On CRISPR-Cas9

As we enter 2016, one technology is getting touted as the most important scientific advance of 2015 – and rightly so. That technology is CRISPR-Cas9, named “2015 Breakthrough of the Year“by Science. Unheard of just a few years ago it has rapidly been introduced into labs worldwide as a cheap and relatively easy tool to add to their kit. But the breakneck speed with which it’s been adopted has raised some ethical concerns – even from a major innovator of the system (Dr. Jennifer Doudna). These concerns are medical and ecological in nature, but also fundamentally about the effect our species can have on evolution; both on our own evolutionary trajectory and that of the rest of our planet’s species. As such I’d like to add my voice to the growing number of conversations about CRISPR-Cas9 and reflect on the real (and the maybe overblown) concerns for the future of this work.

But first, what is CRISPR-Cas9? I’ll not pretend to be an expert but I do work with genetics and have followed the news for a while. In it’s natural state, it’s a bacterial defense system. Similar to RNA interference (RNAi) in eukaryotes in that it fights invaders by attacking their ability to form proteins. Unlike RNAi which chops up whole strands of messanger RNA, CRISPR cuts at site specific nucleotides. A different nucleotide can then be pasted in. This allows for precise DNA editing.

This brings up one of the first hurdles to overcome. While we can cut, we’re still working on efficient pasting. Until we get this worked out the technique will have a low success rate. The second (and more important to this essay) is that there can be quite a lot of “off-target” effects – changes that occur in unintended regions. These have the potential to cause missense (wrong protein) or nonsense (no protein) mutations, both of which are associated with genetic disorders. There’s a good chance those mutations won’t do ANYTHING (each of us carries somewhere between 50-150 new mutations that we don’t likely notice) but it’s a risk that would be better to minimize. Very (VERY – out in Science today) recent research has shown that a simple change of three amino acids can reduce the off-target effects to undetectable levels (less than 1%). Still, we’d like to do better.

Although these are technical issues that reduce the utility of CRISPR-Cas9, the real problem comes when these hurdles have the potential to impact evolution. This can happen when we edit an individual in a way that impacts the germline, and can thus be passed onto future generations. There are potential medical and ecological consequences, both of which amount to the unknowns. Now typically I’m critical of, “but we don’t know for sure!” criticisms of science. It’s true, we don’t always know for sure. But because it’s true this argument can be trotted out whenever a person meets a science they don’t like (while they usually ignore it for all the sciences they’re fine with) and can come to lose any real meaning. In this case, however, the science is very new and the known issues (primarily off-target effects) are a big enough concern to warrant caution.

The main concern is with human embryo editing. The big news with CRISPR this year (what put it on the radar of much of the public) was the attempt by Chinese scientists to do just that. The embryos they used were not viable, but it still raised some hackles  (hint: off-target effects). The concerns here are both that unknown off-target effects could be passed on and become prevalent in a lineage, or even recombined into other lineages. A sort of genetic pollution. That’s valid until we can get more precision. But also of concern is how we’ll use this technology even if we get it to be successful. Much of this is technophobia of the sort found in science fiction like the film Gattacca, and that’s a long way off, but it’s not paranoid or irrational to suggest we think about these things before they become possible.

The ecological concerns center mostly on an application of CRISPR technology known as “gene drives.” The idea is similar to a really cool naturally occurring phenomenon called meiotic drive (or segregation distortion) – a sort of intragenomic conflict where transmission of one allele is favored over others. [Side note: When I started my Ph.D. I was in the old lab space of the guy who discovered this, he seemed to have collected a lot of data on 3×5 cards from what I could tell.]

Gene drives are similar in that a CRISPR edit in a gamete is copied from one chromosome to the other chromosome so that the edit is guaranteed to get passed onto the next generation. This allows for much more rapid spread of the edit in a population than normal alleles enjoy, even when they’re under strong positive selection. So an engineered gene can rapidly take over a population. This technique is being studied in malaria spreading mosquitoes, as a way to preclude them from carrying the pathogen. The concerns here are the same as with human evolution, we don’t know the potential consequences and unintended effects. And what will be the ethical use even if we get the technique perfect? Again, these are worth considering but not really a cause for widespread fear.

The fact of the matter is that we’ve been working toward medical and ecological goals like these for as long as science has been around, and I don’t think that we should start to worry more just because we’re getting better at achieving them.

In fact we should be optimistic, as scientists are aware of and concerned with addressing these issues. Two conferences (this past January and  December) have been held to discuss how to proceed, the first of which was initiated by Dr. Doudna and resulted in a paper in Science urging caution. A good set of point-counterpoint articles stemming from the “big” conference appeared in the Guardian here  and here, the latter pointing out the important fact that while the concerns are rooted in science, they’re not solely in the realm of science. Dr. Doudna has herself written a very good personal essay for Nature raising some of the concerns and admitting her lack of expertise (indeed the same is true of many scientists) with ethical quandries. It was one of the most interesting things I’ve read in a long time – a great insight into how scientists think and the very personal way we view our research. Like Dr. Doudna, I’d encourage cautious optimism as we move forward with this research. Be sure to read her essay when you get the chance.

On CRISPR-Cas9

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