Q&A video with Paul Episode 2: stem cell & CRISPR questions answered

This is the second in a series of videos I’m doing where I answer questions about the stem cell field. You can see the Episode 1 video here.

Today I tackle more questions on the stem cell field. If you have more stem cell questions, let me know and I’ll try to answer them next time.

One reader asked me about stem cells for stroke and about one company, Athersys, in particular, but I haven’t had time to tackle that one in such a way as to do it justice so stay tuned on that good question.

I realized after the fact that regarding stem cell epigenetics I should have said broadly that this is a process of regulation of gene expression.

Where are all the new CRISPR human embryo papers?

Last year I heard from several sources that there somewhere between 3-5 unpublished manuscripts reporting the use of CRISPR gene targeting in human embryos being shopped around at various journals in addition to the one that had been published. Since that time we’ve seen a grand total of one additional paper reporting on CRISPR of human embryos.

So what gives?

Were the sources wrong?

I don’t think so and I believe there are additional labs pursuing research on the use of CRISPR in human embryos.

Depending on the context, the oversight, and the training of those involved, there may be nothing wrong with these studies at all. In fact, they could be positive and teach us a lot if the teams are careful. However, CRISPR’ing human embryos without a good rationale and appropriate oversight is unwise. I also cannot imagine supporting use of CRISPR with the intent to make a modified new human being for many years to come if ever. You can learn more about the history of genetic modification and my views as well as those of CRISPR leaders in my new book, GMO Sapiens.

So where are all the CRISPR human embryo papers? I can think of a few main reasons why we haven’t seen more so far.

embryo human

Wikimedia Photo

Editors as gatekeepers? One possible reason we haven’t seen more CRISPR’d human embryo papers is that journal editors are reluctant to publish them and are acting as essentially gatekeepers for this kind of work. If true, what are the potential risks or benefits of such a de facto filtering system and what is the basis by which the editors are making such decisions?

Outcomes of first 2 pubs discouraged more? Another possibility is that other research teams have been discouraged by the first two papers reporting CRISPR use in human embryos. I can see at least two levels at which those considering working and publishing in this area might be reluctant to proceed because of the first two papers. On the one hand, both papers reported technical challenges with this research, which was discouraging. On the other hand, both papers were heavily criticized by some.

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4 areas of debate on 1st human embryo genetic modification paper

Last week was a big one for the life sciences in that we saw the milestone of the first ever published paper reporting genetic modification of human embryos (see here and here).

It was one of those situations where we knew it was coming, but it was still a jolt.

Not surprisingly this event sparked intense discussion and even some arguments.human genetic modification

Below are 4 areas of contention at this moment and some additional thoughts on them. I value diverse views so please weight in with comments.

A big deal or a mountain out of a molehill?

My own view is that this paper is on the one hand a very big deal because it crossed the line and reported the production of GM human embryos. This certainly paves the way for more such research and papers.

On the other hand, the actual research methods and data reported were not especially surprising, groundbreaking, or enabling of other new research. So perhaps it was not such a big deal in that latter sense?

Did use of non-viable embryos largely negate ethical concerns?

The non-viability of the embryos is notable and that does make a difference, but I’m not sure how much that changed the line that was crossed in the long run. My sense is that reports of editing of near-normal human embryos (e.g. normal except containing a single mutation to be targeted) will just be a matter of time.

I support the idea of gene editing research in vitro on human embryos, but only in certain cases with specific oversight and bioethics training. I also feel that there should be some compelling rationale for doing the work in embryos versus just say a human cell line.

Disrespect to oversight in China?

Not really.

Yes, some of us pointed out that there are different ethical and regulatory paradigms at work in China compared to say the US or the European Union, but that’s just a fact. I don’t see why that should be some kind of taboo topic.

For instance, Mitalipov’s Mitogenomics, which is operating in the cutting edge and controversial area of 3-person IVF and mitochondrial transfer, is now set to do that work in China specifically because of the liberal oversight there related to this work. You can’t do that work in the US, but you can in China. That’s a fact and one that concerns me. Notably you can also do this 3-person IVF research in the UK too and that worries me as well. I have certainly voiced concerns about the 3-person IVF regulatory oversight situation in the UK as well.

It is worth noting that the day after the embryo editing paper came out, a Cell paper came out from a team at the Salk that was very pro-human embryo editing and I raised concerns about that level of enthusiasm for clinic use of human genetic modification technology as well.

You can expect that if a human embryo editing paper comes out of my own home country of the US or other places that I will provide a rigorous critique of it too.

Human embryo editing a non-starter clinically?

This is the most important and contentious area of discussion today.

There certainly are advocates for using germline genetic modification of human embryos to try to prevent any number of genetic diseases and the aforementioned Salk group is just one.

At the same time others think to put it mildly that this is a really bad idea. Edward Lanphier, et al. presented just one example of a case articulated against heritable human genetic modification and they are opposed even to in vitro research in this area. They view this kind of work as dangerous.

A nice NY Times piece by Gina Kolata includes comments from scientists raising additional concerns including stem cell and genetic modification pioneer, Dr. Rudy Jaenisch:

“A pressing question, said Rudolf Jaenisch, an M.I.T. biology professor, is why anyone would want to edit the genes of human embryos to prevent disease. Even in the most severe cases, involving diseases like Huntington’s in which a single copy of a mutated gene inherited from either parent is enough to cause the disease with 100 percent certainty, editing poses ethical problems. Because of the way genes are distributed in embryos, when one parent has the gene, only half of the parent’s embryos will inherit it. With gene editing, the cutting and pasting has to start immediately, in a fertilized egg, before it is possible to know if an embryo has the Huntington’s gene. That means half the embryos that were edited would have been normal — their DNA would have been forever altered for no reason. “It is unacceptable to mutate normal embryos,” Dr. Jaenisch said. “For me, that means there is no application.”

The bottom line at this point in a new week since the embryo editing paper came out is that there is a whole range of opinions on germline human genetic modification as well as about how it has been discussed. I view the fact that these discussions and even arguments are ongoing as a very positive thing even if disagreements can be uncomfortable.

Just a few months ago there was essentially complete silence on germline human genetic modification. Things have changed greatly for the better in terms of the level of dialogue and this will aid in charting a positive course to deal with this new area of biomedical research.

Concerns surface on Chinese paper on genetic modification of human embryos

The paper that came out Wednesday from a research group in China reporting the first genetic modification of human embryos has sparked a lot of discussion. Some concerns about this paper have surfaced.

GM human embryo review

2-day review? The paper (HT to John Borghi) was in review only from March 30-April 1 — so at most 48 hours. Really? That certainly raises a red flag of inadequate or absent peer review. That kind of “review” in the past with high-profile papers has been associated with a high risk of errors being found later in such papers. I’m not saying that will happen here, but it wouldn’t shock me.

The journal? The paper was also published in the journal, Protein & Cell, which Buzzfeed reports is partially owned by the Chinese government. Could there be some kind of COI there? Also, why was the paper reportedly rejected at more rigorous journals? There have been suggestions that reviewers raised ethical issues, but this remains unclear.

Rushed as evidenced by striking typo. The paper’s abstract has a pretty bad typo in the abstract (emphasis mine) suggesting issues with preparation and peer review again:

Taken together, our work highlights the pressing need to further improve the fidelity and specificity of the CRISPR/Cas9 platform, a prerequisite for any clinical applications of CRSIPR/Cas9-mediated editing.

Of course anyone can make a typo and I certainly do on a regular basis in emails or draft blog posts, but in a published paper abstract?

Unnecessary and premature? Another question to ask here is whether doing these studies specifically in human embryos was at all necessary or provided novel insights specifically because it was done in human embryos (as opposed to limiting the work to say just 293 cells as they did in part of the paper). So far, I don’t see much if anything that has been gained from using human embryos here other than maybe a hint of unique DNA repair. Jennifer Doudna has raised that kind of concern with the paper:

“I don’t see the value in working with human embryos right now. There’s a lot to be learned by working in other systems,” she says. In her view, the Huang paper provided little new scientific insight and seemed intended to “attract attention.”

The bottom line seems to be a final question of whether publishing this paper now and including human embryos was prudent given all the circumstances. I’m on the fence.

What do you think?