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.

A Stem Cell Clash: Silva Comments on MBD3/NuRD Debate with Hanna

Researchers probing how to reprogram cells into powerful stem cells (induced pluripotent stem cells or IPSCs) and what the molecular mechanisms are behind this process have become entangled in a conflict.

Of course over the years scientists including stem cell scientists have had their share of disagreements and debates in the past including heated ones, but this reprogramming clash has taken it up a notch beyond past ones and has some unique elements to it.

For example, this scientific clash is unfolding largely in the public domain and involves post-publication review such as on PubPeer.

Looking under the “hood” of cells so to speak, their reprogramming involves a molecule called MBD3 and a corepressor complex called “NuRD” ( for more on NuRD see my review with my postdoc mentor Bob Eisenman on NuRD here in Cell). It seems that most everyone agrees that MBD3 and NuRD play some role in reprogramming.

However, what the exact roles of MBD3 and NuRD might be in this area are very unclear at this time and there are quite distinct views.

Jacob Hanna

On one side we have Jacob Hanna, a well-known stem cell scientist who was previously a postdoc in the lab of Rudy Jaenisch. Hanna (pictured at right) has had a number of very high profile papers including on induced pluripotency.

One major assertion from the Hanna Lab is that a repressive chromatin complex including MBD3 and NuRD proteins is inhibitory for pluripotency (e.g. in their Rais et al. paper that I discussed on this blog when it came out in 2013). I also had a chance hear Hanna talk at the 2013 Till & McCulloch meeting, where I asked him some questions from the audience (see here).

On the other side we have José Silva, another top stem cell investigator. Silva did his post-doctoral work in the lab of Austin Smith. Of course Jaenisch and Smith are two of the top scholars in the stem cell field. The Silva lab has published a Cell Stem Cell paper coming to pretty much the opposite conclusion of Hanna.

Jose SilvaThis stem cell conundrum has been the subject of vigorous discussion on PubPeer. Now this MBD3 disagreement has also spilled over to bioRxiv where further back and forth is ongoing. On Silva’s side of the MBD3/NuRD fence are also well-known researchers Brian Hendrich and Paul Bertone.

In an effort to get to the bottom of this and build a bridge for constructive discussion, I have invited both Silva and Hanna to comment here on this situation.

Hanna has indicated that he would prefer to wait a month or so until additional work is published and then will provide comment. Stay tuned for that as my invitation to him stays open.

Silva has provided comments now, which are included verbatim below:

“Please find below the key elements (in no particular order) being discussed on the ongoing debate on MBD3/NuRD and reprogramming and my view on these:

1- Levels of Mbd3 expression and its relation to reprogramming.

Rais et al. evaluated the potential of Mbd3 depletion primarily in the Mbd3fl/- heterozygous background. Dr Hanna claimed that these cells express hypomorphic levels of Mbd3, corresponding to 20% that observed from wild type cells. Dr Hanna also claimed that these cells could reprogram with near 100% efficiency. However, our analysis of Dr Hanna’s data revealed that Mbd3fl/- cells express instead nearly wild type levels of Mbd3. This is also in line with the quantification of Mbd3 levels in Mbd3fl/- cells assessed in Dr Hendrich’s lab and mine. This evidence led us to question the effective depletion of Mbd3/NuRD function as having been a significant factor in the reported increase in reprogramming efficiency. (Please note that Dr Hanna’s Mbd3fl/- cells used in the Rais et al. study were generated by Dr Hendrich’s lab.)

2- Use of elevated copy number of Oct4-GFP reporter transgenes to assess ongoing reprogramming efficiency

The high copy number of randomly integrated Oct4-GFP reporter transgenes may lead to spurious GFP expression in non-reprogrammed cells.

3- Comparison of reprogramming efficiency to a control cell line harboring a deficient Oct4-GFP reporter transgene.

While Mbd3fl/- cells harbored an intact Oct4-GFP reporter known to be promiscuous for expression in a range of cell types, the control cells were transfected with an alternative Oct4-GFP reporter with much greater specificity for pluripotent cells. This finding indicates that key methodology was absent from the paper, and the comparison of reprogramming efficiency between cell lines representing compatible measurement conditions was potentially invalid.

4- Reproducibility of Dr Hanna’s claims. Rais et al. was regarded as a  landmark paper in stem cell biology and numerous labs around the world have tried to reproduce these results. Their attempts using independent systems have been unsuccessful. We do not dispute that Dr Hanna’s cells reprogram relatively efficiently. However, based on our own experimental work and on the detailed analysis led by Dr Bertone of genomic datasets published by Rais et al., we found no evidence to support the claim that depletion of Mbd3 leads to deterministic reprogramming.

José Silva

Five stem cell legends & a blogger walk into a bar: the increasing influence of social media

stem cell leaders

Five legends and a blogger walk into a bar together.

The bartender asks the first legend “What can I get for you?”

The legend orders their drink.

The bartender eventually serves up drinks to all five legends and turns to the blogger, “And what can I get for you?”

The blogger replies, “Do you have Wi-Fi?

“…..and a beer.”

I’ve now been doing my stem cell blog for about 2 1/2 years.

It started as an experiment and sort of took on a life of its own.

I find it very rewarding, but does all this blogging mean anything real and substantial?

Traffic continues to increase on this blog and it seems that the blog still has a who’s who audience of the stem cell world. So I guess the answer is “yes” to many people.

I’m very proud of the research that my lab does and I believe in making a difference through this research, but my hope is that this blog also makes a difference and means something to readers.

This past week we had a company announce the 50 most influential people in the stem cell world.

I was very skeptical of such a list, but curious who they had picked and why. So I opened it up and was very surprised that there I was at the very top….no, not #1, but #50.

However, they chose to put #50 first at the top of the first page of the PDF.

Funny.

Heck, I’m not complaining. I don’t totally understand how this group picked the most influential stem cell people and such lists are clearly arbitrary in some ways, but it’s neat to be on the list.

I think this blog had a lot to do with me being there.

CIRM recently ran a piece on this Top 50 stem cell influencers and included a picture of some CIRM-related folks including me (see pic at the top of this piece.)

What an honor it is for me to be with those 5 legends in the stem cell field in that montage.

In case you are not in the stem cell field or if you are you have been doing research on stem cells on Mars for a few decades, I can tell you who the other 5 are.

Starting at the top left is Nobel Laureate Shinya Yamanaka, then to his right is CIRM President Alan Trounson, and then we have Bob Klein who made Prop 71 a reality and is Chairman Emeritus of the CIRM Board. Then the next row starts with me on the left, then stem cell legend Jan Nolta who is Editor-in-Chief of the fantastic journal Stem Cells (and my colleague here at UCD), and finally Fred Gage, who has been doing pioneering stem cell work for decades and is the past President of ISSCR.

This montage reminds of that song on Sesame Street “…which of these things do not belong” where they have pictures of maybe five balls of different shapes and sizes, and then a zebra. I feel kinda like that zebra. Yeah, you can tell I’m a dad from the Sesame Street reference.

I can think of many others who did not even make the top 50 in this particular list who I believe are amazing stem cell stars that could and arguably should have been included: Irv Weissman, George Daly, Len Zon, Sean Morrison, Konrad Hochedlinger, Jeanne Loring, and Rudy Jaenisch, just to name a few, but there dozens more I could list. I could probably list 50 people just in the state of California here in the US.

Do I belong there with those 5 stars in that photo montage above? Or on that list of top 50?

I don’t know, but I think one message from all of this is that social media is increasingly influential in science and in the stem cell field.

A stem cell blog can have a powerful impact on the field. I didn’t remotely imagine that in 2010.