of Huntington’s disease. So we are asking people who have the disease to play brain training computer games to see how they get on.</p>
<p>Half of the participants will be asked to play the brain training computer games and half will continue as normal, in a control group. This is important as it will allow us to compare the results of the people who played the brain training games to those who did not. We are asking the participants playing the brain training computer games to play them for three 30-minute sessions a week, for 12 weeks. We will then be asking them how they got on with playing the games and what they liked and disliked so that we can improve the study in the future. </p>
<p>Not all games marketed as brain training are equal – most are designed to specifically test or train your thinking skills but some are designed purely for entertainment and pleasure. So we have carefully chosen the games our participants will play to make sure that the games specifically train thinking skills. The brain training games that we are using are focused on training thinking skills of executive function – the higher thinking skills of the brain. These include number puzzles, word games and tasks that measure attention.</p>
<p>Although our study is focused on Huntington’s disease, it will help us learn about brain training more generally, too. We already know that the more often you play a game, the better you get at it. If you play the card game Snap!, for example, you might get much quicker at pairing the cards and beating your opponent, but how does this translate to the rest of your life? </p>
<p>Brain training will not be able to change the faulty gene that causes Huntington’s, but it might just help improve day to day life for people who are impacted by the disease.</p>
<hr>
<p><em>For further information about Huntington’s disease and support, visit <a href="https://www.hda.org.uk/">The Huntington’s disease association</a>, or <a href="https://en.hdbuzz.net/">HDBuzz</a>, which provides excellent summaries of current Huntington’s research.</em></p><img src="https://counter.theconversation.com/content/97797/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Emma Yhnell receives research funding from The Welsh Government, through Health and Care Research Wales and the Jacque and Gloria Gossweiler Foundation. She has previously received funding from the Medical Research Council (MRC).
Emma will be giving the Charles Darwin Award Lecture at the British Science Festival in Hull, UK, on September 12, 2018. Free tickets for the event are available via: <a href="https://www.britishsciencefestival.org/event/hunting-for-a-huntingtons-treatment/">https://www.britishsciencefestival.org/event/hunting-for-a-huntingtons-treatment/</a></span></em></p>Specially designed computer games might improve the lives of people with Huntington’s disease.Emma Yhnell, Health and Care Research Wales Fellow, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/889472017-12-11T19:13:38Z2017-12-11T19:13:38ZTasmanian tigers were going extinct before we pushed them over the edge<figure><img src="https://images.theconversation.com/files/198462/original/file-20171211-27686-lrmoci.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gone since 1936, and ailing since long before that.</span> <span class="attribution"><span class="source">Tasmanian Museum and Art Gallery</span>, <span class="license">Author provided</span></span></figcaption></figure><p>There’s no doubt that humans killed off the <a href="https://australianmuseum.net.au/the-thylacine">Tasmanian tiger</a>. But a new genetic analysis suggests this species had been on the decline for millennia before humans arrived to drive them to extinction.</p>
<p>The Tasmanian tiger, also known as the thylacine, was unique. It was the largest marsupial predator that survived into recent times. Sadly it was hunted to extinction in the wild, and the last known Tasmanian tiger died in captivity in 1936.</p>
<p>In a <a href="http://nature.com/articles/doi:10.1038/s41559-017-0417-y">paper published in Nature Ecology and Evolution today</a>, my colleagues and I piece together its entire genetic sequence for the first time. It tells us that thylacines’ genetic health had been declining for many millennia before they first encountered human hunters.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/will-we-hunt-dingoes-to-the-brink-like-the-tasmanian-tiger-19982">Will we hunt dingoes to the brink like the Tasmanian tiger?</a>
</strong>
</em>
</p>
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<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=738&fit=crop&dpr=1 600w, https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=738&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=738&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=927&fit=crop&dpr=1 754w, https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=927&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/198466/original/file-20171211-27693-1jgss5o.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=927&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Hounded by hunters.</span>
<span class="attribution"><span class="source">Tasmanian Museum and Art Gallery</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Our research also offered the chance to study the origins of the similarity in body shape between the thylacine and dogs. The two are almost identical, despite having last shared a common ancestor more than 160 million years ago – a remarkable example of so-called “convergent evolution”. </p>
<p>Decoding the thylacine genome allowed us to ask the question: if two animals develop an identical body shape, do they also show identical changes in their DNA?</p>
<h2>Thylacine secrets</h2>
<p>These questions were previously difficult to answer. The age and storage conditions of existing specimens meant that most thylacine specimens have DNA that is highly fragmented into very short segments, which are not suitable for piecing together the entire genome.</p>
<p>We identified a 109-year-old specimen of a young pouch thylacine in the Museums Victoria collection, which had much more intact DNA than other specimens. This gave us enough pieces to put together the entire jigsaw of its genetic makeup.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=747&fit=crop&dpr=1 600w, https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=747&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=747&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=939&fit=crop&dpr=1 754w, https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=939&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/198463/original/file-20171211-27708-kte384.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=939&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 preserved young, thylacine with enough DNA to reveal its whole genome.</span>
<span class="attribution"><span class="source">Museums Victoria</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>Next, we made a detailed comparison of thylacines and dogs to see just how similar they really are. We used digital imaging to compare the thylacine’s skull shape to many other mammals, and found that the thylacine was indeed very similar to various types of dog (especially the wolf and red fox), and quite different from its closest living marsupial relatives such as the numbat, Tasmanian devil, and kangaroos. </p>
<p>Our results confirmed that thylacines and dogs really are the best example of convergent evolution between two distantly related mammal species ever described.</p>
<p>We next asked whether this similarity in body form is reflected by similarity in the genes. To do this, we compared the DNA sequences of thylacine genes with those of dogs and other animals too. </p>
<p>While we found many similarities between thylacines’ and dogs’ genes, they were not significantly more similar than the same genes from other animals with different body shapes, such as Tasmanian devils and cows.</p>
<p>We therefore concluded that whatever the reason why thylacines and dogs’ skulls are so similarly shaped, it is not because evolution is driving their gene sequences to be the same. </p>
<h2>Family ties</h2>
<p>The thylacine genome also allowed us to deduce its precise position in the marsupial family tree, which has been a controversial topic.</p>
<p>Our analyses showed that the thylacine was at the root of a group called the Dasyuromorphia, which also includes the <a href="http://www.environment.gov.au/cgi-bin/sprat/public/publicspecies.pl?taxon_id=294">numbat</a> and <a href="http://www.parks.tas.gov.au/?base=387">Tasmanian devil</a>. </p>
<p>By examining the amount of diversity present in the single thylacine genome, we were able to estimate its effective population size during past millennia. This demographic analysis revealed extremely low genetic diversity, suggesting that if we hadn’t hunted them into extinction the population would be in very poor genetic health, just like today’s Tasmanian devils.</p>
<p>The less diversity you have in your genome, the more susceptible you are to disease, which might be why devils have contracted the facial tumour virus, and certainly why it has been so easily spread. The thylacine would have been at a similar risk of contracting devastating diseases.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/198465/original/file-20171211-27698-1sg40zd.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=471&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The last thylacine alive.</span>
<span class="attribution"><span class="source">Tasmanian Museum and Art Gallery</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>This loss in population diversity was previously thought to have occurred as a population of thylacines (and devils) became isolated on Tasmania some 15,000 years ago, when the land bridge closed between it and the mainland. </p>
<p>But our analysis suggests that the process actually began much earlier – between 70,000 and 120,000 years ago. This suggests that both the devil and thylacine populations already had very poor genetic health long before the land bridge closed.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-curiosity-can-save-species-from-extinction-52006">How curiosity can save species from extinction</a>
</strong>
</em>
</p>
<hr>
<p>Now that we know the whole genome of the Tasmanian tiger, we know much more about this extinct animal and the unique place it held in Australia’s marsupial family tree. We are expanding our analyses of the genome to determine how it came to look so similar to the dog, and to continue to learn more about the genetics of this unique marsupial apex predator.</p><img src="https://counter.theconversation.com/content/88947/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Pask receives funding from Australian Research Council (ARC), National Health and Medical Research Council (NHMRC), The University of Melbourne. </span></em></p>The new Tasmanian tiger genome reveals some fascinating facts about this extinct marsupial, including why they were so similar to dogs, and how they were growing more vulnerable to genetic disease.Andrew Pask, Associate Professor, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/785922017-06-08T19:25:51Z2017-06-08T19:25:51ZWhy we don’t know what causes most birth defects<figure><img src="https://images.theconversation.com/files/172181/original/file-20170605-20586-sgg1qn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">About 3% of babies are born with birth defects, when there is a problem with how they develop in the womb.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/411340129?src=8_HRpVr2qj1DFZqztQ4QrA-2-85&size=medium_jpg">from www.shutterstock.com</a></span></figcaption></figure><p>The development of a baby, from the time of fertilisation through to the moment of birth, is an incredibly complex journey. Most of the time the result is a perfect new baby. However, in <a href="https://www.cdc.gov/ncbddd/birthdefects/facts.html">about 3% of babies</a> mistakes happen and a birth defect occurs. This is when an anatomical difference has come about as the baby develops in the womb.</p>
<p>Birth defects (also known as congenital anomalies) are a major cause of <a href="https://www.cdc.gov/nchs/products/databriefs/db279.htm">infant hospitalisation and deaths</a> in the first year of life. These are not only costly to manage in the health-care system, but can also have an enormous impact on the lives of the child and their family.</p>
<p>Some birth defects are relatively mild, can be repaired with simple surgery and the child will go on to lead a perfectly normal life. These include an additional little finger or webbing between two toes.</p>
<p>Other types, including serious <a href="https://www.mja.com.au/journal/2012/197/3/congenital-heart-disease-current-knowledge-about-causes-and-inheritance">heart defects</a> and facial deformities such as <a href="http://www.rch.org.au/kidsinfo/fact_sheets/Cleft_Lip_and_Palate_an_overview/">cleft lip and palate</a>, are more complex to manage. These may involve treatment spanning childhood and into adolescence.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.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">Children born with a cleft lip (above) are offered surgery to correct this common birth defect.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/success?src=AE4bGoW-NCVhXMEt6f6vdQ-1-9">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Some birth defects are so severe the baby cannot live outside the womb. These kinds usually involve major malformation of essential structures, such as <a href="https://www.cdc.gov/ncbddd/birthdefects/anencephaly.html">anencephaly</a> where the brain fails to form.</p>
<p>When a single cause affects multiple systems in the body the birth defect is described as a syndrome. An example is <a href="http://www.downsyndrome.org.au/">Down syndrome</a>. This is one of the most common birth defects in Australia and causes intellectual disability and other physical and learning challenges.</p>
<p>The outlook for children with syndromes, like the syndromes themselves, is highly variable. A syndromic birth defect is not necessarily more severe than an isolated birth defect. However, the involvement of multiple systems or structures may require ongoing management to ensure the best outcomes for the child and their family.</p>
<h2>What causes birth defects?</h2>
<p>Birth defects have two major causes, environmental and genetic. </p>
<p>Environmental causes (known as teratogens) include medicines that can harm the unborn baby. The most high-profile of these was <a href="https://theconversation.com/thalidomide-taught-us-to-use-medications-with-care-during-pregnancy-not-to-stop-using-them-51862">thalidomide</a>, which women took for morning sickness in the late 1950s and early 1960s. It led to thousands of babies born with irreversible congenital defects ranging from limb deformities (phocomelia) to facial malformations.</p>
<p>A more recently identified environmental cause of birth defects is the <a href="http://www.who.int/csr/disease/zika/en/">Zika virus</a>, which leads to <a href="https://theconversation.com/explainer-what-is-microcephaly-and-what-is-its-relationship-to-zika-virus-54049">microcephaly</a> (babies born with smaller-than-normal heads).</p>
<p>More everyday factors include alcohol and smoking, which have been associated with an <a href="http://www.aihw.gov.au/child-health/risk-factors/">increased risk</a> of abnormalities. Estimates from the USA suggest <a href="https://www.cdc.gov/ncbddd/fasd/data.html">0.1-1% of children</a> may be affected by alcohol in the womb. And smoking during pregnancy is associated with a <a href="http://www.tobaccoinaustralia.org.au/3-8-infant-health-and-smoking">range of conditions</a>, including heart defects and facial clefts.</p>
<p>Environmental factors can also involve physical restriction that may occur in the womb from <a href="http://jech.bmj.com/content/70/11/1114">twin pregnancies</a>.</p>
<p>The genetic causes of birth defects are equally diverse. These include chromosomal abnormalities in conditions like <a href="http://www.downsyndrome.org.au/">Down syndrome</a> (an extra copy of chromosome 21) and errors in specific genes such as the <a href="http://www.yourgenome.org/facts/what-is-achondroplasia">FGFR3 gene</a>, which causes a form of dwarfism.</p>
<h2>But most causes remain a mystery</h2>
<p>Recent US <a href="http://www.bmj.com/content/357/bmj.j2249">research</a> examined the frequency and causes of birth defects by looking at medical records for over 270,000 births between 2005 and 2009. The researchers found 5,504 cases of birth defects, or about 2% of total births.</p>
<p>But they found the cause behind only one in five of these birth defects. The rest (79.8%) remained a mystery.</p>
<p>Of the known causes, 94.4% were genetic, 4.1% resulted from environmental exposure (teratogens) and 1.4% were linked with twin pregnancies.</p>
<p>The study also confirmed <a href="https://npesu.unsw.edu.au/surveillance/congenital-anomalies-australia-2002-2003">Australian findings</a> that individual birth defects seem to affect a higher proportion of males than females; we still don’t know why.</p>
<h2>Where to from here?</h2>
<p>This study highlights reasons for hope. The 4.1% of birth defects resulting from teratogen exposure were mainly caused by uncontrolled <a href="http://www.mydr.com.au/diabetes/diabetes-and-getting-pregnant">diabetes</a> in women before becoming pregnant. While the mechanism for this is unclear, this figure could be reduced through increased education of women intending to become pregnant to ensure their diabetes is controlled before and during pregnancy.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.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">Controlling a woman’s diabetes before she becomes pregnant reduces her chance of having a child with a birth defect.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/552199903?src=xkZZVKGo6IjBrt_ktxrowQ-1-21&size=medium_jpg">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Yet, the finding that the cause of nearly 80% of birth defects remains unknown is confronting and highlights the scale of the task ahead.</p>
<p>In Australia, for instance, we do not have a clear picture of the types and frequencies of birth defects across the nation. This is because we have state-based systems that collect different information.</p>
<p>Birth defects are also diverse, affecting many different structures in the body. Each specific birth defect results from a different cause, most of which are genetic. Identifying the factors responsible requires each birth defect to be examined independently so that individuals with a particular condition can be grouped and studied together. This takes time, research and funding.</p>
<p>Greater support for genetics research and information collection on birth defects would allow us to understand the origins of these conditions. Only then can we be begin the task of intervention and prevention to reduce the burden of these conditions on health-care systems and families.</p>
<hr>
<p><em>If you have concerns about birth defects, please speak to your doctor. For more information and support, contact the <a href="http://www.gsnv.org.au/">Genetic Support Network of Victoria</a> or the <a href="http://www.geneticandrarediseasenetwork.org.au/">Genetic and Rare Disease Network</a>.</em></p><img src="https://counter.theconversation.com/content/78592/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Peter Farlie receives funding from the National Health and Medical Research Council Australia. </span></em></p>We still don’t know what’s behind four out of every five birth defects. But that can change.Peter Farlie, Developmental Biologist, Murdoch Children's Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/731102017-02-27T00:44:29Z2017-02-27T00:44:29ZSafe and ethical ways to edit the human genome<figure><img src="https://images.theconversation.com/files/158348/original/image-20170224-23000-tob9rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Human genome editing raises a lot of questions. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/255876943?src=raRdH4wR0Oftl9_tRKTL9g-1-13&size=huge_jpg">Gene sequence image via www.shutterstock.com.</a></span></figcaption></figure><p>The National Academies of Science and Medicine (NASEM) released a <a href="https://www.nap.edu/catalog/24623/human-genome-editing-science-ethics-and-governance">report</a> on Feb. 14 exploring the implications of new technologies that can alter the genome of living organisms, including humans. </p>
<p>Although scientists have been able to edit genes for several decades, new genome editing technologies are more efficient, more precise and far less expensive than previous ones. One of these techniques, known as CRISPR-Cas9, could allow for new applications ranging from editing viruses and bacteria to animals, plants and human beings. </p>
<p>For example, scientists could design <a href="http://news.berkeley.edu/2017/01/24/crispr-research-institute-expands-into-agriculture-microbiology/">pest-resistant plants</a>. They could modify the genome of animals, bacteria and <a href="http://www.nature.com/news/hiv-overcomes-crispr-gene-editing-attack-1.19712">viruses</a> to help fight diseases and plagues. </p>
<p>CRISPR could potentially be used by <a href="http://newatlas.com/home-crispr-gene-editing-kit/40362/">almost anybody</a> willing to tinker with the genome. This, and the fact that it can be used either for beneficial or harmful purposes, have raised fears that CRISPR could become a <a href="https://www.technologyreview.com/s/600774/top-us-intelligence-official-calls-gene-editing-a-wmd-threat/">weapon of mass destruction</a>.</p>
<p>CRISPR could also be used to modify the human genome. The big question scientists are wrestling with is whether these technologies should be used to make modifications in human reproductive cells. Changes made in these cells are heritable from one generation to the next, and are called germline modifications.</p>
<p>Some scientists working with these techniques called for a <a href="http://www.nature.com/news/don-t-edit-the-human-germ-line-1.17111">moratorium</a> for editing that could result in germline modifications. Others thought that a <a href="http://science.sciencemag.org/content/348/6230/36.full">prudent path</a> for using these technologies was needed.</p>
<p>The NASEM report did not endorse a moratorium. But it recommended that at least <a href="http://nationalacademies.org/cs/groups/genesite/documents/webpage/gene_177255.pdf">10 stringent conditions</a> should be met before authorizing this use. The report also said that more discussion – with wide public participation – was needed before proceeding with human germline modification. </p>
<p>I explore the ethical and policy questions raised by emerging technologies such as CRISPR at the <a href="https://scienceandsociety.duke.edu/">Duke Initiative for Science and Society</a>. I am particularly interested in how different countries regulate these technologies. </p>
<h2>What does the report say?</h2>
<p>For research using human cells and tissues, the <a href="http://nationalacademies.org/cs/groups/genesite/documents/webpage/gene_177259.pdf">NASEM Committee</a> said that existing regulatory and ethical frameworks were able to address the questions that might arise from genome editing. The same is true for genome editing of cells in the body that are not reproductive cells –called somatic cells – for therapeutic purposes.</p>
<p>So while clinical trials for modifications of somatic cells were given a green light, the modification of reproductive cells (eggs, sperm and embryos) which would lead to germline modifications, was given a <a href="http://www.sciencemag.org/news/2017/02/us-panel-gives-yellow-light-human-embryo-editing">yellow light</a> for the moment. </p>
<p>These types of genome modifications have raised fears about a <a href="http://dx.doi.org/doi:10.15779/Z38FM40">brave new world</a> of “designer babies.” </p>
<p>These questions are not new. The difference is that scientists are closer than ever to actually being able to significantly and accurately <a href="http://dx.doi.org/10.1007/s13238-015-0153-5">alter the human genome</a>.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/158349/original/image-20170224-22983-14ois3d.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">New gene editing technologies have raised ethical questions about ‘designer’ babies.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/144900970?src=eJaNOjLeVy2YHU3VVbSrHQ-1-4&size=huge_jpg">Babies image via www.shutterstock.com.</a></span>
</figcaption>
</figure>
<h2>Recommendations for germline modification</h2>
<p>The NASEM report concluded that it would be fine to proceed with the modification of germline cells only if three requirements are met. </p>
<p>One is that further research should prove that there are sufficient prospective benefits relative to the risks of using these techniques before starting clinical trials. </p>
<p>Another is that the public should be involved in a broad dialogue about the use of these technologies. </p>
<p>And a sound regulatory and oversight framework should be in place to guarantee that the following <a href="http://nationalacademies.org/cs/groups/genesite/documents/webpage/gene_177255.pdf">10 conditions</a> are met before using genome editing to alter sperm, eggs or embryos:</p>
<ol>
<li> that genome editing is used only when no other “reasonable alternatives” exist;<br></li>
<li> that it is only used to prevent a “serious disease or condition”; </li>
<li> that use is restricted to altering genes “that have been convincingly demonstrated to cause or strongly predispose to that disease or condition”; </li>
<li> that use is limited to converting genes into “versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects”; </li>
<li> that credible preclinical and/or clinical data on both potential risks and potential health benefits of the use of these technologies exist;</li>
<li> that the effects of these technologies on the health and safety of the research participant are subject to ongoing and serious oversight during the trial; </li>
<li> that a comprehensive plan for “long-term, multigenerational follow-up” that respects personal autonomy exists; </li>
<li> that a balance is achieved between ensuring maximum transparency and respecting patient privacy; </li>
<li> that both health and societal benefits and risks are continuously reassessed, including through the input provided by the public; and </li>
<li>that reliable oversight is put in place to prevent the use of these technologies for reasons going beyond the prevention of a “serious disease or condition.”</li>
</ol>
<p>Most of these conditions aim at ensuring that germline genome editing will be used only to prevent a serious disease, where no reasonable alternatives exist, and under strong supervision. Some of them will be very difficult to meet. For instance, how can the long term follow-up of children (and their children) born with the help of genome editing be guaranteed? This would be specially difficult with people traveling to other countries to access these technologies. </p>
<p>Finally, the use of genome editing for enhancement purposes was given a red light for the moment and should be subject to further and wider discussions.</p>
<h2>Genome modification in a globalized world</h2>
<p>The NASEM report cited <a href="https://www.pasteur.fr/en/institut-pasteur/history">Louis Pasteur</a> – a French microbiologist famous for his many discoveries, including the process of pasteurization – who once said “science has no homeland, because knowledge is the heritage of humanity.” The report and the human gene editing <a href="http://nationalacademies.org/gene-editing/index.htm">initiative</a> from the National Academy of Sciences and the National Academy of Medicine are paying special attention to international considerations.</p>
<p>An open question is whether the recommendations about human germline editing, which has been interpreted by some as an <a href="https://medium.com/@C_G_S/the-center-for-genetics-and-society-comments-on-new-human-gene-editing-report-e8786f9d5b8e#.wakru2fn9">endorsement</a> of the practice, are a good starting point for a wide international dialogue. </p>
<p>A <a href="https://dx.doi.org/10.1186/1477-7827-12-108">2014 study</a> found that 29 out of 39 surveyed countries have decided to ban the use of technologies to modify the human germline. Of these, countries such as Austria, Italy, Spain and the Netherlands have a ban in place. And others such as Argentina, Greece, Peru and South Africa have ambiguous regulations.</p>
<p>Other genetic modification techniques have been used to conceive babies free of genetic diseases carried by their parents. One such technique, <a href="https://theconversation.com/the-next-frontier-in-reproductive-tourism-genetic-modification-67132">mitochondrial replacement therapy</a>, has recently been used in <a href="http://www.nature.com/news/reports-of-three-parent-babies-multiply-1.20849">China</a>, <a href="https://www.newscientist.com/article/2107219-exclusive-worlds-first-baby-born-with-new-3-parent-technique/">Mexico</a> and <a href="http://www.cnn.com/2017/01/18/health/ivf-three-parent-baby-girl-ukraine-bn/">Ukraine</a> and will probably be used in the <a href="http://www.ncl.ac.uk/press/news/2016/12/worldsfirstmitochondriallicence/">U.K. soon</a>.</p>
<p>However, in the U.S., a rider included in a <a href="https://www.congress.gov/bill/114th-congress/house-bill/2029/text">Congressional Appropriations Act</a> in place until April 2017 forbids the FDA from considering any trials that will alter the human germline. Experience with <a href="https://newsatjama.jama.com/2015/11/05/jama-forum-selective-regrets-the-dickey-amendments-20-years-later/">other riders</a> shows that this ban could be extended indefinitely.</p>
<p>The report sought to develop “a framework based on fundamental, underlying principles that may be adapted and adopted by any nation.” But how could this framework be adopted by nations that currently ban any germline modification? </p>
<p>In a globalized world, patients can potentially cross borders for medical interventions that are not available in their own countries. This has already happened with mitochondrial replacement therapy. Some countries might decide <a href="http://dx.doi.org/10.1056/NEJMp1600891">to relax their standards</a> in the hope of attracting “tourist” patients or boosting their research capabilities. An international agreement to regulate these technologies would help to set a minimum set of standards that countries should comply with. </p>
<p>But it is unlikely that countries will reach any agreement in the near future. The report noted that different regulatory approaches could be tested in different countries until we better understand these technologies and the best way to regulate them. </p>
<p>Regardless of whether one believes that an international agreement is needed or feasible, international cooperation and dialogue seem to be essential components of good governance for new technologies.</p><img src="https://counter.theconversation.com/content/73110/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rosa Castro does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A new report from the National Academies of Science and Medicine outlines conditions that have to be met before gene editing that results in heritable genomic changes can be considered.Rosa Castro, Postdoctoral Associate in Science and Society, Duke UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/421562015-08-19T10:05:26Z2015-08-19T10:05:26ZOur obsession with hereditary cancers didn’t start when we discovered the breast cancer gene<figure><img src="https://images.theconversation.com/files/87058/original/image-20150701-27131-1bd895l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">RTR TDGQ</span> </figcaption></figure><p>Angelina Jolie received much public attention for her decisions to undergo first a prophylactic double mastectomy and, later, prophylactic surgery to remove her ovaries and fallopian tubes.</p>
<p>The procedures were Jolie’s response to learning she had the BRCA 1 gene mutation, which predisposes women to a higher-than-average cancer risk. </p>
<p>She <a href="http://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html">framed her choices</a> within her family history (her mother died from cancer at 56), her own disease risk and her motivation to stay healthy for her children.</p>
<p>Featured on Time’s May 27 2013 cover, titled “<a href="http://healthland.time.com/2013/05/15/the-angelina-effect-times-new-cover-image-revealed/">The Angelina Effect</a>,” the actress was celebrated for promoting awareness about the connection between genetics, risk and health to the extent that doctors anticipated being overwhelmed by a “stampede of women” requesting genetic testing for their BRCA status. </p>
<p>The discovery of the BRCA genes (and the resulting genetic tests) in the early 1990s is often touted as the watershed moment when genetics and heredity became important to cancer. This is not, however, the case. </p>
<p>We did not suddenly recognize that some cancers are hereditary once we could test for gene mutations. </p>
<p>Looking back at this history shows how scientists and the public tried to understand hereditary cancer risk well before we had the technology to discover mutations and test for genetic disorders. This history also demonstrates that the experience of hereditary disease and genetic testing is deeply gendered, affecting women and their reproductive choices.</p>
<h2>Understanding hereditary cancer – a brief history</h2>
<p>BRCA mutations account for <a href="http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet">5%-10% of all breast cancers</a> – yet discussion about cancer and risk have been, and continue to be, profoundly shaped by genetics. </p>
<p>But researchers had identified that some cancers, like breast cancer, could be hereditary as far back as the early 20th century. </p>
<p>In the 1910s, the Eugenics Record Office, headed by Charles Benedict Davenport, conducted research on hereditary cancers, collecting information on “cancer families” through pedigree charts and detailed medical histories. </p>
<p>Back then, people wanted to know about hereditary cancers for the same reason people might want to be tested for the BRCA mutation today – to understand their own risk and to make decisions about when or if to have children.</p>
<p>We can see this reflected in letters doctors wrote to the Journal of the American Medical Association in the 1930s. One doctor asked how to counsel “a young married couple with regards to their bearing of children in view of [their] cancer history.” Another, inquiring for his patients, wondered whether any tests or examinations existed that could predict cancer in a given family.</p>
<p>In 1958, Sheldon Reed, V Elving Anderson and Harold O Goodman, all researchers at the Dight Institute for Human Genetics at the University of Minnesota, published Variables Related to Human Breast Cancer. The book was a result of a 13-year inquiry into familial clustering of the disease. They <a href="https://books.google.com/books?isbn=081666829">concluded that</a>:</p>
<blockquote>
<p>“mothers, sisters, and daughters of breast cancer patients have a risk of developing breast cancer which is about twice that of other women of the same age.”</p>
</blockquote>
<p>Reed, Anderson and Goodman counseled “at risk” women to consult their physicians for frequent breast exams and for surveillance of “subclinical or pre-pathological signs” in order to catch cancer in its “pre-disease” state. This concept of “pre-cancer” struck a chord with many. Americans concerned about their health (and women in particular) contacted the institute for risk estimates and genetic counseling based on their family history. This may sound familiar to many women today. </p>
<p>By the 1960s, Henry T Lynch, the “father of cancer genetics,” popularized the importance of heredity to cancer control and prevention efforts. He created a system of predisease detection for people at risk for hereditary cancers to help them make proactive health decisions. Lynch suggested that women should be taught to perform a breast self-exam and seek annual mammograms. Knowing’s one’s risk, he estimated, promoted vigilant surveillance and early diagnosis, maximizing women’s sense of control over their health and management options. </p>
<p>In all these examples, you may notice a pattern: women (with the help of researchers) were seeking ways to understand and mitigate their cancer risk in order to control their personal and familial futures. We see the same pattern reflected with genetic testing today. Whether for cancer or for other health issues, it has become largely a women’s issue.</p>
<h2>Genetic testing and women</h2>
<p>For decades, scholars have analyzed how <a href="http://heinonline.org/HOL/LandingPage?handle=hein.journals/amlmed17&div=8&id=&page=">genetic tests</a> like <a href="https://books.google.com/books?isbn=0393309983">amniocentesis</a> and <a href="https://books.google.com/books?id=xREfG-4UGsQC&printsec=frontcover&dq=isbn:1135963916&hl=en&sa=X&ei=-bORVevBEsf3-QHd1ILQBg&ved=0CB4Q6AEwAA#v=onepage&q&f=false">chorionic villus sampling</a> (CVS), as well as technologies like in vitro fertilization, have affected <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508970/pdf/amjph00011-0035.pdf">women’s reproductive choices</a>.</p>
<p>Genetic testing for BRCA prompts us to revisit some of the central questions these scholars raise. How are women’s reproductive choices influenced by the prospect of a disease like breast cancer that appears in adulthood? </p>
<p>As genetics becomes <em>the</em> paradigm for understanding disease, how does it affect how women think of their reproductive options? How does thinking in terms of genetic risk affect women’s psychological and emotional well-being, and how they conceptualize their family life?</p>
<p>BRCA testing also asks us to consider a larger problem in women’s health history: the tendency to think of disease solely in terms of personal risk. Considering environmental health risks helps us to think more about collective impacts and responsibilities. But genomic medicine tends to emphasize uniquely personal risk factors.</p>
<p>This emphasis on personal risk may lead us to ignore the wider range of social and familial factors that affect how women interpret their health status and experience genetic disease. </p>
<p>We risk thinking about genetics as destiny, as though it is only hereditary risk factors that matter. Taken to the extreme, that might mean deemphasizing important nongenetic measures that have curbed cancer risks for decades. </p>
<p>Pap smears, mammograms, prophylactic medications and other public health initiatives have all helped increase early detection of cancers. The predisease infrastructure erected with the help of post-WWII geneticists like Reed and Lynch is now being overshadowed by predictive technologies of the “new” genetics. </p>
<p>Women’s experiences with health, illness and living “at risk” serve as grounds for debating social values around motherhood, reproductive rights, and concepts of disability and disease. BRCA is not the first platform for debating these issues, nor will it be the last.</p><img src="https://counter.theconversation.com/content/42156/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Devon Stillwell holds a postdoctoral fellowship at Johns Hopkins University in the Department of the History of Medicine funded by SSHRC (Social Sciences and Humanities Research Council). </span></em></p>History shows how scientists and the public tried to understand hereditary cancer risk well before we had the technology to discover mutations and test for genetic disorders.Devon Stillwell, Postdoctoral Fellow, History of Medicine, Johns Hopkins UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/415932015-05-13T22:37:20Z2015-05-13T22:37:20ZTurning the tables: using genetic mutations to fix nature’s problems<figure><img src="https://images.theconversation.com/files/81180/original/image-20150511-22733-1ho81lx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Genetic therapy might be able to reverse the harmful effects of sickle cell anaemia.</span> <span class="attribution"><a class="source" href="http://commons.wikimedia.org/wiki/Category:Sickle-cell_anemia?uselang=en-gb#/media/File:Sickle_Cell_Blood_Smear.JPG">Keith Chambers</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Everyone is different. That’s a simple truism, but it’s is also true when it comes to how people respond to diseases; some people are laid low and others shrug off the same ailment.</p>
<p>And it’s true of genetic diseases. Even when two individuals carry the same mutation, the severity of the disease may vary between them.</p>
<p>Sometimes this is due to environmental variation, but in other cases it reflects additional genetic changes that also influence how the disease affects that person. Some people will have other harmful mutations that combine with the main disease gene to make the condition worse, while more fortunate people may have inherited other variations, actual beneficial mutations, that reduce or even eliminate symptoms.</p>
<p>One of the best known illustrations of this phenomenon centres around the inherited blood disorder <a href="https://theconversation.com/explainer-one-day-science-may-cure-sickle-cell-anaemia-28153">sickle cell anaemia</a>. This lifelong condition is due to mutations in the adult <a href="http://en.wikipedia.org/wiki/Globin">globin gene</a> – a <a href="http://ghr.nlm.nih.gov/glossary=pointmutation">point mutation</a> in that gene renders it defective and patients suffer from anaemia throughout their lives. The symptoms can be severe. Damaged blood cells can block blood vessels leading to intense pain and even loss of life.</p>
<h2>In the blood</h2>
<p>But, as mentioned above, symptoms vary between individuals. Environmental variability also influences symptoms, so affected individuals may be advised to avoid high altitude and oxygen stress, for example. But genetic variations also exist. Some individuals carry a second mutation in the regulatory region of another globin gene that alleviates symptoms of sickle cell anaemia.</p>
<p>These individuals have a benign condition called Hereditary Persistence of Foetal Haemoglobin (<a href="http://www.chime.ucl.ac.uk/APoGI/data/pdf/hb/carriers/b/pfh/carbook.pdf">HPFH</a>). They have an “<a href="http://www.biology-online.org/dictionary/Up_mutation">up-mutation</a>” in the control region of a separate globin, the foetal globin gene, which boosts expression of that gene. The extra foetal globin can replace the defective beta globin.</p>
<p>I realise that is fairly complicated. But, put simply: humans have several globin genes. The foetal globins are turned on before birth and have a high affinity for oxygen; they enable the baby to snatch oxygen from its mother’s blood. After we are born the adult, or beta globin, gene comes on and the foetal globin gene is shut off. </p>
<p>But in a few people with HPFH the foetal globin gene stays on throughout life. Interestingly, this doesn’t seem to cause any health problems. Individuals with HPFH can even have normal pregnancies. They just have extra foetal globin in their blood.</p>
<p>The crux of the matter is this: if an individual inherits the sickle cell mutation and an HPFH mutation, they have few if any symptoms, because the extra foetal globin does the work of the defective adult globin gene.</p>
<p>So could one effectively “cure” sickle cell anaemia by introducing the HPFH mutation into blood cells affected by the defective adult globin gene?</p>
<h2>Switching on the backup</h2>
<p>Well, this is precisely <a href="http://dx.doi.org/10.1038/ncomms8085">the approach we have taken</a>. Using the new technique of “<a href="https://theconversation.com/explainer-what-is-genomic-editing-25072">genome editing</a>”, we have introduced one of the best characterised HPFH mutations, and we find that we can successfully turn on the sleeping foetal globin gene.</p>
<p>At this stage we have only done this in cell lines in the laboratory. To turn this into a therapy, one would have to do it in haematopoietic stem cells – i.e. blood-<a href="http://stemcells.nih.gov/info/scireport/pages/chapter5.aspx">forming stem cells</a> – from the patient. It would be necessary to achieve a high frequency of editing in enough stem cells to enable repopulation of the patient’s blood with genetically enhanced cells.</p>
<h2>Gene repair</h2>
<p>But if it is so easy to edit the genome now, why don’t we just correct the sickle cell mutation rather than introducing a new mutation, albeit a beneficial and benign mutation?</p>
<p>Well, that is certainly a good strategy in the case of sickle cell anaemia, and many people are working on just that. But it may be a less ideal strategy for other blood diseases and various genetic diseases where large genes or regions of the genome are deleted. </p>
<p>In the case of the <a href="http://www.thalassaemia.org.au/thalassaemia-and-related-blood-disorders">thalassaemias</a>, for example, many different gene deletions occur. It may not be practical to edit in large gene replacement cassettes, and one would have to design a different insert for each mutation. In contrast, building in the foetal globin activating mutation should provide additional globin and work to compensate in many of these conditions.</p>
<h2>Towards gene therapy using genome editing</h2>
<p>A new age of genetic engineering is beginning, due to the ability to <a href="https://theconversation.com/explainer-what-is-genomic-editing-25072">edit the genome</a> using new DNA-cutting tools, with the technical names: <a href="https://www.addgene.org/CRISPR/guide/">CRISPRs</a>, <a href="https://www.addgene.org/talen/guide/">TALENs</a> and <a href="http://www.sigmaaldrich.com/life-science/zinc-finger-nuclease-technology/learning-center/what-is-zfn.html">ZFNs</a>. </p>
<p>Gene correction or the introduction of beneficial mutations may be important in treatments in the future. </p>
<p>In agriculture they may also be important. Many <a href="http://ghr.nlm.nih.gov/handbook/genomicresearch/gwastudies">genome wide association studies</a> have identified beneficial mutations associated with particular prised qualities. <a href="https://theconversation.com/explainer-what-is-genomic-editing-25072">Genome editing</a> can also be used to introduce beneficial mutations in this context and may give rise to a new generation of crops and livestock.</p>
<p>The techniques are also interesting because no new or artificial material need be introduced. All one is doing is mimicking a naturally occurring beneficial mutation. The introduction of artificial <a href="http://en.wikipedia.org/wiki/Transgene">transgenes</a> has <a href="http://www.fao.org/docrep/006/y4955e/y4955e0a.htm">alarmed</a> some parts of society. </p>
<p>Additionally, transgenes are recognised as foreign by some organisms and are shut down by <a href="https://theconversation.com/explainer-what-is-epigenetics-13877">epigenetic silencing</a>, just as computer viruses are recognised and shut down by anti-virus software. </p>
<p>Beneficial mutations are unlikely to be subject to the same limitations. They are already known to work in nature and introducing them to improve human health or in agriculture may have many advantages.</p><img src="https://counter.theconversation.com/content/41593/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley works for the University of New South Wales. He receives funding from the National Health and Medical Research Council and the Australian Research Council.</span></em></p>Gene therapy is allowing us to switch on natural beneficial mutations to counteract the effects of negative mutations in diseases such as sickle cell anaemia.Merlin Crossley, Dean of Science and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/380242015-03-03T04:06:34Z2015-03-03T04:06:34ZShould doctors share gene tests after a death in the family?<figure><img src="https://images.theconversation.com/files/73547/original/image-20150303-15981-tq7j2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Families share genes but that doesn't mean no individual in a family should be accorded privacy about their genetic tests.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/magw21/126452964">magw21/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Would you want your family members to be told about your genetic tests after your death if it meant saving their lives through early medical intervention? The authors of a <a href="http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(15)00003-9">paper just published</a> in Trends in Molecular Medicine argue doctors may only have a duty to disclose such information if asked by a living relative.</p>
<p>Consider the following case. Mary recently died from thyroid cancer, but some of her tissue is stored in the pathology laboratory where it was tested. For her particular cancer, early detection can mean the difference between life and death.</p>
<p>Mary’s sister Sally may want to know her own risk of developing the cancer, so she can take precautions if she has a genetic mutation. But she may, equally, not want to know, as some people don’t want to be influenced by the results of genetic tests. </p>
<h2>An ethical dilemma</h2>
<p>Mary’s doctor has two options.</p>
<p>The first is active disclosure, which places a legal or ethical duty on Mary’s doctor to warn her living relatives about their genetic risk. This duty violates Mary’s right to privacy and confidentiality. It also violates her autonomy (if autonomy is thought to continue after death), especially if Mary had stipulated that she didn’t want her relatives to know her medical details. </p>
<p>Being contacted by her late sister’s doctors could distress Sally and breach her right not to know her risk. What’s more, it might not be feasible to find or contact Mary’s relatives. </p>
<p>The second option is passive disclosure, which the authors of the paper prefer. For this option, Mary’s doctor would be justified in telling Sally about Mary’s condition if Sally asks. But the doctor does not have to contact Sally to tell her without prompting.</p>
<p>Concerns about the breach of Mary’s rights of privacy, confidentiality and autonomy could be minimised if there was counselling before all tests about possible postmortem disclosure to close relatives. This would also allay any concerns Mary’s doctor might have about breaching her privacy or autonomy.</p>
<p>The authors of the paper say active disclosure may be morally justified only if the risk of severe disease is very high and clinical action makes it possible to avoid disease. </p>
<h2>Australian law</h2>
<p>Australian law supports the authors’ stance, encouraging passive rather than active disclosure. Here, Mary’s doctor wouldn’t have a duty to contact Sally but, if Sally asked about her risk, the doctor could lawfully tell her about the risk revealed by Mary’s test. </p>
<p>The federal <a href="http://www.comlaw.gov.au/Series/C2004A03712">Privacy Act 1988</a> allows personal information about a patient to be disclosed to a genetic relative if the person holding the information: </p>
<blockquote>
<p>reasonably believes that the use or disclosure is necessary to lessen or prevent a serious threat to the life, health or safety of another individual who is a genetic relative of the first individual.</p>
</blockquote>
<p>Mary’s information can be disclosed to Sally without Mary having been counselled about such a possibility when she was tested. But there’s an important point here that the authors of the <a href="http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(15)00003-9">Trends in Molecular Medicine</a> paper do not mention. </p>
<p>Genetic information is of two kinds. The first is that a gene mutation exists in the family. The second is the status of particular family members for that mutation – positive or negative. </p>
<p>In Australia, Sally would be entitled to know the familial information – that the mutation exists in the family, but not whether Mary was positive or negative for the mutation. That part of Mary’s medical information remains confidential as Sally doesn’t need to know it for her own health care.</p>
<p>The Australian law makes it clear that doctors can breach confidentiality where it is necessary to protect the health of a close relative. That person’s health is more important than the privacy of the deceased.</p>
<p>The principle also emphasises the familial nature of genetic information, which is vital in the delivery of genetic services in the future.</p><img src="https://counter.theconversation.com/content/38024/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Loane Skene is a member of the NHMRC Australian Health Ethics Committee and Chair of the Ethics Committee of Peter McCallum Cancer Centre.</span></em></p>When a family member dies from a disease caused by a genetic mutation, doctors have to decide whether to share the deceased person’s test results with the rest of the family.Loane Skene, Professor of Law & Adjunct Professor, Faculty of Medicine Dentistry and Health Sciences, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/161592013-07-17T18:08:13Z2013-07-17T18:08:13ZClouds of decoy viruses help cure genetic disease<figure><img src="https://images.theconversation.com/files/27639/original/n8jz4rhz-1374069183.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Helpful viruses get protected by decoy viruses in the bloodstream.</span> <span class="attribution"><span class="source">Maddy Cow</span></span></figcaption></figure><p>The presence of foreign objects, like viruses, in our bloodstream is usually a bad thing. Evolution has created some extremely efficient immune cells that patrol the blood, seeking out material that should not be there, and shutting it down.</p>
<p>Sometimes, though, viruses circulate in the blood for beneficial purposes. <a href="https://theconversation.com/gene-therapy-using-stem-cells-prevents-inherited-diseases-15980">Gene therapies</a> often deliver viruses as couriers to deliver new DNA to repair faulty cells. Getting viruses into the bloodstream is simple, but keeping them “active” during their time inside the body is difficult. This is particularly true if the immune system has encountered them before. Even though therapeutic viruses are engineered to be beneficial, the immune system doesn’t recognise the difference, and starts a defensive response. </p>
<p>Now a team led by Federico Mingozzi at the Children’s Hospital of Philadelphia has come up with a way of preventing such therapeutic viruses from being decommissioned by the immune system, by hiding the virus particles inside a cloud of decoy empty virus particles. </p>
<p>As they report today in the journal <a href="http://dx.doi.org/10.1126/scitranslmed.3005795">Science Translational Medicine</a>, the team developed an engineered version of adeno-associated virus (AAV) as a genetic courier for the treatment of haemophilia B. This disease stems from a mutation in the DNA of liver cells that prevents them from producing normal levels of an enzyme called coagulation factor IX. Such patients can bleed to death without proper treatment.</p>
<p>Mingozzi’s AAV was designed to deliver a DNA payload to the liver. This DNA contained instructions to produce the correct version of coagulation factor IX, a crucial protein involved in blood clotting, in the hope that it would cure this genetic disease. </p>
<h2>Stealth tactics</h2>
<p>Viruses consist of two parts: a genetic core (either DNA or RNA) and a protective protein shell. When a virus infects a human, the host immune system typically triggers a cascade of defensive reactions. One of the most effective responses is the production of neutralising antibodies that recognise and attach to the virus shell and squelch its activity.</p>
<p>Mingozzi’s choice of AAV as a genetic courier would seem counter-productive then, since between 30% to 60% of the human population has previously been exposed to AAV. Thus, their immune systems have learned to recognise AAV shells. In such immune individuals, even though the engineered version of AAV contains beneficial genetic information, it gets quickly tagged for destruction and obliterated long before it reaches its target destination (the liver).</p>
<p>Even when a large number of AAV particles are administered to improve the odds of some getting through, the immune system mops them up. The few particles that do survive the journey initiate the production of normal coagulation factor IX in liver cells, but only manage to reconstitute around 10% of the normal volume of the coagulation factor IX pool.</p>
<p>So Mingozzi came up with an idea to fool the immune system. He mixed therapeutic AAV particles containing the right genetic information with lots of empty AAV shells lacking a DNA core, and injected them into mice (used as a proxy for humans). This created a smokescreen, allowing the therapeutic AAV particles to dodge the immune system’s attack.</p>
<p>This new approach enhanced AAV survival in the bloodstream of mice. Depending on how immune each individual mouse was to AAV, a personalised ratio of empty AAV particles to real AAV particles was administered. Mice with higher levels of AAV antibodies received more empty decoy shells. </p>
<p>Circulating AAV antibodies, which exist in immune individuals, attacked both empty and active versions of AAV, but enough active virus got to the liver to boost coagulation levels beyond those seen in an average mouse. These beneficial effects lasted up to four weeks – an excellent timeframe given that a severely affected haemophilia B patient has to inject themselves every day. </p>
<p>They also tested out the same idea using animals more closely related to humans - <a href="http://pin.primate.wisc.edu/factsheets/entry/rhesus_macaque">rhesus macaques</a> – where the presence of decoy virus gave real AAV particles the same survival extension, and boosted coagulation factor IX levels to a similar degree. </p>
<p>Importantly, when different monkey tissues were examined after administering empty and real AAV formulations, all the activity predominantly happened in the liver, with no unsafe, off-target effects in other organs.</p>
<h2>Perfecting the decoy trap</h2>
<p>The first generation of decoy viruses used in this study were designed to be exact replicas of AAV, but without the DNA payload. Unfortunately, these decoy viruses behaved too much like the real thing, attaching to target liver cells and by virtue of their overwhelming numbers, out-competing the binding of real, therapeutically-relevant virus. Once inside liver cells, bits of these empty viruses then presented enticing foreign targets to the immune system.</p>
<p>Tweaking the design of the empty virus shell in the second generation of decoy viruses prevented it from binding liver cells, boosted the binding of real virus and replicated the rise in coagulation factor IX levels. It also had the happy consequence of dampening certain sections of the immune response. </p>
<p>Using fake viruses as bodyguards is an ingenious way of protecting therapeutic viruses in the bloodstream. This approach could represent the start of a therapeutic revolution for haemophilia B patients, and others with genetic diseases.</p><img src="https://counter.theconversation.com/content/16159/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Stephanie Swift 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>The presence of foreign objects, like viruses, in our bloodstream is usually a bad thing. Evolution has created some extremely efficient immune cells that patrol the blood, seeking out material that should…Stephanie Swift, Postdoctoral Researcher, McMaster UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/75992012-09-27T04:21:49Z2012-09-27T04:21:49ZWhat’s the genetic disease risk for children of related couples?<figure><img src="https://images.theconversation.com/files/13460/original/8qq4fdg6-1343274397.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Depending on the condition a couple risk passing to their child, testing can be offered as carrier screening.</span> <span class="attribution"><span class="source">Shirl/Flickr</span></span></figcaption></figure><p>Marriages between people who are related is more common than you might think. Unlike what many people think, their offspring are not doomed to birth defects or medical problems. </p>
<p>In fact, unless they both carry the same gene mutation, the couple’s chance of having a healthy child is almost as high as any other couple. Let’s examine why, through the story of one couple.</p>
<h2>And baby makes three</h2>
<p>Maria is planning a pregnancy with her partner Max. They visit their doctor to discuss family planning and pregnancy health, and during questioning, they disclose that they’re first cousins. Their doctor refers them to a clinical genetics service for further advice. </p>
<p>What risks do they face, if any? And what information would be requested by the clinical genetics service?</p>
<p>In multicultural Australia, marriage between family members <a href="https://theconversation.com/why-not-marry-your-cousin-millions-do-7503">does occur</a>, most commonly between first or second cousins. From a medical perspective, Mary and Max have several issues to consider.</p>
<p>The first of these relates to their exact genetic relationship. Genetically speaking, the closer one is to a family member, the more genes will be shared. Monozygotic (identical) twins have the same genetic make-up and share 100% of their genes. A parent and child share half their genes, as do siblings. An uncle and his niece, or an aunt and her nephew (a second-degree relationship) share a quarter of their genes. </p>
<p>Maria and Max, being cousins (a third-degree relationship), share an eighth of their genetic make-up. This being the case, what are Maria and Max at risk of?</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/13459/original/y3hk7qjq-1343273811.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">
<figcaption>
<span class="caption">Receiving the same faulty genes from both parents puts a child at risk of having a genetic disease.</span>
<span class="attribution"><span class="source">Ryan Croson</span></span>
</figcaption>
</figure>
<p>As they share a significant proportion of their genes, the couple are at risk of having a child with an autosomal recessive condition. This kind of condition is caused by having a “double dose” of a faulty gene. </p>
<p>We have two copies of every gene (for most genes) – one inherited from our father, and one from our mother. For many genes, our body can cope with just a single working copy, but when both copies are faulty, the person gets an autosomal recessive disease. Examples of such diseases include cystic fibrosis, <a href="http://www.thalassaemia.org.cy/pdf/What%20is%20Thalassaemia.pdf">thalassaemia</a> (diseases of the blood), and spinal muscular atrophy. </p>
<h2>Calculating risk</h2>
<p>Most of us carry a handful or so of faulty recessive genes so marrying within your family increases your chance of “meeting” someone else with the same faulty recessive genes as you. And working out the degree of risk to Maria and Max’s offspring depends on whether or not they have a known family history of an autosomal recessive condition. </p>
<p>In the genetics clinic, a medical geneticist would ask them about the health of family members going back several generations, and draw a detailed family tree. Reports about other family members might need to be verified to establish an exact diagnosis. </p>
<p>If Maria and Max do have a family history of an autosomal recessive condition, such as thalassaemia, their degree of risk could be calculated based on who the affected individual was. Depending on the exact condition, testing could be offered as carrier screening. In the case of thalassaemia, for instance, Maria and Max could be offered a blood test to look for changes in their blood cells that might indicate that they’re carriers of the thalassaemia gene.</p>
<p>But if they don’t have any family history of an autosomal recessive condition, the medical geneticist would have to rely on risk estimates based on population data and general experience. We know (based on Victorian data) that approximately <a href="http://docs.health.vic.gov.au/docs/doc/Birth-defects-in-Victoria-2005-2006">four in 100 couples</a> will have a baby with a birth defect, which may be mild or severe. First-cousin marriages add extra risk to this, resulting in an approximate <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1762250/pdf/ajhg00455-0069.pdf">doubling of the background risk</a>.</p>
<p>Without a family history of an autosomal recessive condition, Maria and Max have an 8% chance of having a child diagnosed with a problem after birth. In other words, their chance of having a healthy baby is greater than 90%, a figure that most people find quite reassuring.</p>
<p>This figure is not too different to the general population risk of having a baby with a birth defect. Most related couples accept this risk and focus instead on general measures to have a healthy baby, such as taking folate, losing weight, and reducing their intake of alcohol and cigarettes.</p>
<p><em>For advice on this topic or if you have concerns about a possible genetic condition in your family, contact the <a href="http://www.vcgs.org.au">Victorian Clinical Genetics Services</a> or your local clinical genetics service.</em></p><img src="https://counter.theconversation.com/content/7599/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Tiong Tan 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>Marriages between people who are related is more common than you might think. Unlike what many people think, their offspring are not doomed to birth defects or medical problems. In fact, unless they both…Tiong Tan, Clinical Geneticist at Victorian Clinical Genetics Services and Researcher in Craniofacial Research, Murdoch Children's Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/25242012-02-06T10:18:04Z2012-02-06T10:18:04ZSafety in numbers: how three parents can beat genetic diseases<figure><img src="https://images.theconversation.com/files/7417/original/m2trh3nf-1328522089.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The mitochondrial genome is passed on by mothers – defects and all.</span> <span class="attribution"><span class="source">Marcos Leal</span></span></figcaption></figure><p><strong>Media outlets have been reporting that scientists are planning to “create designer babies” with three parents. Professor Justin St John, Director of the Centre for Reproduction and Development at Monash University explains the technology being proposed and its feasibility.</strong></p>
<p>We inherit most genes from both parents, which determine things like hair colour, eye colour and behavioural patterns, but there’s a small proportion of DNA that we inherit only from our mothers. This DNA is from a region of the ovum (egg) called the cytoplasm, which houses organelles called mitochondria. </p>
<p>One of the main functions of mitochondria is to generate energy and that’s why they’re known as the powerhouses of the cell. Within each mitochondria, there’s a small round piece of DNA called the mitochondrial genome (mtDNA). This has some very important genes because they’re directly involved in the process of making energy. If any of these genes are mutated, then the individual will have severe disabilities related to not being able to generate enough energy or some of their cells will not function properly. </p>
<p>So we inherit our mtDNA only from our mother and what we inherit is the mtDNA that’s in her eggs just prior to fertilisation. Then our father’s sperm comes along and it delivers the chromosomal genes which join with our mother’s chromosomal genes and that’s the bulk of the DNA in the body. </p>
<p>The content of mtDNA gets changed during various stages of the development of the embryo and the foetus, while chromosomal DNA comes together and is then replicated or copied and will appear in each new cell. When the embryo starts to form all the different tissues of the body, the mutant mtDNA can go to some of the cells of the body – it can be distributed quite randomly. </p>
<p>So we can never predict if mutant mtDNA is going to distribute to cells which give rise to the brain, the heart, the kidneys or whatever. What happens is that if the mutant molecules go to cells that have a high requirement for energy, such as the brain or the muscle cells, then you’re likely to be hit by mitochondrial disease. If it distributes to tissues that are not necessarily high-energy requiring cells, then the likelihood of being affected is far less.</p>
<p>Currently, there are technologies that work with embryos, such as pre-implantation genetic diagnosis, which is used in IVF clinics. When an embryo forms, it starts by having two cells and then four, eight, sixteen onwards. This technology takes one of these cells and analyses it to see whether that embryo (and the child that it will form into), will be affected by the specific genetic disease.</p>
<p>And that’s perfectly fine for diseases associated with the chromosomal genome. But because we don’t understand how the mitochondrial genome distributes early on during development, the information that we get from pre-implantation genetic diagnosis doesn’t usually help in avoiding mitochondrial diseases.</p>
<p>The more appropriate process (since we know the mtDNA is in the woman’s egg) is to take out the genome from that egg and transfer it into an egg of a woman who isn’t a carrier of mitochondrial disease. Then you can fertilise this newly created or reconstructed egg with the father’s sperm. So the new baby will have chromosomes from it’s mother and father but it will have another population of mtDNA, which will be from the woman who donated her egg to this treatment. That’s why people will refer to children who would result from this process as having three parents.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/7402/original/rf87hwf3-1328504034.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">The process of ensuring an embryo doesn’t carry mitochondrial disease.</span>
<span class="attribution"><span class="source">Justin St John</span></span>
</figcaption>
</figure>
<p>And we don’t know whether these children will resemble the third parent. This technology is very similar to the way we do cloning and it’s interesting to consider some of the studies that have used cloning technology to, for instance, make different types of fish. Researchers took a cell from a carp and they transferred into a goldfish egg. The resulting fish did have some of the characteristics of the egg donor. </p>
<p>There’s another approach to circumventing mitochondrial disease. Instead of taking an unfertilised egg, you start with one that’s already been fertilised (zygote), so it’s got two populations of chromosomal DNA. You can go in and take out both these populations and transfer them into another zygote that has had these two bits removed.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/7401/original/pggtchtm-1328504032.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">Another way to avoid mitochondrial disease.</span>
<span class="attribution"><span class="source">Justin St John</span></span>
</figcaption>
</figure>
<p>The problem with these processes is that we’re not sure that when you perform these transfers, you’re not going to take a few of the mutant mtDNA with you. We know that mtDNA distributes or segregates unequally during early development and we don’t know if it’s being selected for or selected against – whether it persists or is eliminated. And we don’t know that if you carry over a few of these mtDNA with mutations, whether that will actually still lead to the onset of mitochondrial disease. </p>
<p>So we need some rigorous experiments to determine whether it’s possible to extract the chromosomes either from the mum’s egg or the newly fertilised egg, without taking any mutant mtDNA along.</p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/19710649?dopt=Abstract&holding=npg">Authors of some studies</a> performed on monkeys in the United States have argued they didn’t carry mtDNA from the original egg when they performed this first process. But <a href="http://www.nature.com/gt/journal/v17/n2/full/gt2009164a.html">we suspect</a> their detection processes weren’t rigorous enough, and they didn’t look at every tissue in the monkeys they created. Because mtDNA distributes unequally during early development, you’d have to check all the tissues to be sure there are no passed on mutations.</p>
<p>In Australia, the <a href="https://legislationreview.nhmrc.gov.au/2010-legislation-review-committee">Heerey Committee</a> sat last year to review whether we should keep certain technologies going for experimental purposes. Whether, for instance, we should still use cloning to try and make embryonic stem cells with human eggs and human embryos. </p>
<p>One of the matters the Committee discussed in <a href="https://legislationreview.nhmrc.gov.au/sites/default/files/legislation_review_reports.pdf">their report</a> was whether we could try to make embryos by transferring the mother’s and father’s chromosomes from one egg to another under experimental conditions. And our interpretation is that it might be allowable under license from the NHMRC but an application would have to be made that would be ruled on.</p>
<p>The other process of taking the chromosomes from an unfertilised egg wouldn’t be allowed because we’re talking about generating a new embryo for research purposes. That’s where the distinction between the two processes lies.</p>
<p>What we need to do is get a large body of data that’s based on sound experimental analyses together. Then scientists would be in a strong position to go to the government and show these technologies have been validated. And the government could make an informed decision about whether we can travel down this path to eradicating mitochondrial disease.</p>
<p>There are going to be groups that won’t want this to happen. It’s quite a controversial technology because we’re dealing with embryos; some people accept this but others find it abhorrent. Nevertheless, we have the opportunity to prevent the next generation of children from having mitochondrial disease. </p><img src="https://counter.theconversation.com/content/2524/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Justin St. John receives funding from the NMHRC and used to receive funding from the MRC in the United Kingdom.</span></em></p>Media outlets have been reporting that scientists are planning to “create designer babies” with three parents. Professor Justin St John, Director of the Centre for Reproduction and Development at Monash…Justin St. John, Professor and Director, Centre for Genetic Diseases, Monash Institute of Medical Research, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.