TGIF: NatGeo sell out, GM Humans, Wild West, Science backstabbing, & more

Wild West

Image from Wikipedia

It’s a shame that National Geographic has become part of a corporate empire that is not always consistent, to put it nicely, with data-based reality. Can NatGeo maintain its credibility and impact, when it is owned by a climate change denier (quoted for example as dissing folks as “extreme greenies”) who also has other very non-scientific priorities?

There’s been an increasing amount of discussion of the technology that could produce GM humans. This dialogue includes the new Hinxton Statement (my take on that here) and George Church’s quoted that Hinxton (which BTW did not call for a moratorium of any kind) was being too cautious nonetheless. Church is quoted:

“seems weak on addressing why we should single out genome editing relative to other medicines” that are potentially dangerous”

Should we push pause, stop, or fast-forward on human genetic modification? asks Lisa Ikemoto. Is there a rewind or edit button too? 

The NEJM published a new piece on stem cell clinics run amok and the lack of an effective FDA response. Sounds awfully familiar including the use of “Wild West” in the title, right? My gripe with these authors is that they didn’t give credit where credit is due to those of us on the front lines of this battle and in particular to social media-based efforts to promote evidence-based medicine in the stem cell arena. Still, their message was on target.

Are men more likely to commit large-scale scientific fraud? Check out RetractionWatch’s leaderboard. Of course the sheer number of retractions does not take into account the impact of any one or two given retractions that had a disproportionate toxic effect like the STAP pubs. Maybe another calculation to do is the # of citations to a retracted paper.

DrugMonkey talks about perceived scientific backstabbing.

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?

Scientists in China create genetically modified human embryos: ‘A cautionary tale’

Update: apparently this paper (HT to @JohnBorghi) was only reviewed for 2 days (see image at bottom of post), raising major concerns about the depth of peer review.

Rumors have been flying for months that researchers in China and possibly elsewhere were shopping papers around at high-profile journals that reported gene editing and genetic modification of human embryos.

The rumors were right.

Today, one of the Chinese teams of researchers published their paper on genetically modified (GM) human embryos in the journal Protein & Cell.

The paper is open access so that’s good.

According to an excellent news piece in NatureNews by David Cyranoski and Sara Reardon, the paper had been submitted and rejected at top journals such as Nature and Science due at least in part to ethical issues. I had heard the same thing.

NatureNews quoted George Daley on this development:

“I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale,” says George Daley, a stem-cell biologist at Harvard Medical School in Boston. “Their study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes.”

The paper, entitled “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes” came from the lab of Junjiu Huang and is Liang, P. et al.

The authors apparently sought what they thought would be a relatively more ethically acceptable way to go by using the abnormal human 3PN embryos (that cannot develop normally because they have two sperm genomes) as a basis to create GM human embryos.

Liang, P. et al.

The team reported that the CRISPR gene editing in the human embryos didn’t go well (see Figure 2A above from the paper summarizing the basic numbers):

“We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic.”

Specific mutations in the HBB gene can cause beta thalassemia.

To make matters worse technically, there were high levels of off-target activity:

“These data demonstrate that CRISPR/Cas9 has notable off-target effects in human 3PN embryos.”

According to the NatureNews piece the issue was raised by some that the problems with the CRISPR-Cas9 targeting reported in this paper could have been due to the embryos being abnormal.

While formally possible, I think that is unlikely to be the whole explanation. I’m with George Daley on this being a cautionary tale.

It is worth noting that the current study had institutional ethical approval according to a statement in the paper:

“This study conformed to ethical standards of Helsinki Declaration and national legislation and was approved by the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University. The patients donated their tripronuclear (3PN) zygotes for research and signed informed consent forms.”

Would an institutional review board in another country such as the US have given the green light to making GM human embryos? I don’t know.

This study reaffirms the reasons that a pause is needed on in vivo human gene editing studies.

Even though in principle I could support some kinds of in vitro work on gene targeting in human germ cells and even early embryos (see my ABCD plan), I have to admit that this kind of work and the outcomes reported here, where we now can see this in the real world as a paper and not just hypothetically, make me very uncomfortable from an ethical perspective.

I feel like I need to have more time to read this paper carefully and to learn more about how the work was done before coming to more concrete conclusions as to whether it is acceptable from an ethical perspective. In addition, it would be helpful to learn more specifically about why other journals rejected the manuscript and what ethical concerns were raised.

Several other groups in China (and perhaps elsewhere) are conducting similar research and rumor has it that at least one is using normal or near-normal human embryos that have only specific disease-associated mutations.

GM human embryo review

Is ‘GM human’ a loaded name?

Craig MelloDuring the still ongoing discussions of genetic modification in the human germ line and potentially in actual human beings in the future, an interesting, but difficult question has emerged:

What words or names would be most appropriate for the community to use to refer to potential future human beings that have gene edits?

I have up until now referred to such hypothetical people as “genetically modified humans” or “GM humans” for short.

To me this terminology seems most accurate.

Keep in mind that people bearing gene edits don’t exist and in principle may never come into being, although I think the odds are increasing that this might happen.

It is also worth noting that nearly everyone who has weighed in on the potential production of humans with germline gene edits has been opposed to it.

Others have used the “genetically modified human” terminology as well. For example, Nobel Laureate Craig Mello uses the term “genetically modified humans” (at the ~36 minute time point in video above, HT to Antonio Regalado @antonioregalado, screen shot at top of post from video).

Still, however, I can see how the phrase “GM human”, even if used in a discussion of only hypothetical future beings, could be complicated.  For example, Julian Hitchcock raised the concern on Twitter that the nomenclature “GM Humans” could have negative connotations.

Why is this issue of what to call modified humans important if we are only talking about a hypothetical case scenario that might never become reality?

Even if we are just talking about potential future people who might have gene edits, we need words right now to accurately refer to them during discussions of human germ line gene editing/genetic modification. Such discussions are urgently needed at this time given evolving biotechnology and part of the agenda for dialogue needs to include what happens if (again for lack of a better term currently) GM people are produced.

If GM people were ever created, they would from a scientific perspective indisputably possess genetic modifications from the original genome that they would have inherited or did inherit as a 1-cell embryo. In addition, they would be genetically modified organisms or GMOs. Should we do a PC tap dance around that fact by avoiding the phrase “genetically modified”?

Yet it can be very complicated.

As Hitchcock asked, if a 1-cell embryo has a disease-causing mutation and CRISPR were used to revert that back to a wildtype, healthy genetic state, should we still call that a “genetic modification”?

At the moment I would say “yes”, but I realize this is a difficult issue on a new technology that we are talking about using in a hypothetical application so it’s not a hard-and-fast “yes”.

This kind of question is made even more complex by the fact that CRISPR is not necessarily going to be entirely specific when used somewhat on the fly during human embryogenesis (again hypothetically) so even with correction of a mutation, how can we be 100% sure other unintended genetic modifications didn’t occur?

We also do not know, as Baltimore, et al. pointed out, whether “correction” of a mutation even if done in a perfectly specific hypothetical context, could lead to unintended consequences in a particular specific embryo or the human produced from it. Everything is context dependent.

What if the same kind of technology were used to experimentally try to reduce risk rather than outright try to prevent disease?

What if this approach were used to attempt to alter behaviors or traits?

Can we draw clear lines between these different applications of the same kind of technology?

For the purposes of community discussion today, what might be the best words to use to refer to these hypothetical cases of new versions of humans?