Alliance for Regenerative Medicine (ARM) Opposes REGROW Act, Risks to Patients Cited

The biggest debate today in the stem cell world is over how much regulation is needed for new, investigational stem cell therapies that are not as yet approved.

Sometimes it feels very lonely being out there publicly advocating for appropriately thorough regulation of stem cell therapies and at times I get a lot of heat for that, especially from stem cell clinics. For instance, I am publicly opposed to the REGROW Act, a piece of legislation that would dangerously weaken oversight of experimental stem cell therapies. Still, I have not yet seen a statement from major stem cell organizations on these issues. It was therefore a great boost to hear just now that the top stem cell biotech industry organization, The Alliance for Regenerative Medicine (ARM), has issued a statement firmly opposing the REGROW Act.

Alliance for Regenerative Medicine

I want to send kudos to ARM and its more than 250 members.

For years in this debate there was a bright line between the academics as well as mainstream organizations in the stem cell arena (together supporting the need for rigorous science-based stem cell medicine and for the FDA, even if some reforms are needed) versus the dubious stem cell clinics out to make a quick buck and wanting as little regulation as possible.

However, in the past year we’ve seen a troubling seismic shift such that some academics and others who used to support the FDA have begun arguing for dramatically less regulation of experimental stem cell treatments. For more background on these pushes for stem cell deregulation, please see my past posts on the Bipartisan Policy Commission (BPC) report that proposed extreme measures such as conditional approval of experimental stem cell interventions, charging patients to be experimented upon, and eliminating Phase III trials in some cases and also see my post opposing the REGROW Act.

It is a big, positive decision for ARM to oppose the REGROW Act, and I’m encouraged to see that I’m not alone in opposing this overreaching legislation. The reasons for ARM’s opposition and my own rationales for being against the bill substantially overlap. We both focus on the dangers posed to patients by inappropriately extreme deregulation. I can’t speak for ARM, but my impression is that they like many of us support some changes in how stem cell therapies are regulated. Perhaps there is hope that the REGROW Act could reemerge in a new incarnation in the future that is more balanced and would chart a prudent path forward.

I’ve pasted ARM’s statement on the REGROW Act below:

“The Alliance for Regenerative Medicine is appreciative of Senator Kirk’s longtime support of the regenerative medicine sector and his belief in the transformative durable treatments and potential cures this field holds for patients. Our organization is committed to our continued cooperation with Senator Kirk and his staff to advance policies supportive of this sector and expediting potentially life-saving cell therapies, gene therapies and other regenerative medicine products. 

However, ARM cannot support the REGROW Act. We continue to believe the proposal does not contain critical statutory protections for patients. We look forward to a continuing dialogue with the sponsors of REGROW Act as well as other stakeholders to create alternative approaches to ensure access to safe and effective regenerative medicine therapies without putting patients at risk, disadvantaging American therapeutic developers and potentially damaging a very promising field of medicine. 

Note that ARM leaders Michael Werner and Edward Lanphier seem to be the point people on the REGROW issue.

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.

Practical Plan for Managing Human Germline Genetic Modification

CRISPR-Cas9 gene editing technology is a game changer on many levels both inside and soon outside the lab. There is a growing sense of urgency amongst biomedical scientists to take a proactive approach to current and future use of CRISPR technology in human germ cells and embryos.

These concerns have been heightened by rumors of multiple papers currently in various stages of peer review that will reportedly describe CRISPR-mediated gene editing of human embryos. A number of scientists and scientific organizations have recently come out with policy statements on human germline genetic modification: Lanphier, et al. NatureBaltimore, et al. Science, and ISSCR.

I’ve outlined a proposed plan (see figure below) that I call ABCD for simplicity to try to practically manage the situation with human germline genetic modification. This plan shares a few key features with some of those already proposed by others, but in some ways it is different or more specific. This ABCD idea is just a possible plan coming from one person (me) with the intention of positively adding to the overall dialogue.ABCD Plan Human Germline Modification

My view is that in vitro research on genetically modified human germ cells and early embryos–with appropriate training and oversight–is ethical and can in fact be of great value. Such work will provide new, valuable information about gene editing itself and early human development, fertility, and more. Therefore, such research should not be prohibited, but should only be conducted under certain conditions.

For example, the In vitro studies of genetically modified human germ cells and embryos would require appropriate approval and oversight. This is the A part of the plan. Given the urgency in terms of timing on this issue, it seems impractical to create new committees from scratch solely for this purpose. Thus, I propose that standing SCRO committees have the authority and responsibility to regulate genetically modified germ cell and embryo-related work. They already are the ones overseeing similar research now. The human germ cell and embryo CRISPR work would have to have a compelling justification to get SCRO approval.

Researchers proposing to the relevant SCRO or similar committee to conduct research related to human genetic modification of germ cells or embryos must also receive bioethics training, which is the B part of the plan. This is particularly important because of the complicated bioethical issues that this unique kind of work raises and such training would serve to provide a strong educational component. Bioethical issues to be discussed would include the human germ cell modification itself, the specific concerns over outcomes if the work were applied in vivo, and other aspects such as the sourcing of human oocytes. As to that last issue, in vitro CRISPR human genetic modification research could substantially increase the research demand for human eggs.

The C part of the plan is clarity. Both the public and scientists would greatly benefit from education and openness in this area. Transparency and outreach in lay terms is essential for public trust. Research on human germline genetic modification, including those manuscripts potentially currently in review, should be published in open access format to make the data fully available to society as a whole. No pay walls here. This area of research is too important and charged to block access.

The D part of the plan is don’t extend the work to in vivo applications involving implantation of genetically modified human embryos. There should be a moratorium on this step given the major ethical and safety issues involved. Whether such a moratorium could ever be lifted is unclear and would depend on what the data that come in the next few years teaches us. Practically speaking the questions of how such a moratorium would work or be enforced are tough ones, especially if one intends to extend it internationally.

With these ABCD guidelines in place the goal would be that innovative, valuable research in this area could proceed in a responsible and ethical manner, while minimizing the risk of negative outcomes.

Within just a year or two the knowledge base regarding CRISPR-based gene editing will be vastly increased. Further, in the same timeline additional next-generation CRISPR approaches will improve accuracy and introduce further refinements in the technology. Plans for managing germline human genetic modification may need to evolve as well. The ongoing dialogue that has ramped up recently already shows signs of having very positive impact and is likely to continue to do so as it proceeds.

ISSCR calls for moratorium on clinical application of human germline nuclear genome editing

The International Society for Stem Cell Research (ISSCR) just now released a new policy statement on human germline gene editing.ISSCR_logo

The statement calls for a ban on clinical application of human germline gene editing technology.

Here is the brief summary statement at the beginning:

The International Society for Stem Cell Research calls for a moratorium on attempts at clinical application of nuclear genome editing of the human germ line to enable more extensive scientific analysis of the potential risks of genome editing and broader public discussion of the societal and ethical implications.

These are very important issues that are raised.

Notably ISSCR is supportive of in vitro research in this area in the lab:

At this time, the ISSCR supports in vitro laboratory research, performed under proper ethical oversight, to enhance basic knowledge and to better understand the safety issues associated with human genome editing technologies, including their potential for application in somatic tissues. The ISSCR also calls for broad public and international dialogue on the capabilities and limitations of these technologies and on the implications of their application to the human germ line. The ISSCR is committed to playing a role in catalyzing both the scientific and broader ethical deliberations about germline genome editing.

The ISSCR also noted that it does not take a position on mitochondrial disease-related, so-called “3-person IVF” technology, which it distinguishes from nuclear genome modification.

This statement overall seems at a middle ground relative to the recent Lanphier piece calling for a broader moratorium.

Stay tuned for more scientists weighing in on this important issue very soon.

Proposed Moratorium on Genetic Modification of Human Germ Cells

human sperm and eggOne of the hottest topics in the biomedical world in 2015 is heritable human genetic modification.

There is an unsettling sense that genetically modified human germ cells and eventually GMO human beings are likely coming even if science and society are not ready for it. There are a hodgepodge of laws against human germline genetic modification, but it’s not clear that these regulations can realistically stop it from happening everywhere and they often do not apply to making GMO human germ cells.

In a commentary piece published today in Nature, the group representing a host of clinical stem cell biotech’s, the Alliance for Regenerative Medicine (ARM), and scientists from genome-editing company Sangamo, called for a moratorium on germline human genetic modification.

The piece had a very strongly worded title: Don’t edit the human germ line.

There’s really no way to misinterpret the sentiment of this article penned by Edward Lanphier, Fyodor UrnovSarah Ehlen HaeckerMichael Werner & Joanna Smolenski. 

Part of what makes their piece so compelling is that some of the authors are themselves deeply involved in clinical gene editing, but for gene therapy and not germline modification.

Notably, the moratorium that the authors propose would be voluntary. I’m not sure how well that’d work. There’s probably a race-to-be-first mentality amongst certain scientists to be the “pioneer” to make genetically modified human germ cells and I’m betting that “top” journals would scramble to want to publish such work even if it is ethically complex to put it mildly. Once human GMO sperm and eggs are produced (image from normal ones from Bing; image in the public domain), it’s hard to imagine them never being used.

Don’t get me wrong. I think the moratorium would be a wise move, but I’m just not sure it will stop human GMO from becoming a reality. Still, a pause could have a positive influence on how this technology unfolds in humans.

Antonio Regalado over at MIT Technology Review has a nice article on this call for a moratorium as well. In it he quoted George Church as not being a fan of the moratorium idea:

“George Church, a professor at Harvard Medical School whose laboratory studies CRISPR and germ-line editing, says a voluntary moratorium would be weak compared with existing regulations that nearly all countries impose on the use of new medical technologies “until they are proven safe and effective in animals or human [tests].” Church was referring to rules governing the birth of actual gene-edited children, not basic research.”

This fits with what Church said in my recent interview with him earlier this week.

Regalado also quoted on the other side, Bernie Siegel, a member of the ARM Executive Committee:

“Bernard Siegel, a patient advocate who is a member of the committee, confirmed that he’d been briefed on the text and agreed with it. “In a broad, sweeping way, [the technology] just raises the prospect of eugenics,” he said. “Who is going to make the decision of making a better human? The technology is so sweeping it’s like the era of science fiction is here and now.”

I tend to agree with my friend Bernie on this.

Bottom line. So what’s next for human germ line gene editing? I expect that there will continue to be calls for a voluntary moratorium and some groups will honor such calls, but I predict that other groups will not and in fact I think that some teams have already made genetically modified human germ cells and some others will make them in the near future.