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This new tech could spell end for mouse plagues

<p dir="ltr">Invasive mice populations could be a thing of the past, thanks to a new genetic tool developed by a team of Australian scientists.</p> <p dir="ltr">Researchers at the University of Adelaide have developed t-CRISPR, which uses gene editing technology to alter the fertility gene in laboratory mice to make females infertile.</p> <p dir="ltr">“This is the first time that a new genetic tool has been identified to suppress invasive mouse populations by inducing female infertility,” said lead researcher Professor Paul Thomas.</p> <p dir="ltr">“The t-CRISPR approach uses cutting-edge DNA editing technology to make alterations to a female fertility gene. Once the population is saturated with the genetic modification, all the females that are generated will be infertile.</p> <p dir="ltr">“We are also developing new versions of t-CRISPR technology that are designed to target specific pest populations to prevent unwanted spread of the gene drive.”</p> <p dir="ltr">The new tool is based on an existing technology, CRISPR-Cas9 gene editing, which has largely been applied to limiting the spread of malaria by making male mosquitoes infertile.</p> <p dir="ltr"><strong>CRISPR 101</strong></p> <p dir="ltr">Since it was unveiled in 2012, the CRISPR method has been used to edit pieces of DNA inside the cells of organisms, primarily insects.</p> <p dir="ltr">“Up until now, this technology has been aimed at insects to try and limit the spread of malaria, which causes up to 500,000 deaths worldwide per year,” Luke Gierus, a post-graduate student and the paper’s co-first author, said.</p> <p dir="ltr">The technology relies on the Cas9 protein found in bacteria, which scientists can program to find and bind to almost any 20-letter sequence of DNA in a gene with the help of a piece of RNA that matches the target DNA sequence.</p> <p dir="ltr">When it finds the target, standard CRISPR cuts the DNA, and the process of repairing the DNA introduces mutations that can disable the gene.</p> <p dir="ltr">Other variations of CRISPR can also replace faulty genes, turn genes on or off, or change one letter of the DNA code to another.</p> <p dir="ltr">In this study, the team simulated what would happen when an edited version of a fertility gene on chromosome 17, which affects the ability of sperm to swim, was introduced to populations of mice. </p> <p dir="ltr">Males who carry one copy of this gene are infertile, while females are still fertile but only have one functioning version of the gene and can pass on either the functioning or non-functioning version to their offspring.</p> <p dir="ltr">In females that had a second edited chromosome that affected their fertility, they found that male offspring would all be infertile, while only 50 percent of female offspring would be fertile.</p> <p dir="ltr">They found that 250 mice with modified genes could eradicate a population of 200,000 mice on an island in around 20 years.</p> <p dir="ltr">“The use of t-CRISPR technology provides a humane approach to controlling invasive mice without the release of toxins into the environment. We are also working on strategies to prevent failed eradication due to the emergence of gene drive resistance in the target population,” Gierus said.</p> <p dir="ltr">While t-CRISPR has been developed to specifically target mice, CSIRO Group Leader for Environmental Mitigation and Resilience Dr Owain Edwards said it could be developed to use on other invasive animals.</p> <p dir="ltr">The researchers, who collaborated with CSIRO, the Centre for Invasive Species Solutions, the Genetic Biocontrol for Invasive Rodents (GBIRd) consortium and the US Department of Agriculture, were supported by both the South Australian and NSW governments.</p> <p dir="ltr">“These promising findings demonstrate how gene drive technology may be a game changer in managing the impacts of mice on our environment, community, and agricultural sector,” South Australian Deputy Premier Dr Susan Close said.</p> <p dir="ltr">“This cutting-edge research also highlights the global leadership of the South Australian research sector, in finding solutions to social, environmental and economic challenges.</p> <p dir="ltr">“The South Australian Government is proud to have supported this proof-of-concept, having granted the University of Adelaide $1 million through the Research and Innovation Fund.”</p> <p dir="ltr">They published their findings in the journal <em><a href="https://doi.org/10.1073/pnas.2213308119" target="_blank" rel="noopener">Proceedings of the National Academy of Sciences</a></em>.</p> <p><span id="docs-internal-guid-bca82366-7fff-dcca-05a4-83502245beac"></span></p> <p dir="ltr"><em>Image: ABC News</em></p>

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China's failed gene edited baby experiment proves we're not ready for human embryo modification

<p>More than a year ago, the world was shocked by Chinese biophysicist He Jiankui’s attempt to use CRISPR technology to modify human embryos and make them resistant to HIV, which led to the birth of twins Lulu and Nana.</p> <p>Now, crucial details have been revealed in a recent <a href="https://www.technologyreview.com/s/614764/chinas-crispr-babies-read-exclusive-excerpts-he-jiankui-paper/">release of excerpts</a> from the study, which have triggered a series of concerns about how Lulu and Nana’s genome was modified.</p> <p><strong>How CRISPR works</strong></p> <p>CRISPR is a technique that allows scientists to make precise edits to any DNA by altering its sequence.</p> <p>When using CRISPR, you may be trying to “knock out” a gene by rendering it inactive, or trying to achieve specific modifications, such as introducing or removing a desired piece of DNA.</p> <p>Gene editing with the CRISPR system relies on an association of two molecules. One is a protein, called Cas9, that is responsible for “cutting” the DNA. The other molecule is a short RNA (ribonucleic acid) molecule which works as a “guide” that brings Cas9 to the position where it is supposed to cut.</p> <p>The system also needs help from the cells being edited. DNA damage is frequent, so cells regularly have to repair the DNA lesions. The associated repair mechanisms are what introduce the deletions, insertions or modifications when performing gene editing.</p> <p><strong>How the genomes of Lulu and Nana were modified</strong></p> <p>He Jiankui and his colleagues were targeting a gene called CCR5, which is necessary for the HIV virus to enter into white blood cells (<a href="https://www.medicalnewstoday.com/articles/320987.php">lymphocytes</a>) and infect our body.</p> <p>One variant of CCR5, called CCR5 Δ32, is missing a particular string of 32 “letters” of DNA code. This variant naturally occurs in the human population, and results in a high level of resistance to the most common type of HIV virus.</p> <p>The team wanted to recreate this mutation using CRISPR on human embryos, in a bid to render them resistant to HIV infection. But this did not go as planned, and there are several ways they may have failed.</p> <p>First, despite claiming in the abstract of their unpublished article that they reproduced the human CCR5 mutation, in reality the team tried to modify CCR5 <em>close</em> to the Δ32 mutation.</p> <p>As a result, they generated different mutations, of which the effects are unknown. It may or may not confer HIV resistance, and may or may not have other consequences.</p> <p>Worryingly, they did not test any of this, and went ahead with implanting the embryos. This is unjustifiable.</p> <p><strong>The mosaic effect</strong></p> <p>A second source of errors could have been that the editing was not perfectly efficient. This means that not all cells in the embryos were necessarily edited.</p> <p>When an organism has a mixture of edited and unedited cells, it is called a “mosaic”. While the available data are still limited, it seems that both Lulu and Nana are mosaic.</p> <p>This makes it even less likely that the gene-edited babies would be resistant to HIV infection. The risk of mosaicism should have been another reason not to implant the embryos.</p> <p>Moreover, editing can have unintended impacts elsewhere in the genome.</p> <p>When designing a CRISPR experiment, you choose the “guide” RNA so that its sequence is unique to the gene you are targeting. However, “off-target” cuts can still happen elsewhere in the genome, at places that have a similar sequence.</p> <p>He Jiankui and his team tested cells from the edited embryos, and reported only one off-target modification. However, that testing required sampling the cells, which were therefore no longer part of the embryos - which continued developing.</p> <p>Thus, the remaining cells in the embryos had not been tested, and may have had different off-target modifications.</p> <p>This is not the team’s fault, as there will always be limitations in detecting off-target and mosaicism, and we can only get a partial picture.</p> <p>However, that partial picture should have made them pause.</p> <p><strong>A bad idea to begin</strong></p> <p>Above, we have described several risks associated with the modifications made on the embryos, which could be passed on to future generations.</p> <p>Embryo editing is only ethically justifiable in cases where the benefits clearly outweigh the risks.</p> <p>Technical issues aside, the researchers did not even address an unmet medical need.</p> <p>While the twins’ father was HIV-positive, there is already a well-established way to prevent an HIV-positive father from infecting embryos. This “<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779710/">sperm washing</a>” method was actually used by the team.</p> <p>The only benefit of the attempted gene modification, if proven, would have been a reduced risk of HIV infection for the twins later in life.</p> <p>But there are safer existing ways to control the risk of infection, such as condoms and mandatory testing of blood donations.</p> <p><strong>Implications for gene editing as a field</strong></p> <p>Gene editing has endless applications. It can be used to <a href="https://www.nature.com/articles/d41586-019-02770-7">make plants such as the Cavendish banana more resistant to devastating diseases</a>. It can play an important role in the adaptation to climate change.</p> <p>In health, we are already seeing <a href="https://www.npr.org/sections/health-shots/2019/11/19/780510277/gene-edited-supercells-make-progress-in-fight-against-sickle-cell-disease">promising results</a> with the editing of somatic cells (that is, non-heritable modifications of the patient’s own cells) in beta thalassemia and sickle cell disease.</p> <p>However, we are just not ready for human embryo editing. Our techniques are not mature enough, and no case has been made for a widespread need that other techniques, such as preimplantation genetic testing, could not address.</p> <p>There is also much work still needed on governance. There have been individual calls for a moratorium on embryo editing, and expert panels from the <a href="https://www.nature.com/articles/d41586-019-00942-z">World Health Organisation</a> to <a href="https://en.unesco.org/news/unesco-panel-experts-calls-ban-editing-human-dna-avoid-unethical-tampering-hereditary-traits">UNESCO</a>.</p> <p>Yet, no consensus has emerged.</p> <p>It is important these discussions move <a href="https://www.nature.com/articles/d41586-019-03525-0">in unison</a> to a second phase, where other stakeholders, such as patient groups, are more broadly consulted (and informed). Engagement with the public is also crucial.</p> <p><em>Correction: this article originally described RNA (ribonucleic acid) as a protein, rather than a molecule.<!-- Below is The Conversation's page counter tag. Please DO NOT REMOVE. --><img style="border: none !important; box-shadow: none !important; margin: 0 !important; max-height: 1px !important; max-width: 1px !important; min-height: 1px !important; min-width: 1px !important; opacity: 0 !important; outline: none !important; padding: 0 !important; text-shadow: none !important;" src="https://counter.theconversation.com/content/128454/count.gif?distributor=republish-lightbox-basic" alt="The Conversation" width="1" height="1" /><!-- End of code. If you don't see any code above, please get new code from the Advanced tab after you click the republish button. The page counter does not collect any personal data. More info: http://theconversation.com/republishing-guidelines --></em></p> <p><em><a href="https://theconversation.com/profiles/dimitri-perrin-392467">Dimitri Perrin</a>, Senior Lecturer, <a href="http://theconversation.com/institutions/queensland-university-of-technology-847">Queensland University of Technology</a> and <a href="https://theconversation.com/profiles/gaetan-burgio-202386">Gaetan Burgio</a>, Geneticist and Group Leader, The John Curtin School of Medical Research, <a href="http://theconversation.com/institutions/australian-national-university-877">Australian National University</a></em></p> <p><em>This article is republished from <a href="http://theconversation.com">The Conversation</a> under a Creative Commons license. Read the <a href="https://theconversation.com/chinas-failed-gene-edited-baby-experiment-proves-were-not-ready-for-human-embryo-modification-128454">original article</a>.</em></p>

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