November 26, 2020

The Niche

Knoepfler lab stem cell blog

Countering that Pro-Heritable Human CRISPR WSJ Piece

human embryo modification with CRISPR
Diagram of an actual human embryo with individual cells colored to represent genetic modifications. Knoepfler image.

It’s germline, heritable human CRISPR time, right?

Wrong.

But the particularly enthusiastic supporters of heritable human CRISPR often cite hypothetical benefits in glowing terms, but either don’t mention risks or strongly downplay them. These fans also tend to leave alternative, proven and safe technologies such as preimplantation genetic diagnosis (PGD) out of the discussion or only mention them as an afterthought. In reality, the vast majority of anything that CRISPR could hypothetically achieve heritably in human reproduction can be done better, more simply, and at dramatically lower risk by PGD.

A new WSJ opinion piece from Henry I. Miller of Stanford enthusiastically espouses the pro-human germline CRISPR view. Note, Miller also wrote an earlier pro-human germline CRISPR piece entitled, “In defense of germline gene therapy” that has stirred some controversy. I have a very different perspective than Miller.

Amongst other things Miller in the new piece argues that now is probably the time for trying to make babies with CRISPR in part because of that recent Mitalipov Nature Ma, et al. paper:

“Now, after the Oregon study, the technology is arguably at the stage where clinical trials could be undertaken to see whether gene-edited human embryos can develop into healthy babies.”

There are some problems with this statement.

First of all, what about those serious, unresolved scientific doubts on the Ma paper? The manuscript’s main conclusions remain up in the air, but even if they are ultimately proven 100% correct, do we base high-risk, new clinical science on one paper targeting one mutation conferred to embryos by one sperm donor in research done by one research group? We shouldn’t. It’s unwise to rush into human clinical research of any kind and that’s especially true if it includes heritable genetic modification. You first need reproducible, rigorous data to back you up from sufficiently power studies and a good sense of anticipated risks.

Are we there yet? No. Not even close.

Secondly, what if the answer to that implied experimental question in the above quote from Miller’s piece “to see if embryos can develop into healthy babies” is “no”? It could be disastrous. For instance, what happens to the unhealthy or deceased CRISPR’d humans you made in your experiment that didn’t turn out the way you had hoped? We just say “oops”? Or what if the babies seem OK at first, but then later they become ill or die?

These are not fun questions to ask or ponder, but they are deeply important if we are going into this with our eyes open. I wish Miller had discussed the risks of what he is proposing more in the WSJ piece, but that would have undermined his own argument. I realize that biomedical science needs to take on a certain level of risk to boost innovation, but the risks for heritable human CRISPR at this point would be sizable and span multiple generations.

To be clear, I’m not referring to innovative clinical trials of the non-heritable use of CRISPR in cell-gene therapies, which I strongly support. These too have risks, but have much more data behind them and do not involve heritable changes.

I emailed Miller to ask a few questions about his article. In response, he described the goal for his WSJ piece this way:

“The primary point of my article was the unwisdom of the absolute prohibition of clinical studies by federal law (FDA) and binding guidelines (NIH). If regulators at FDA or NIH feel that a proposal is premature or inappropriate for any reason, they can reject it, but absolute prohibitions are bad public policy.”

However, in his piece he wasn’t so much arguing against a prohibition, but in favor of trying CRISPR in the human germline now. Keep in mind that even absent a clear prohibition, the sense I have is that the vast majority of scientists still don’t favor going ahead with germline CRISPR now.

While I have at times advocated for an at least temporary moratorium (established by the scientific community itself, not by law) on heritable use of CRISPR in humans, I realize that there are practical difficulties to that idea. Who if anyone enforces a moratorium and how? Where? What about the many different perspectives around the globe that may make a moratorium far from universal? There are no easy paths or fixes in this arena, but the scientific community needs to take stronger stands in my view that now is not the time to proceed and that time, if it comes, is a long way off.

Miller’s piece also resonated for me with a recent USA Today opinion piece by Alex Berezow of the American Council of Science and Health (ACSH) and Ben Locwin of the BioPharma Research Council. Their piece told us all to kind of ‘chill out’ about the idea of designer babies.

I emailed Alex to ask about Miller’s piece and also because some critics of Miller suggested in the past that he was affiliated with ACSH. Alex said that Miller isn’t part of ACSH. Alex also had this to say about his own views of human germline gene editing:

“My position is that we should proceed cautiously, keeping in mind that “designer babies” are science fiction. It’s easier to discard genetically defective embryos than to fix them. I see the biggest promise for CRISPR being in research, assuming the federal government eventually lifts the funding ban on deriving new stem cell lines from human embryos.”

It seems there’s common ground there between me and Alex on the wisdom of PGD-based embryo screening rather than attempting risky heritable human CRISPR. As to concerns (or not) over designer babies, much depends on how one defines them and what genes are targeted.

I also asked Miller by email about PGD as an established alternative to human germline genetic modification and he had this to say:

“PGD isn’t feasible in all situations, such as if the male prospective parent has two copies of a defective gene where the disease is transmitted as an autosomal dominant, or where two sickle-cell homozygotes (autosomal recessive) wish to have children.”

Yes, PGD isn’t a panacea (and it can have its own bioethical issues), but the instances where PGD won’t work (the unique window where CRISPR could in theory help, potentially justifying its weighty risks with heritable use) include only very rare and sometimes even hypothetical situations. The rarity of such reproductive cases doesn’t mean they should be dismissed entirely, but the context is important.

Arguably, Miller and others who are so upbeat about human heritable CRISPR should be mentioning the reality that situations where CRISPR could hypothetically potentially fill an important clinical gap left by existing technologies like PGD are realistically probably in the realm of one-in-a-million kind of cases. Even if we knew it to be relatively safe, there just is no convincing case now for a broad need for taking a stab at using CRISPR heritably in humans to try to prevent common genetic diseases rather than using PGD.

When pressed on this reality, some folks start mentioning other tangential hoped-for outcomes of reproductive human CRISPR use, such as supposedly preventing more IVF-produced human embryos from being discarded by “fixing” and trying to use them, but that’s a weak argument too. So, you are going to make, CRISPR, and analyze (and hence in a sense discard) potentially thousands of human embryos for research to try to figure out how to hopefully, safely correct mutations in some embryos in the future primarily so they might not be discarded after PGD earlier determined they have mutations? Isn’t there some inherent illogic there?

Furthermore, no matter how good the data get from human embryo CRISPR preclinical studies, there will always be some unique risk facing CRISPR’d human embryos used for reproduction. Again, that risk needs to be discussed realistically and balanced against a common-sense assessment of potential benefits compared to alternative technologies like PGD.

Miller in winding down his WSJ piece, makes a broad statement that I view as having some issues:

“It’s easy to invoke hypothetical fears when actual lifesaving interventions are decades away…Today they aren’t—and desperate patients deserve access to whatever cures this technology may be able to provide.”

The reality is that human germline use of CRISPR (assuming we decide it’s a prudent thing to try) is in fact one or more decades away if to be done in a responsible manner, even if some bozo could technically try it tomorrow or could have tried it last year. Also, the use of the word “cures” by Miller here is off-base because germline CRISPR would prevent, not cure disease. In addition, there is near zero basis at this point to argue that CRISPR can be specifically “lifesaving”. Overall, for these reasons this passage strikes me as hype.

In the end, heritable human CRISPR is still largely a wild idea whose time has definitely not come today. From scientific and medical as well as perspectives, it’s not something close to being ready to even just test reproductively in humans in a responsible way. Unfortunately, again it could be tried in an irresponsible manner at just about any time now.

Let’s keep the dialogue going on the many possible human uses of CRISPR including heritable human CRISPR. I realize that this discussion is a marathon even as CRISPR seems technologically like a sprint, but we have to keep talking things through to make the best decisions as a community.

For more on my “big picture” level perspectives and concerns related to the ongoing CRISPR research in human embryos see here with some key points regarding Mitalipov’s recent work, where I try to place it in a wider context and ask bioethical questions. Also, see my interview with Steven Pinker and my follow-up piece on why I largely disagree with him on this issue. You can also check out my book GMO Sapiens on possible heritable human use of CRISPR here.

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