August 14, 2020

The Niche

Knoepfler lab stem cell blog

Why Mitalipov’s ‘magic’ room for human embryo CRISPR may give us pause

Shoukhrat Mitalipov
Shoukhrat Mitalipov points to an image of a potential CRISPR’d embryo inside an incubator at the Center for Embryonic Cell and Gene Therapy in Portland, Ore. Photo credit: Rob Stein on NPR.org, re-used with permission.

The debate over whether the main conclusions of the Nature paper on human embryo CRISPR led by Shoukhrat Mitalipov’s lab at Oregon Health Sciences University (OHSU) are correct remains unresolved. Note that Nature just added an editorial alert just above the references section to their paper:

“Updated online 02 October 2017. Editorial Note: Readers are alerted that some of the conclusions of this paper are subject to critiques that are being considered by editors. Some of these critiques have been publicly deposited in preprint form. A further editorial response will follow the resolution of these issues.”

This research should be shaking us up on another level besides just the core science. Recent developments deepen societal and ethical questions about this kind of research. A unique look by NPR inside Mitalipov’s lab ups the stakes and I believe should give us pause. The surprisingly huge scale and clear clinical intent together magnify the risks.

Also, if Mitalipov’s team in particular actually might not be CRISPR’ing the human embryos the way they thought they were, could many of the human embryos being made and used in their work not be contributing to useful data production? The importance of this question is magnified by the large-scale of the embryo use. In responding to the concerns raised by the Egli preprint that questioned the central conclusions of the Ma Nature paper, Mitalipov mentioned that his lab has worked with “hundreds of human embryos”.

Hundreds?

Were those all CRISPR’d?

How many hundreds are we talking about and where did all the human eggs come from to make those? Overall, how many human embryos are being made and/or used for genetic research around the world? It’s hard to say but CRISPR genetic modification of human embryos is likely now ongoing widely across the globe, with active work in at least four and probably more countries. Could there soon be in the range of thousands of human embryos having been CRISPR’d and if so, does that number matter?

Kathy Niakan’s group in the UK just published a knockout of the OCT4 gene in healthy human embryos that involved dozens of embryos, but only those leftover from IVF procedures, and another team, this time from China led by Zhou Songyang and Junjiu Huang, reported in a new paper that they actually cloned somatic cells to make human embryos via somatic cell nuclear transfer (SCNT), which they then modified using a somewhat different version of gene editing called “base editor” involving chemical modification of DNA.

Researchers in Sweden have explicit governmental approval permitting them to do CRISPR on healthy human embryos. Since they’ve had this green light for quite some time they probably are well into such work already and we can expect a paper from them soon. There also have been several older published papers on CRISPR genetic modification of human embryos (here, here, and here).

Taken all together this means that genetic modification of human embryos is rapidly becoming more common and that trend is likely to continue. Large-scale human embryo genetic modification isn’t going to be clearly ethically permissible in all cases. Some of the upbeat perspectives on this kind of research could be too aspirational with premature clinical objectives.

CRISPR ‘Magic’. Rob Stein was the NPR reporter invited into the Mitalipov lab. He was taken to the specific place in the lab for CRISPR of human embryos that Mitalipov reportedly referred to this way:

“This is our small room, but that’s where usually lots of big science happened,” says Mitalipov, who was born in the former Soviet Union. “We believe this room is really magic in terms of science.”

Magic? That’s a risky word for us scientists to use.

This small room is where they inject CRISPR into human embryos. The human embryos are often apparently made there earlier by IVF, including using donor eggs collected in the same building a few floors down or elsewhere.

Assembly line feel. Mitalipov and members of his team showed Stein the process by which they put CRISPR-Cas9 into the human embryos. One of the most striking aspects of Stein’s report was that the OHSU lab can attempt to CRISPR many human embryos over a short period of time. Stein reported after seeing a first CRISPR’ing of a human embryo that:

“Mitalipov and his team immediately do a second edit and then transfer the embryos to a larger incubator. The scientists will then spend the next few days monitoring live video of the two embryos, along with 17 others they had edited the weekend before, to see how they develop.”

Nineteen human embryos made and CRISPR’d in a day or two?

Even if this doesn’t happen every day, just this one lab alone could produce and genetically modify hundreds of human embryos in a short period of time. Is that scale of human embryo production and CRISPR for research ethically permissible? Who knows? It seems the justification is based in this case on hoped-for future clinical benefit. Mitalipov has indicated that he definitely wants to try this in the clinic in a heritable manner.

In addition, health risks to egg donors are often downplayed despite there being astonishingly little data on whether egg donation is safe, and anecdotal reports of cancer in young donors (see recent NYT article). The use of CRISPR in human zygotes should be understood to be transformative, both in potentially positive and negative ways. It is not just another experiment. It requires extraordinary care and sober reflection as well as transparency.

Even more transparency and openness about perspectives would be useful. It’d be great if Mitalipov penned a perspectives kind of piece to place his research here in a larger context, discussing things like preimplantation genetic diagnosis (PGD; a.k.a. “embryo screening for mutations”) and why he believes germline CRISPR is even needed (more on PGD below). I haven’t really seen him get into the meaty issues in interviews so far. For example, it’s still not clear to me why he thinks germline CRISPR would be better than PGD alone.

In the gray zone. In the last few years discussion of CRISPR human germline research has taken off. That’s great. For instance, there have been many meetings with wide-ranging discussions. These have yielded beneficial results in the form of greater awareness and exchange of diverse ideas, but we are a long way from having some clear framework for what’s permissible and what isn’t when it comes to changing the genetic code of human embryos and potentially humans. Such a framework may vary by country as well. Collectively as a field we are in a gray zone. The National Academies report released earlier this year did a nice job of outlining many challenges issues with human gene editing, but in my view it ended up not being too much in the gray zone too. They left the door open to human germline CRISPR.

Some are wanting to go through and quickly. “I don’t think I’m playing God,” Mitalipov says as quoted by NPR, “We have intelligence to understand diseases, eliminate suffering. And that’s what I think is the right thing to do.”

Don’t forget PGD. It is concerning just how often the already proven alternative of embryo screening by PGD is not brought up when people discuss heritable human genetic modification as a basis to try to prevent genetic diseases. Basically, in almost every clinical case one can imagine, there would be no point to CRISPR’ing human embryos because you can just simply screen for mutant versus non-mutant embryos without taking the big risks of genetically modifying them. In fact, you’ve got to do PGD when you do CRISPR anyway to know what is going on so why not just do PGD alone instead?

PGD isn’t perfect but from an unbiased viewpoint CRISPR has to have some very strong case for its superiority over PGD for the arguments for its eventual clinical use to make sense. If such cases cannot be made and PGD almost always is going to better, should we be CRISPR’ing massive numbers of human embryos based on the supposed justification of a reasonable expectation of safe and effective, future clinical use?

Advancing knowledge or wanting to go to the clinic? It’s important to point out that the research that Niakan and others is described as being done to advance knowledge, not to enable future germline use of CRISPR in humans, and again they used leftover IVF embryos rather than making new embryos by doing IVF themselves or cloning. Even if the Niakan team did not report a definite blockbuster scientific finding on targeting OCT4 in human embryos, I still think their work was interesting and I generally am supportive of that kind of research if done with a good scientific justification, strong transparency, proper institutional/governmental approvals, and bioethical discussions in advance. However, if many more such experiments go on to largely recapitulate what is already known from mouse studies without major unique human-specific findings then the case for use of healthy human embryos may become more difficult. See my ABCD plan for human genetic modification.

I asked Marcy Darnovsky, Executive Director of the Center for Genetics and Society about the Stein NPR article and the importance of including PGD in the dialogue about human embryo CRISPR, and here’s what she said:

“There’s no way to accurately think through the enormous safety and societal risks of human germline editing without knowing just how weak its medical justification is. You don’t need to engineer your future child’s genes to avoid passing on serious genetic conditions. The embryo screening technique PGD can accomplish that in pretty close to every situation. Embryo selection itself raises questions about what counts as serious disease and what’s just human variation. But the fact is, PGD is safe, effective, and has been available in fertility clinics for decades.”

Bottom line. As CRISPR work on human embryos is expanding around the world, societal and bioethical issues take on more urgency. Maybe we can’t or shouldn’t entirely hit “pause” on this kind of research even if it is just limited to the lab without clinical intent, but it feels like some folks have hit “fast forward” instead and there might be an almost race-like atmosphere, which boosts risks on many levels.

Broader discussion, transparency, and thoughtful contemplation are urgently needed.

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