New #CRISPR updates: Editas to go public, patent issues, dragons & more

CRISPR dragon

Dragon image from Wikipedia

A lot has been going on in the CRISPR world. Here are some key CRISPR updates.

Editas has filed the paperwork on the road to going public as a company. Such an IPO, should it come to fruition, could raise billions of dollars. Will the other CRISPR companies like Caribou and CRISPR Therapeutics follow suit? Simplistically, it seems like the first CRISPR IPO could get the lion’s share of investor money, but then there’s the patent thing hanging over all of this (see below)

Patent dispute rolls on. Jacob Sherkow over at the Stanford Law Blog dug into recent developments in the CRISPR patent battle. One big thing is the interference proceeding. A patent person I recently communicated with on this topic has some different views than Sherkow on much of this. I’m hoping to blog about that soon.

CRISPR on the news. If you missed it, Jennifer Doudna and I were interviewed by Gwen Ifill on the PBS News Hour last week (see below).

A BBC piece came out that was the subject of quite a bit of discussion on Twitter about whether CRISPR could be used to make a dragon. The item mentioned an article by Hank Greely and Alta Charo on CRISPR Critters (animals made using CRISPR) that had referenced the possibility of making a dragon. I tweeted that that was unlikely but that making a unicorn (adding a horn genetically to horses) was relatively more plausible.

A lively discussion followed including Carl Zimmer, Leonid Kruglyak, and Matthew Herper.

US Congress Wants FDA to Consult Religious Experts and Ban Human Embryo Genetic Modification

Crystal_Structure_of_Cas9_in_Complex_with_Guide_RNA_and_Target_DNAThe US Congress recently held its first hearing on human germline genetic modification.

The meeting included CRISPR-Cas9 pioneer Jennifer Doudna (see video here) on the panel. See image of Cas9 structure from Wikipedia. CRISPR-Cas9 is a powerful, strikingly efficient tool for genetic engineering of cells and whole organisms.

Now Republican congressional leaders have included a provision in the current spending bill that would block editing of viable human embryos and could interfere with important research.

Concern over a possible reactive move by Congress on human embryo editing has been building so this was not exactly a shock, but is still a concern. The National Academy of Sciences and its Institute of Medicine (IOM) have taken on the task of holding a meeting more broadly on the issue of heritable human genetic modification and issuing a report.

According to multiple sources including a great new piece in Nature News by Sara Reardonthe US House would also require the US FDA to consult religious “experts” as it weighs three-person IVF, a form of human genetic modification intended to prevent genetic mitochondrial diseases. Three-person IVF has been approved in the UK, but not in the US due at least in part to unresolved safety concerns. I have been one of the main scientists openly questioning whether three-person IVF is ready for prime time because of limited relevant pre-clinical data.

From Reardon’s article:

“The House legislation calls for another layer of review. It would direct the FDA to establish “an independent panel of experts, including those from faith-based institutions with expertise on bioethics and faith-based medical associations” to review the IOM report once released.”

I am concerned over the possibility of heritable human genetic modification including the future possibility of efforts at human enhancement. However, requiring that religious figures in a sense instruct the FDA or the biomedical community is the wrong way to go.

I’m also not a fan of the idea of legislation restricting the use of genetic modification technology. So I’m with Hank Greely of Stanford who said, “This step seems dumb…”.

To me the best approach instead would be a moratorium imposed promptly by the scientific community specifically on clinical use of human germline modification technology, while allowing in vitro research to occur on a limited basis with careful bioethics training, transparency, and institutional oversight (see my ABCD plan). Could someone violate such a moratorium? Of course that is possible, but a moratorium would at least reduce that risk and importantly serve to place any rogue efforts into an appropriate context both for the scientific community itself and the public.

Guest Post by Christopher Thomas Scott–The Great CRISPR Controversy: What’s Next?

Christopher Thomas Scott

Stanford Center for Biomedical Ethics

Director, Program on Stem Cells in Society

 

A decade ago I wrote an article in the journal Nature Biotechnology about the rise of a new gene editing technology called zinc finger nucleases (ZNF). It was one of those “drumbeat” discoveries: at the time, my sense was it would revolutionize how we deliver genes to cells and tissues, and profoundly change the way we think about gene therapy.

I was partially right. Although ZNFs are now well along in clinical trials for HIV, successive advances in precision gene editing now include transcription activator-like effector nuclease (TALENS), and most recently, clustered regularly interspaced short palindromic repeats (CRISPR-Cas9). Of the three methods, CRISPR-Cas9 has clear advantages. It’s cheaper, faster, more efficient, and can target multiple genes simultaneously.

CRISPR primatesRecently, experiments using the CRISPR-Cas9 system have provoked a firestorm of controversy, raising old fears about gene therapies and “designer babies.” Things began to heat up in 2014 when a Chinese team successfully used CRISPR-Cas9 to edit the germline of monkeys. Live, engineered monkeys were born (here’s a photo of the cute little guys). It was only a matter of time before someone attempted the system using a human embryo—doing controversial germline research.

In anticipation of that experiment, two recent essays in Science and Nature outlined policies for the use of precision germline editing. The scientists in each group are experts in ZFN (Nature) and CRISPR (Science) and also have commercial interests in companies developing the technology. In the papers, the authors describe the risks of human germline modification and the limitations of the technology, while promoting research that would better understand safety and efficacy, including off target effects. Both groups would ban using the technology to make babies, but are split on whether to continue research in the laboratory under existing ethical guidelines (Science = yes; Nature = no).

Just weeks after the essays appeared, a second Chinese team announced it had used CRISPR-Cas9 to edit non-viable (three sets chromosomes) embryos, a byproduct of vitro fertilization (IVF). The paper, published in a little known journal Protein & Cell, targeted a human disease. It modified the endogenous beta-globin gene (HBB): a mutated form of HBB causes Beta-thalassemia. Reportedly, the paper had been rejected at Science and Nature “in part because of ethical reasons.” The researchers reported three results: 1) low efficiency: only about half of the embryos were edited; 2) mosaicism: the embryo started dividing before all the cells were edited; and importantly, 3) significant numbers of off-target mutations. The last result is especially worrisome, because off-target problems plagued early gene transfer technologies, inserting genes into the genome in unintended places. For example, a wayward insertion could turn on a cancer-causing gene.

The paper made headline news and generated heated discussion. Media reports were very uneven—the main points of confusion being whether this experiment edited a viable human embryo (it did not), that the experiment was unethical (it appears to be conducted ethically), and that familiar problem at the intersection of science, technology and society: drawing conclusions that designer babies were at our doorstep (not anytime soon, if ever).

In my reading of things, the current controversy centers on:

1) Whether experiments like the Protein & Cell paper should be permitted; 2) the reasoning (ethical? scientific? both?) behind Nature and Science’s rejection of the paper; 3) the speed of the peer-review (at only two days, some believe that the paper was rushed to press); 4) the defense of publishing the paper by the journal’s editor-in-chief (see the quote below and definitely worth a read); and most recently, 5) whether the research was important (scientists are divided on this point).

CRISPR embryo paper editorial

Where does this leave us?  The experiment appears to be ethically sound. The Chinese group used non-viable embryos and disclosed the research had an ethical review. The group was clearly addressing the need for “further research” and the rationale for the study centers on safety and efficacy. The editors’ reasons for publishing the paper, though late in the process and quite interesting, seem reasonable.

More public discussion will attempt to sort these questions out. Along these lines, I recently participated in a panel discussion at Stanford with Hank Greely, Lynn Westphal, Paul Knoeplfer, and Marcy Darnovsky (Paul’s excellent summary of the panel can be found here). The biggest question I took home from our panel is “what now”? Should we allow laboratory germline-editing research to go forward? I think we should. The technology could help scientists uncover problems behind infertility or reveal insights into failures of early human development. Scientists are divided on the issue whether the Protein & Cell paper was important or groundbreaking. This raises the question whether journals should publish controversial research just to demonstrate the technical feat, rather than research that moves science ahead in meaningful and important ways. Other interesting questions include the obligations of researchers and journal editors to explain the ethical and social significance of the research they publish—in my view, the Protein & Cell example laid bare how far we have to go to clearly justify why this research is important, and how deeply we have thought through the ethical and social implications of human germline research. On this last topic, stay tuned for a commentary I’ve written with a Stanford researcher, Arun Sharma, in the June issue of Nature Biotechnology. The next few months will be interesting times for scientists and policymakers as they attempt to sort these questions out.

Report from Stanford Event: Human Germline Modification: Medicine, Science, Ethics, & Law

Greely_HankLast Thursday I participated in a meeting at Stanford Law School on human germline genetic modification hosted by Hank Greely (pictured at left), Professor of Law and Genetics at Stanford.

The meeting was entitled, “Human Germline Modification: Medicine, Science, Ethics, and Law”. The panel included in addition to Hank and me, the following speakers: Marcy Darnovsky, Executive Director of the Center for Genetics and Society (CGS); Christopher (Chris) Thomas Scott, Stanford Center for Biomedical Ethics, and Lynn M. Westphal, Professor of Obstetrics and Gynecology, Stanford University Medical School.

We each spoke for about 10-15 minutes, followed by a rousing discussion with the audience of about 50 people and between us panelists. The audience asked great questions. A video of the meeting is now available (below).MarcyDarnovsky_2012

I’m just going to blog here focusing on my impressions of the meeting and I’m in no way speaking for the other panelists. I hope that if they have other ideas about how the meeting went or their own views in response to my post that they will weigh in as well. I want to thank Hank for the invitation to participate and the other panelists for a great meeting. I came away having learned some important new things and with a broader perspective on human embryo editing.

Part of what made this meeting so interesting to me was the wide range of views on human  modification of the participants and the audience. My sense was that Marcy (picture above right) has the strongest concerns about heritable human genetic modification amongst us speakers. CGS, her organization, just last week I think outlined 7 reasons on their website to “just say no to human genetic modification” and she articulated some of her concerns at the meeting. I share some of her concerns, but don’t feel quite as strongly about human embryo editing and I favor allowing in vitro research under some conditions. Marcy and I also disagreed on whether human germline modification is inevitable. I think it is, while she doesn’t. I got the sense that she is concerned that talk of inevitability could discourage efforts to restrict the technology.

Christopher Thomas ScottOn the other side, it seemed to me that Lynn was perhaps more open to the possibility of modification being used in the future if deemed safe, particularly if it could help infertile couples have their own genetically related children. I found it very interesting to hear about Lynn’s experience as a physician on the medical frontline interacting with couples dealing with infertility or genetic problems including mitochondrial disorders. In communicating with Chris afterwards he mentioned that he was struck by the way in which Lynn indicated that there could well be pressures from patients for therapeutic embryo editing. My sense too was that Lynn wouldn’t be shocked if clinical application of human editing technology was eventually attempted by fertility doctors.

Hank and Chris seemed relatively less concerned than Marcy about human germline modification overall and more confident that it can be regulated appropriately. Chris, pictured above left, also did an excellent job explaining the science behind CRISPR and highlighting what makes it so important and unusual compared to past technologies. Like Chris, I’m more inclined to let some in vitro research (conduced with appropriate ethical and institutional approval and oversight) on human germline modification proceed (see my ABCD plan) and I got the sense that is Hank’s view as well. But there should be a compelling, logical rationale for doing the work in embryos rather than cells.

My impression was that we all could agree that for dealing with most genetic disorders preimplantation genetic diagnosis (PGD) would be far preferable to trying to make a genetic correction in a human embryo.

Hank pointed out three scenarios where PGD likely wouldn’t work to correct a problematic genetic situation and hence gene editing could be needed:

  • 1. Dominant genetic disease with one parent being homozygous
  • 2. Both parents have some kind of mutation in the same gene
  • 3. Certain kinds of mitochondrial disease

I know a lot of people have been trying to think through possible situations where gene editing might be needed and PGD wouldn’t solve a particular problem so it was great to hear Hank articulate how these three fit into that category. Hank and others mentioned how these would be very rare circumstances, but not entirely unheard of so in principle at least there could be a unique role for editing over PGD in humans if proven safe and effective. It is also possible that some rare sex-linked disorders could not be resolvable by PGD.Lynn M. Westphal

Lynn, pictured at right, also added in importantly I thought that for some couples there are so few embryos that PGD is unlikely to work to find one lacking a mutation. I wondered aloud: how many human embryos might take to get CRISPR to work for editing too? It might take quite a few.

We had a good discussion of the example of potential genetic modification of a human embryo for the correction of a BRCA1 breast/ovarian cancer-associated gene mutation. It was pointed out by several that this mutation is not a “causal” mutation in the sense of always leading to disease, but only a predisposition to disease.

If it were decided that human editing for BRCA1 is acceptable, then I suggested that other weaker genetic predispositions might be considered legitimate as well. This could create somewhat of a gray area whereby human genetic modification becomes considered appropriate simply for predispositions including some that might be viewed as only moderate such as say a 30% increased risk of Alzheimer’s or cognitive disability in children. There’s could end up being a bit of blurring there where we could see enhancements occurring too. I felt that there wouldn’t always been a clear, bright line between medical use and enhancements with human germline editing.

I thought Chris raised some great points about issues related to scientific publishing and human germline modification. Why did the journal Protein & Cell, which published the first human embryo editing paper just a few weeks ago, only come out with an editorial days later explaining why they decided to publish the paper rather than having an editorial accompanying the actual research article? To me it definitely seemed reactionary and in response to critical questions raised about the embryo editing paper rather than with forethought about how it would be important to place this publication in an appropriate context right from the beginning.

Chris also pointed out that a key question still open for debate is whether this embryo editing paper should have been published at all. To me it seems like not a whole lot was gained specifically by doing this CRISPR’ing in actual human embryos rather than cell lines.

Some of the questions from the audience included asking about how human modification might change the relationship between parents and children as well as how commercialization could impact the evolution of human editing via CRISPR-Cas9. Another point that came up during the discussion was the concern over potential strong negative impact of gene editing of animals (not humans) either for us as novelty pets or in the wild.

Overall it was a wonderful, very useful meeting that advanced the discussion of human modification forward. I hope that these types of meetings continue and that there is more discussion of this kind involving diverse stakeholders as well as the public.

Reactions to New Hank Greely Human Germline Modification Post

CRISPR-Cas9Hank Greely over at The Center for Law and Biosciences at Stanford Law School was one of the participants in the recent Napa meeting on approaches to human germline genetic modification. Hank was also one of the authors on the resulting position paper in Science with David Baltimore as first author (here).

Now Hank, pictured below, has written an intriguing blog post that kind of gives a behind the scenes look at what has gone on in this area in the last few months and in addition he articulates his personal views on this situation.

I’m not a bioethicist or legal scholar myself, being rather a basic and translational lab scientist, so I enjoy and value reading the work of scholars such as Hank who are more focused in these areas and have that specific training. I really enjoy Hank’s work and his style of directness. In this case of human germline modification I mainly agree with him, but we differ on some key points.Hank Greely

I agree with Hank’s notion and that of the group represented in the Baltimore paper that we should draw a distinction between (A) in vitro research on human germline modification and (B) in vivo work and/or clinical applications, which should not be done for the foreseeable future and possibly never unless safety and efficacy issues can be resolved. My own views (ABCD plan) just already dive more into the specifics and practical issues.

Where Hank and I differ is that he does not see heritable human germline modification as particularly concerning at this time. He writes, “I don’t expect engineered human germline modification to be a big issue – as a practical matter – for a long time, if ever, for several reasons.”

Why?

Hank argues this is in large part due to the fact that it would be so unsafe:

“You’d have to be criminally reckless, or insane, to try to make a baby this way unless and until we’ve had a decade or more of preliminary research, with human tissues and with non-human animals (including certainly primates and maybe even some of the non-human apes), showing that it is safe.”

Ironically, for the same reason, I come to the exact opposite conclusion: human germline modification is a major issue right now.

I believe that there are numerous people who would go ahead and try to make genetically modified people in the coming years despite the safety risks. Factoring in hubris and a desire for fame, I just don’t see that this kind of safety or legal risk would be a broad deterrent to certain folks.

The technology is simple and available as well, which is an enabling factor.

I predict that unfortunately that someone and probably more than one group will try it with the intent to make modified people in the coming years. It could well be catastrophic, but again I don’t see that stopping some folks from trying it. We may also never know about certain attempts to make designer babies, particularly if it fails badly, but that doesn’t mean people won’t try and do serious harm in that way.

Hank goes on to say, “If the moral risk isn’t enough of a deterrent, the potential legal liability should be.”

As to legal risk it is not clear to me that there would be one.

In the US, for example, at the federal level and in many states I’m not aware of specific laws that would confer a clear legal risk to someone recklessly trying to either do human germline therapeutic editing prematurely or even outright attempting to make designer babies.

The FDA has indicated it has regulatory oversight in this area, but the situation is rather vague in terms of real world consequences should someone take the “ask for forgiveness later rather than permission now” kind of approach to making designer babies.

The other two reasons that Hank gives are that the medical and non-medical demand would be small for this kind of technology.

I’m not so sure about that.

It is very difficult to make that kind of prediction about what could be such a powerful technology.

Aside from patient or “customer” demand, also again what about the potential quest of a few wildly misguided doctors or scientists involved for a place in history? I don’t think that can be ignored as a possible motivation for some and it could prove relatively easy for them to get the tools they need to try.

Further, Transhumanism needs to be part of the equation and discussion as well. Already the transhumanist movement seems to be embracing CRISPR-Cas9 technology as a tool for improving humanity and not just minor tweaks here or there. They appear to want humans to become more than human with transcendent changes. There are a lot of very smart and rich folks who are at the very least toying with the idea of Transhumanism.

In the end, Hank and I agree on far more than we disagree upon.

Perhaps I just have a lot less faith in human nature and wisdom, particularly when a new technology arises that is so transformative and exciting. If you think about the case of nuclear physics in the 20th century, for example, it is a striking lesson in how complicated and thorny the real world emergence of a powerful, new technology can be and how difficult it usually turns out to be to control.