The CRISPR Quandary

Wednesday, February 22, 2017

With the advent of CRISPR technology, editing human genomes is no longer the stuff of science fiction. But Hank Greely, a Stanford law professor and bioethicist, isn’t too concerned: “I don’t think it’s very important, I don’t think it’s gonna happen, but I don’t care about it even if it does,” he remarked (perhaps with a bit of tongue in his cheek), speaking at UCSF in January.

This is at odds with the dystopian future predicted by some scientists and journalists concerned about using CRISPR in the human germline.

Mr. Greely has pretty good reasons for discounting these fears of designer babies and eugenics. We don’t understand the genetic basis of many traits we would want to enhance, such as intelligence. And we are already capable of avoiding most diseases whose genetic causes we understand with preimplantation genetic diagnosis and embryo selection.

But Mr. Greely thinks there is a more urgent, and potentially dangerous issue, and that it isn’t receiving the attention it deserves: “It annoys me and worries me that the human side is getting almost all the attention, and the non-human side is not getting enough,” he said.

What does he mean about the non-human side, and why is it so important? Part of the answer is a technology called gene drive, which causes mutations to become selfish, spreading rapidly through populations.

Purely from a scientist’s perspective, gene drives are fascinating. The laws of Mendelian inheritance are familiar to any geneticist. There are two copies of most genes, with one copy coming from each parent. So a mutation coming from one parent will affect one copy of the gene in the child, yielding a heterozygous mutation.

With a CRISPR-based gene drive, however, this exact mutation is made to the other copy of the gene, in the child, which is now homozygous for the mutation. Beautifully, the entire CRISPR system for targeting and cutting is copied into the second gene where the mutation was made.

Now, with a homozygous mutation and CRISPR insertion, the whole system is inherited by the next generation, where the heterozygous to homozygous conversion can occur again and then again in all subsequent generations.

While the initial concept is impressive, gene drives like this are not particularly technically challenging or expensive to make, so we can think about how to use them outside the lab, at greater scale.

If used in a wild population, we suddenly have the ability to change an entire species, in just a few generations. And just as suddenly, a plethora of applications have been proposed – eradicate malaria or dengue fever, control pests that destroy crops, protect ecosystems from invasive species – each with its own specific design principles and possible consequences.

These proposals are exciting enough that there will soon be enormous pressure to put them into practice. Malaria, for example, kills 1000 people every day. Already, this elegant gene drive strategy has been used to drive malaria resistance genes through laboratory mosquito populations with high efficiency.

But the risks are also great. We could damage an ecosystem irreparably and ultimately do more harm than good to the humans living there. So, it is crucial that we figure out how to evaluate risk and regulate gene drives, soon.

From the perspective of a policymaker, this is a nightmare. This is well demonstrated by a 216 page report/book recently produced by a committee of the National Academies of Sciences seeking to place gene drives in the context of current United States law.

This is actually a good sign that at least someone in Washington is taking seriously the concerns of Mr. Greely and others. However, the report is a little unsatisfying in that, on one hand it summarizes the current U.S. regulations that might apply to gene drives, and on the other describes the uniqueness that places them outside any law, without really providing a path to actual gene drive policy.

Who should make these decisions? In the United States, it will be a federal agency, but which one? Perhaps the Environmental Protection Agency would have jurisdiction, since gene driven alterations of populations are likely to change the environment and biosphere. Maybe the Centers for Disease Control and Prevention should be involved, at least when gene drives are aimed at controlling the spread of disease.

Surprisingly, in the case of insect control, the most likely scenario is that the Food and Drug Administration will have priority, treating a gene drive as a veterinary drug. This sounds strange, and it reflects the lack of any regulatory framework appropriate for the special characteristics of gene drives.

At some point, Congress will need to pass legislation that specifically addresses this unique technology. This type of policy is probably a long way off, and for now, each emerging question will be met with an improvised interpretation of existing law.

Even after consensus is reached in the United States, gene drive policy will remain an international concern. Some of the most promising applications are aimed at other countries, and in some cases these countries lack the infrastructure to regulate them.

Furthermore, many species easily cross geopolitical lines; use in one country is also a decision made for nearby countries and maybe the world. It is hard to imagine bringing many countries together to address this, and it is even harder to imagine them creating any effective international law.

Fear of unintended consequences from otherwise benevolent use of gene drives is one thing, but we should also be wary of intentional use to cause harm. Their previously mentioned advantages – rapid spread, low cost, and relative ease of engineering mean they can be created and employed to great effect not just by governments and research institutions, but also by smaller groups or even individuals.

How do you keep track of these people, when the biological tools for gene drive creation are essentially freely available? If a malevolent gene drive in an insect was aimed at a population or a country, how would you even know?

All of these questions make it clear that we are in a unique situation. Science has far outpaced the law. We need to decide how to proceed in each of these scenarios, and we have no regulatory structure to guide us.

What role will scientists play? The NAS report gave scientists from many fields the opportunity to weigh in, which at least suggests we are wanted in the conversation. But the NAS is not the same as Congress, and as Mr. Greely pointed out last month, “Congress and science don’t necessarily understand each other very well.”

We may have another way into the conversation. The NAS report also emphasizes the importance of public engagement in the decision making process, especially since some communities will be profoundly affected. A good track record of developing gene drive technology responsibly and keeping the public informed could give us some extra clout when it comes time create actual gene drive policy.

On the other hand, a poorly executed gene drive, especially one that goes haywire, could ruin the reputation of biomolecular science. Scientists should take this responsibility seriously, as we understand the technology and some ways it could backfire. And if problems do arise, it will be our job to solve them.