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.
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.
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 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.
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.
My initial views to this:
Well, of course it was accepted after one day.
There’s nothing fundamentally wrong with the paper. It looks pretty solid. I hoped for maybe a MALBAC-based approach instead for genome amplification, but oh well, journal choice and editorial prerogative, etc.
I bet the real reason it got rejected was “wrong answer.”
After all, it’s a much less glam-journal story if the conclusion is “we see off-targets, oh and remember how the TALENs and ZFNs against HBB target the homologous gene? yeah we see that too with CRISPR/Cas9.”
…Or I could be just extremely jaded after the whole STAP debacle on the editor’s side. I am most certainly not speaking about the reviewers’ intentions. Most likely we’ll never see the actual reason from Nature. Oh well.
Thx Paul for the viewpoint.
I believe you´re correct to have reservations about the unknown steps on the discovery path to geneline editing. However, I do believe it’s important to participate in order to have any chance to mold the outcome. As we have just learned the science is indeed moving ahead, like it or not. I don’t believe debating the merits of the possibilities does justice to the technology – at least to me that doesn’t seem productive at this stage.
Some may not wish to go down this discovery path but as many have pointed out – it’s not something anyone or even a group(s) can put a halt to, it seems.
I would like to see the West actively engaged in an initiative to put a scientific team of institutional investigators together to spearhead a collaberative international effort to lead coordinated research into geneline editing – in all it’s forms (there are many of course research methods to explore). This way the open nature of such an initiative would be beneficial to all stakeholders and those on the ground can draw down from this central resource.
Attention grabbing science papers as a methodology to present the public the work being done adhoc doesn’t strike me as proactively getting ahead of the issues…
Also, isn’t it possible to establish an seperate and arm’s length oversight department into an existing organizational structure to officially sanction & coordinate the independent local discovery groups in order to inform and assist the lab work & valid data collection for the entire space? Or are we looking at global independent action, reaction, applied science and IP castle building for human elitism?
Cheers
I only have cursory and layman’s knowledge on this subject. But I didn’t find this surprising at all; actually it’s quite logical that their would be substantial “off-target” activity. If you go with the obvious premise that there are tons of things we still don’t understand about genetics, it’s no surprise there are unpredictable outcomes. Didn’t they just discover that information may be encoded in more than one way with DNA? Seems there is still much to learn and viable “editing” like this seems to be at least 100 years away.