Better, Faster, Stronger, CRISPR: The Future of Gene-Editing and its Implications
Patricia Lu
CRISPR (pronounced “crisper”) is a revolutionary gene-editing tool that has the scientific world abuzz. Viewed by many as “one of the greatest biotechnology advances of the past century”[1] since its discovery 6 years ago, CRISPR’s potential is found to be both extensive and varied. Talks of an inevitable Nobel Prize are also frequently thrown around.[2] With applications in medicine, energy and agriculture (just to name a few), CRISPR will only become more and more relevant. Already raising important ethical and regulatory questions, up-to-date awareness among the general public about how it works and its implications will be significant in how it will be eventually integrated in the real world.
THE SCIENCE: What CRISPR is
CRISPR is short for Clustered Regulatory Interspaced Short Palindromic Repeats and are sequences of DNA involved in the bacterial defence system which helps in the protection against viral threats and invasions.[3][4] The systems can be designed to target particular genetic code and make accurate edits to DNA in specific areas.[5] It is also often referred to as “CRISPR-Cas9” in the genome engineering field because it is the Cas9 protein that acts as the “molecular scissors” that cuts the DNA (while CRISPR is responsible for locating the right area).[6] CRISPR-Cas9 is not the only type of the CRISPR enzyme – in fact, 2 different classes of CRISPR-Cas systems are recognized, with 6 CRISPR types and at 33 subtypes identified so far.[7] But CRISPR-Cas9 was the original and is the most widely used.[8] However, the CRISPR-Cpf1/Cas12a system was recently discovered as a “simpler and more precise” alternative for genome editing.[9] Emmanuelle Charpentier, one of the pioneers of this technology, has essentially described CRISPR as akin to a “Swiss Army knife that allows you to repair genes.”[10]Genome manipulation has been around since the 1970s.[11] But what makes CRISPR so special lies in its simplicity and efficiency: it is a “fast[er], cheap[er] and easi[er] method” than any technology before it.[12] Scientists have better control in genome manipulation because of it. It is even possible to buy CRISPR kits for personal use[13], and some schools in the United States have already added it to their curriculum.[14] CRISPR technology is has sparked such excitement in the scientific community that it is only a matter of time before it gets outside the lab and into the real world.
THE APPLICATION: What CRISPR can do
CRISPR’s precision and ease of use suggests an almost a limitless potential for application. The use of CRISPR for plants means genetic modification is more feasible and specific so advances in nutrition, in disease and pest resistance, and improved tolerance in difficult conditions can be engineered.[15] CRISPR may be especially significant for agriculture, as it could be the answer to food shortages and climate change issues that have constantly plagued the industry.[16] For animals, research is already underway to pursue the possible eradication of malaria through CRISPR gene editing. [17] CRISPR may even bring back extinct species to life – or at least species that share its traits and functions. Projects are already in place to bring back the woolly mammoth in order to, among other reasons, prevent greenhouse gas emissions by introducing grazers and combatting permafrost in the tundra.[18] CRISPR technology for humans could mean new ways to tackle and even permanently eliminate serious genetic diseases like Huntington’s disease or sickle cell anemia.[19] More controversial is the potential for “designer babies” and enhancements that lie outside fighting disease and illness.[20] External to gene editing, CRISPR can also be used to generate more efficient disease diagnosis, identify harmful fungi and aid in reducing antibiotic resistance.[21]These are merely a small sample of CRISPR’s uses and many more are likely to be discovered as the research delves deeper. But it is enough to at least gain a snapshot of how world-changing CRISPR can (and will) be and clearly justifies the hype that has surrounded it.
THE ISSUES: CRISPR’s limits and risks
Every newly discovered use of CRISPR also brings with it an exponential amount of risks and considerations. Many of these ethical and legal questions are not new but with the ease of exploitation of CRISPR and the speed of its development it may be time for consideration of the ethical limits of our use of CRISPR.In scientific terms, recent studies have discovered two particularly significant limitations that have dampened enthusiasm about CRISPR.Firstly in June of this year, two independent studies have identified that cells that have undergone the CRISPR process could be lacking in important anti-cancer mechanisms and potentially trigger cancer.[22] This does not mean that CRISPR causes cancer or turns cells cancerous. Rather, cells that were already lacking an operational p53 protein (which works as a tumor-suppressant and is therefore highly valuable in keeping cancer from forming) were more likely to be effectively edited by CRISPR technology.[23]The second key finding, published only in July, identified that CRISPR can lead to mutations and errors in the DNA that occur further down from the area where the edit occurred.[24] In a similar vein to the previous finding, these errors could then lead to the suppression of important cells or activate risky (and possibly cancer-causing) cells.[25] As a result, researchers anticipate slower clinical uses for CRISPR and urge more caution both in treating diseases and in keeping constant vigilance for harmful consequences.[26] Though these findings might appear as slight bumps in the road of CRISPR’s real world adoption, it is necessary information in perfecting the technology and ensuring it does what it is designed to do. In addition, the possible risk of cancer may be seen by many as the better alternative than living with a more fatal and less manageable disease.[27]
Any conversation about genome editing would naturally bring up ethical concerns. And the underlying question is always (to quote Kate Evans in her article for The New Zealand Geographic): “But presuming we can – should we?”[28]
The fears over designer babies and using the technology for enhancement rather than therapeutic purposes have been around since genetic engineering became a possibility. While the technology is still far from making designer babies a reality,[29] the fast pace of CRISPR developments necessitates immediate discussion about where to draw the line with gene editing. China’s use of CRISPR on unviable human embryos in 2015 sparked such a huge debate at the time that influential scientists called for a temporary moratorium on editing inheritable human genomes until better risk assessment and social consensus was attained.[30]Editing inheritable genomes is another controversial issue because germline editing would make any changes transmissible to future generations.[31] This obviously leads to consent problems: who can say whether those future generations would have even wanted that modification for themselves? And besides its application on humans, as Ellen Jorgensen observes, “how can we justify wiping out an entire species that we consider harmful to humans off the face of the Earth, using this technology?”[32]In light of all this, the regulation of CRISPR and its uses is also up in the air. There is currently no international consensus on a regulatory framework.[33] This means the ways CRISPR is used are very country- and resource-specific. China’s early embryo editing lead is largely attributable to its less stringent medical research regulation.[34] The risks may play a larger role in preventing immediate testing in the West, but for China, its likely benefits are enough of an incentive to pursue this kind of testing.[35] Accessibility to the technology also becomes a factor. Medical tourism could also result from the variability of national regulations.[36] Further, decisions in one area could have consequences outside its borders. For example, the European Union’s decision to put CRISPR gene editing in food under the rules that govern Genetically Modified Organisms (GMOs), has reprecussions in Africa.[37] As its largest single trading partner, this ruling limits the ability of African farmers to adopt gene-editing technology to improve their crops.[38]THE NEW ZEALAND PERSPECTIVEWhile it may feel like CRISPR revolutions are happening outside New Zealand, its development is equally relevant here and warrants the same conversations about its application and regulation.
New Zealand has traditionally been very cautious around gene-editing, and this approach is based significantly on the Royal Commission’s 2001 report on Gene Modification.[39]
Producing or selling genetically engineered food is illegal and any exceptions regarding imported foods with GE ingredients are strictly monitored.[40] Embryotic research is also banned.[41]Notwithstanding this cautious approach we must not be blind to the potential benefits this technology could bring. Keeping GMO-free can be seen as an advantage as more and more countries open their arms to genetically modified food. But this would also make it harder to regulate the modified foods being imported, given the difficulties in identifying origins.[42] Additionally, this strict approach may affect the competitiveness of our exports to countries that can, for example, edit more vitamins into similar produce.On the conservation end, the use of CRISPR and gene drive technology has been brought up in discussions as a possible aid to our Predator Free 2050 commitment.[43] Gene drive technology is incredibly controversial in itself. There are huge question marks surrounding how to prevent it from crossing borders and the ethics of eradicating whole species. Simon Terry, director of the Sustainability Council, has argued: “One man’s pest could be another’s desired plant or animal”. An “edited possum” making its way across the Tasman would not sit well.[44] This clearly demonstrates CRISPR’s national/international regulatory difficulties.The notion of de-extinction has also raised possibilities of reviving native species or helping current ones thrive better by editing their genes. The extinct huia, for example, has been described as the “ideal candidate” for revival.[45] But the consequences are just as life-altering. It could constrain conservation funding and add further management and prioritisation issues once the restored species are brought out to the wild.[46] The presence of pests would also still be a concern.Conservation Minister Eugenie Sage expressed her aversion to the use of any Predator Free 2050 funding on gene editing technology and notes the lack of any public mandate for it.[47] And despite the acnowledgement of genetic modification’s “significant development in the coming years”, the Government currently has no plans to make any legislative changes.[48]Genetic modification is also controversial from a Maori perspective. Tampering with genes between species can be seen as interfering with whakapapa or modifying the mauri of an organism.[49] But if gene-editing can be used to help pursue other values, such as guardianship or in benefitting healthcare, then it may be less opposed.[50]Informed and involved dialogue, taking special account of the New Zealand context, will be at the heart of how CRISPR may eventually be applied. The Royal Society of New Zealand has provided resources on its website and also through published discussion papers outlining the New Zealand gene-editing scenario. They explored gene editing in pest management and healthcare respectively and are also planning on publishing one focused on the primary industry and on the examination of current legislation and regulation.[51] These were all done to encourage an educated and informed discussion in deciding how CRISPR and similar gene editing technology will eventually be used in New Zealand.Being cautious is not necessarily a bad thing. In fact, with technology of this kind, the precautionary approach is often preferable. But caution does not mean all doors must be closed. It means checking through the peephole before letting anything in. In considering whether gene editing technology should be used in conservation or whether it should be under moratorium, Helen Taylor, conservation geneticist and research fellow at Otago University, notes: “Discussion is so important…There’s too much at stake for either of those extreme positions to be appropriate.”[52]
THE FUTURE
I have presented only a smidgeon of CRISPR’s issues and concerns. CRISPR is powerful technology but its use necessitates careful precautions. At this point of development, it would not be an exagerration to say that any misuse or carelessness would have Earth-shattering consequences. The notion of CRISPR’s endless potential does not mean that all options are pursuable. It means choices have to be made. And with technology as impactful as CRISPR, these decisions cannot be made only by industry or only by the government. In order to achieve any semblance of regulation and conformity, interdisciplinary contributions and broad multilevel societal dialogue are necessary.It is difficult to regulate a technology with so many unknowns. What is critical is that science remains responsive.[53] Proper communication of CRISPR’s risks and benefits, particularly by the media, should focus on informing rather than fear-mongering. Science tends to focus on results but a discussion of gene editing needs to consider existing public concerns if effective policies are to be put in place.[54] Any unsettled misconceptions could lead to public rejection of CRISPR, similar to the current negative treatment of GMOs in many countries (despite research proving its safety).[55] The stakes are too big to be lax about precautions.It is important not to overstate the potential of this technology. In terms of the big issues like gene drives and designer babies, it is not ready yet and likely will not be for many years. But the possibility is nascent. And that should be enough to prepare ourselves and discuss what we will do with it.CRISPR technology is seen as exciting, groundbreaking and revolutionary – and rightly so. But the greater the power, the greater the responsibility. This responsibility goes beyond borders and species. The lines will only continue to blur, so each stakeholder must exercise their part in contributing to its eventual implementation. “Playing God” has never been more tangible and the tech is coming eventually. We need to be ready for it when it does.
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Featured image source: https://geneticliteracyproject.org/2018/08/06/what-is-crispr-and-why-should-you-care/
[1] John Rennie “CRISPR Gene-Editing Pioneers Win Kavli Prize for Nanoscience” Quanta Magazine (United States, 31 May 2018).
[2] Rennie, above n 1.
[3] Megan Molteni, “Everything You Need to Know About CRISPR Gene Editing” Wired (online ed, San Francisco, 05 December 2017).
[4] See also: Ekaterina Pak, “CRISPR: A game-changing genetic engineering technique” (31 July 2014) Science in the News: Harvard University The Graduate School of Arts and Sciences <sitn.hms.harvard.edu>.
[5] Broad Institute “Questions and Answers About CRISPR” Broad Institute <www.broadinstitute.org>.
[6] “BBC News Health “Editing human embryos ‘morally permissible’” (17 July 2018) BBC News <www.bbc.com>.
[7] Daan C. Swarts and Martin Jinek “Cas9 versus Cas12a/Cpf1: Structure–function comparisons and implications for genome editing” (2018) 9 WIREsRNA 1 at 1.
[8] Swarts and Jinek, above n 7, at 1.
[9] Broad Institute “Information About CRISPR-Cpf1 (Cas12a) Systems” Broad Institute <www.broadinstitute.org>.
[10] Rennie, above n 1.
[11] Jennifer Doudna “How CRISPR lets us edit our DNA” (September 2015) TED <www.ted.com>.
[12] Megan Molteni, “The WIRED Guide to CRISPR” Wired (online ed, San Francisco, 27 April 2018).
[13] “DIY Bacterial Gene Engineering CRISPR Kit” The Odin <www.the-odin.com>.
[14] Alan Yu “How a Gene Editing Tool When From Labs To a Middle-School Classroom” (27 May 2017) National Public Radio <www.npr.org>.
[15] Ana Nordberg and others “Cutting edges and weaving threads in the gene editing (Я)evolution: reconciling scientific progress with legal, ethical, and social concerns” 5 JLB 35 at 37.
[16] Nordberg and others, above n 15, at 44.
[17] Dylan Matthews “A genetically modified organism could end malaria and save millions of lives – if we decide to use it” (31 May 2018) Vox <www.vox.com>.
[18] “Woolly Mammoth Revival” Revive & Restore <reviverestore.org>.
[19] Nordberg and others, above n 15, at 37.
[20] Nordberg and others, above n 15, at 38.
[21] Molteni “WIRED Guide”, above n 12.
[22] Sharon Begley “Potential DNA damage from CRISPR has been ‘seriously underestimated,’ study finds” (16 July 2018) StatNews <www.statnews.com>.
[23] Sharon Begley “Archived chat: last week in CRISPR — cancer, patents, and a dip in the market” (19 June 2018) StatNews <www.statnews.com>.
[24] Daniel Oberhaus “DNA Damage from CRISPR Has Been ‘Seriously Underestimated’” (18 July 2018) Vice: Motherboard <www.motherboard.vice.com>.
[25] Begley “Potential DNA”, above n 22.
[26] Oberhaus, above n 24.
[27] Begley “Archived chat”, above n 23.
[28] Kate Evans “Life Hackers” New Zealand Geographic (online ed, New Zealand, November-December 2017).
[29] Brad Plumer and others “A simple guide to CRISPR, one of the biggest science stories of the decade” (23 July 2018) Vox <www.vox.com>.
[30] Nicholas Wade “Scientists Seek Moratorium on Edits to Human Genome That Could Be Inherited” The New York Times (online ed, New York, 03 December 2015).
[31] Nordberg and others, above n 15, at 39.
[32] Ellen Jorgensen “What you need to know about CRISPR” (June 2016) TED <www.ted.com>.
[33] Kathleen M. Vogel and Students from PLCY 306 “Crispr goes global: A snapshot of rules, policies, and attitudes” (05 June 2018) Bulletin of the Atomic Scientists <www.thebulletin.org>.
[34] Rob Stein “Doctors In China Lead Race To Treat Cancer By Editing Genes” (21 February 2018) National Public Radio <www.npr.org>.
[35] Stein, above n 34.
[36] Annalisa Choy “Rewriting the Human Genome: CRISPR and an International Gene-Editing Standard” (03 November 2017) Cornell International Law Journal Online <cornellilj.org>.
[37] Eric Niiler “European Ruling Could Slow Africa’s Push For Crispr Crops” Wired (online ed, San Francisco, 25 July 2018).
[38] Niiler, above n 37.
[39] “Genetics Regulation in New Zealand” University of Otago <www.otago.ac.nz>.
[40] Richard MacManus “NZ could miss out on gene-editing revolution” (03 April 2017) Newsroom <www.newsroom.co.nz>.
[41] Evans, above 28.
[42] Evans, above n 28.
[43] Ed Yong “New Zealand’s War on Rats Could Change the World” The Atlantic (online ed, Washington D.C., 16 November 2017).
[44] Evans, above n 28.
[45] Evans, above n 28.
[46] Evans, above n 28.
[47] Kate Gudsell “Gene-drive technology needs global regulation – Sustainability Council” (30 July 2018) RadioNZ <www.radionz.co.nz>.
[48] Jamie Morton “Gene-editing: How it could be used in NZ” The New Zealand Herald (online ed, New Zealand, 19 December 2017).
[49] Evans, above n 28.
[50] Evans, above n 28.
[51] “New Zealanders encouraged to consider potential uses of gene editing” (19 December 2017) The Royal Society <royalsociety.org.nz>.
[52] MacManus, above n 40.
[53] Tamar Haspel “The public doesn’t trust GMOs. Will it trust CRISPR?” (26 July 2018) Vox <www.vox.com>.
[54] Nordberg and others, above n 15, at 46.
[55] Niiler, above n 37.