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Genome Unknowns: Raising the Ethical Bar for CRISPR Research

CRISPR: Either it’s the best thing since the smallpox vaccine, or it’s bound to plunge the human species into Aldous Huxley’s world of incubated tubes. But regardless of where you fall on the spectrum of biotech-induced paranoia, nearly everyone agrees that CRISPR is a major player when it comes to the future of the human genome. Though many fear CRISPR’s worst capabilities, calls to ban research using the technology are the wrong way forward. The question facing the world today is one of regulation, not prohibition. To ensure the safety and efficacy of CRISPR research, the international community must push toward codified, actionable, and enforceable regulations to ensure this revolutionary technology remains a force to fight pestilence, not people.

To understand the functionality of CRISPR, it helps to understand its origin. The technology is, in essence, a bacterial defense system that allows bacteria to chop up the DNA of invading viruses; it’s the anti-tank weaponry of the Bacteria Kingdom. After a virus invades, the bacterial cell uses CRISPR to take a sample of the virus’s DNA. It then stores the viral DNA in a specific part of its genome—a genetic library of all of its enemies. Cas9 proteins in the bacteria use this stored DNA to patrol the cell, looking for the genetic footprints of invading viruses. If the Cas9 protein encounters a match for the viral DNA it’s carrying, it destroys the virus, protecting the cell from attack. Most relevantly, the Cas9 protein acts on any kind of DNA, even human. All a potential user has to do is identify a target sequence of DNA, and the Cas9 scissors will “chop up” that gene. As genetic mutations are responsible for a staggering variety of medical problems, the ability to use CRISPR-Cas9 to edit faulty genes could save millions of lives. These little DNA-chopping scissors could feasibly be used to make mosquitoes resistant to malaria, make plants resistant to disease, develop treatments for HIV, leukemia, or hemophilia—the list goes on. Clearly, the potential upside is enormous.

If this sounds too good to be true, it is. Cutting out problematic genes isn’t quite that easy. CRISPR can identify a specific problematic segment of DNA, but a lot of DNA looks similar. Consequently, CRISPR will often modify or delete other sequences in what are called “off-target mutations.” A 2013 study found that given a target sequence, CRISPR made edits in as many as 12 of the 46 off-target sites identified. Even when CRISPR does edit the right gene, some traits and diseases involve the interplay of so many genes that the desired edits could lead to undesired consequences.

Fears of CRISPR aren’t limited to human trials. One of the most alluring prospects for CRISPR is to prevent mosquitos from transmitting malaria; however, the sheer complexity of the animal kingdom suggests that the unforeseen consequences of doing so could be unconscionable. Without a predesigned plan to reverse any edits done to a species’ genome, such uses of CRISPR aren’t ethical; synthetic changes to a species’ genome could have substantial negative implications for that species and others. And here lies the real concern with CRISPR: Although there is so much good that could be done with this technology, until steps are taken to prevent off-target mutations, reverse edits, and limit unintended side-effects, governments must ensure that CRISPR research be done carefully, methodically, and publicly. It costs about $40 for an individual to get a CRISPR kit, but the costs of its consequences could be much steeper.

One oft-cited example of an uncertain—though not immediately realistic—prospect for CRISPR is its ability to make changes to the unborn. Most research done to date has targeted the DNA of somatic cells, DNA which is not passed on during reproduction. Still, the possibility of editing reproductive, or germline, cells sits tantalizingly on the horizon. In theory, germline therapies make a lot of sense. If scientists can fix mutations in reproductive cells, there won’t be any need to fix the same mutations in subsequent generations; children will simply inherit edited DNA from their parents. But any off-target mutations will also be passed on from generation to generation, with all the unintended consequences they carry.

The possibility of clinical germline editing is now only in the distant future. The technology is still in the earliest stages of development. Still, research in genetics moves quickly, and it’s critical to sort out regulations before any breakthroughs force a haphazard declaration of ethical and unethical use. Just after an Oregon study on germline editing—the first successful germline study conducted by a lab—was released, a team of international bioethicists published a statement regarding the future of the practice. The group, led by Stanford genetics professor Kelly Ormond, stated that editing the genes of an embryo intended for implantation was unethical, but that germline research itself should continue. This research is highly sensitive, and should be closely regulated and subject to public oversight. Unfortunately, research regulations vary widely country to country, and many of the regulations currently in place make it more difficult to make informed decisions about the risks and benefits of potential CRISPR applications.

For instance, the US does not support embryonic research. Germline research can take place there, but it can’t be publicly funded or directly supervised by the government. Such wide-ranging bans and regulations have the potential to drive research into regulatory havens—countries whose governments keep regulations lax in order to generate medical tourism. Ormond and her co-authors actively pushed for public funding for germline research, arguing that it will force transparency and openness in a way that private research will not. With such a sensitive ethical subject, lack of regulation could lead to serious violations. The best way to prevent these violations is to establish rigorous, legally binding, international standards for CRISPR research.

International regulatory institutions are currently too weakly framed to properly protect against possible CRISPR misuse. The cornerstone of global medical research ethics, the Declaration of Helsinki, was first developed by the World Medical Association in 1964 and has been growing longer ever since. However, it can’t officially enforce its stipulations. It is framed as a set of philosophical principles, not as a legally binding document. A stronger, more enforceable doctrine, or perhaps even an amendment to the Declaration of Helsinki, is needed to ensure that no country skirts its responsibility to conduct ethical CRISPR research. This new standard would ideally enforce broad publication of all CRISPR research, limit the accessibility of CRISPR to labs committed to ethical practices, and require it to be used for purely medical purposes. This technology is too great a tool to ban scientists from using it, though its immense power necessitates careful regulation.

Fears of CRISPR are neither unfounded nor insurmountable. Though it causes more anxiety than other methods of artificial selection that have been around for millennia, CRISPR differs only in power and scope—not in kind. The question facing the world today is not whether we should radically alter the world around us, but how we choose to do so. The international community must answer this question together, wary of CRISPR’s risks, while never losing sight of the lives that this new technology could improve.