Live Blogging #GeneEditSummit Day 1 Post #2: State of the Science, #CRISPR

Human gene editing science session smallNow we hear from the scientists on the front lines of CRISPR, covered in this post #2 of the Human Gene Editing Meeting. You can read Post #1 here.

Jennifer Doudna starts off the big human gene editing science session on the current state of the human gene editing science and CRISPR. She gave an overview of how this session will be organized including a panel discussion and questions from audience.

Maria Jasin, Memorial Sloan Kettering Cancer Center, was up next. She gave a nice overview of genome modification technology.

Emmanuelle Charpentier, Max Planck Institute of Infection Biology, spoke next. She explained the origins of CRISPR-Cas9. It is very cool to hear from one of the discoverers about how this technology came to be.

Up next is Jin-Soo Kim of Seoul National University / Institute for Basic Science. He talked about the concept of “Genome Surgery”. He talked also about the different kinds of off-target effects. “You cannot identify off-target effects of CRISPR in bulk populations of cells.”

Jonathan Weissman, University of California, San Francisco, talks about the use of CRISPR to control gene expression, a unique application. How do genes control complex organisms such as people? It is through elegant regulatory systems. Weissman uses the analogy of a piano with finite number of keys producing an infinite complexity of music.

J. Keith Joung, Massachusetts General Hospital and Harvard Medical School, talked about the work that his team is doing on CRISPR-Cas9. “A lot of improvement has been made in Cas9 systems in just the last few years”.

Next up Bill Skarnes from Wellcome Trust Sanger Institute gave some historical perspective on how hard gene editing used to be such as in mice. He highlighted the relative power of CRISPR systems to make different mouse models.

Feng Zhang, one of the top CRISPR-Cas9 innovators, spoke next. He shared his excitement about gene editing technology and to advance it to treat human diseases.

Update: Overall one striking thing about this session (so far as of 11:30am EST) is that the scientists are not voicing any societal, medical, or bioethical concerns. Perhaps this session was defined to be focused just on science.

Discussion and questions. Jennifer Doudna now follows up by asking some questions of the panelists.

  • “What about prospects for controlling DNA damage?”
  • “What do you see as the prospects for controlling genetic information (e.g. regulate expression)?”
    • Weissman–“challenge is delivery”.
    • Zhang –talks about both dead and active Cas9 for therapeutic options. Cas9 could be immunogenic and could be a challenge.

Question from audience on difference between CRISPR-Cas9 in the natural world and how it is being used by scientists.

Another question from audience: how can we get to a point where we feel it is safe from an off-target perspective? Zhang answer, “In part it will depend on the number of cells used. We need a standardized way to measure off-target effects”.

A third question–how long do you measure for changes or off-targets in cells? Joung answers this by saying that so far it has been arbitrary.

Another audience member, “What about regulations? Are you worried that some could be too restrictive?” Jasin, “I wish there were clearer discussions on ethical issues and guidelines”.

Live Blogging NAS Human Gene Editing Summit: #GeneEditSummit

Jennifer Doudna

Jennifer Doudna at a NAS planning meeting.

The National Academy of Sciences (NAS)  summit on Human Gene Editing will begin in a few days on December 1 in Washington, D.C. This summit is in part the extension of discussions that started at a more informal meeting on CRISPR earlier this year in Napa organized by Jennifer Doudna and colleagues.

The NAS meeting will bring together scientists, ethicists, and policymakers from around the world and in particular from the US, the UK, and China. These three countries are presently the hotbeds of human genetic modification research, both academically and commercially.

I’m planning to be there live blogging the meeting with posts right here on this blog to give a sense of what is going on, the mood at the meeting, and more including pictures. Hopefully I can do some quick interviews with speakers at the meeting as well.

Many questions surround this topic and I’m curious how the meeting will tackle them. Will a consensus for a moratorium on clinical use of CRISPR on humans be reached? How much participation by the public will occur? What kind of range of opinions will be presented?

You can follow the meeting on Twitter with the #GeneEditSummit hash tag.

Haunting Doudna nightmare about Hitler wanting CRISPR

Nazi Propaganda Poster Eugenics

Nazi Propaganda Poster Eugenics. Source unknown

A recent piece on CRISPR-based genetic modification in the New Yorker called The Gene Hackers or Human 2.0 by Michael Specter is striking in a number of ways. I highly recommend it.

The article provides an in-depth look at CRISPR and its potential use for human editing. I like how the article brings so many viewpoints to bear on this important topic.

The thing that struck me the most was the recounting of a dream, really a nightmare, that left CRISPR pioneer Jennifer Doudna waking up in a cold sweat.

In the nightmare Adolph Hitler wants to learn more about CRISPR and presumably to use it for eugenics (see Nazi eugenics poster above). This dream can be seen as a reflection of the disturbing possible future reality that some may take CRISPR technology in unethical directions and there could be not a whole lot that any of us including a leading scientist like Dr. Doudna could do to stop them.

At the same time this also highlights the importance of a moratorium on clinical human genetic modification. We must make efforts at public education and at frankly doing all we can to stop misguided or even outright destructive people from running with CRISPR in the eugenics direction.

This theme is also dealt with in my upcoming book due out December 1, GMO Sapiens: The Life Changing Science of Designer Babies, which you can now pre-order.

Here is the recollection of the Dr. Doudna’s dream:

“I had a dream recently, and in my dream”—she mentioned the name of a leading scientific researcher—“had come to see me and said, ‘I have somebody very powerful with me who I want you to meet, and I want you to explain to him how this technology functions.’ So I said, Sure, who is it? It was Adolf Hitler. I was really horrified, but I went into a room and there was Hitler. He had a pig face and I could only see him from behind and he was taking notes and he said, ‘I want to understand the uses and implications of this amazing technology.’ I woke up in a cold sweat. And that dream has haunted me from that day. Because suppose somebody like Hitler had access to this—we can only imagine the kind of horrible uses he could put it to.”

Could the “next Hitler”, if there is one which I hope there isn’t, already be interested in human modification?

There are so many amazing, positive things being done and learned via CRISPR and it truly does have great potential for health, but in addition there will be huge risks including to society. That’s not from a dystopian work of fiction. It’s a possible reality that comes with this transformative technology. One at least partial solution is more public engagement and transparency. Sugarcoating what is going on or dishing out overly optimistic views of only positive possible outcomes for the public doesn’t help anything or anyone.

Dr. Doudna deserves enormous kudos not only for her science, but also for her leadership, balanced views and public engagement on wider CRISPR issues. She and her colleagues at IGI really started the ball rolling with discussions of the key, larger CRISPR issues last year. That spark has catalyzed more recent and still ongoing healthy discussions of this revolutionary technology that are incredibly valuable (see more in my interview with her here).

Perspectives on Hinxton Human Germline Modification Statement

The international stem cell policy and ethics think tank, the Hinxton Group, weighed in yesterday on heritable human genetic modification with a new policy statement.

The Hinxton statement is in many ways in agreement with the Baltimore, et al. Nature paper proposing a “prudent path forward” for human germline genetic modification, which came out of the Napa Meeting earlier this year.

However, while several of the Napa authors have now thrown their public support behind a clinical pause or moratorium on heritable human modification (e.g. Jennifer Doudna as well as David Baltimore and Paul Berg in a later piece in the WSJ), Hinxton didn’t explicitly address either positively or negatively the question of a moratorium.Hinxton Group

My initial reading of the Hinxton statement is that I mostly agree with it. In my own proposed ABCD plan on human germline modification from earlier this year, however, I included at least a temporary clinical moratorium.

I also would have appreciated a more detailed risk-benefit analysis in the Hinxton statement. For instance, I didn’t see a discussion of specific possible risks in their statement. Via my own risk-benefit analysis, I come to the conclusion that on the whole a temporary clinical moratorium has the potential for far more benefit than harm.

What would be the specific, possible benefits of a moratorium?

If the scientific community has united behind a moratorium on clinical use not only will that discourage rogue or potentially ill-advised stabs at clinical use, but also if a few such dangerous efforts proceed anyway (which is fairly likely) and come to public light, these unfortunate events will be placed in the appropriate context of the scientific community having a moratorium in place. Therefore, a moratorium both discourages premature and dangerous clinical use as well as putting potential future human gene editing clinical mishaps into the proper context for the pubic.

Another potential benefit of a moratorium is that it could discourage lawmakers from passing reactionary, overly restrictive legislation that bans both clinical applications and important in vitro research. It would give the politicians and the public the right sense that the scientific community is handling this situation with appropriate caution. If you don’t think that a law on human germline modification is likely in the US, consider that conservative lawmakers have already proposed such a law be included as part of the pending appropriations bill and Congress a few months ago held a hearing on germline human modification.

Other benefits of a moratorium include that it would a) demonstrate to the public that the research community is capable of reaching consensus about important ethical issues and b) increase accountability within the research community. Any rogue researchers or clinicians who would violate the moratorium, even if it were not illegal for them to do so, would at least be subject to the disapproval and possible sanction of their professional peers or institutions. Without a moratorium in place, it is far less likely there would be these kinds of consequences.

What about risks to a clinical moratorium? The primary possible risk of a clinical moratorium is that it could, should human heritable genetic modification someday down the road be viewed as a wise course to pursue directly, impede clinical translation. This warrants discussion, but in my view the risk here is somewhat reduced by the possibility that continuing basic research develops a compelling case that a blanket clinical moratorium might no longer be needed.

The other risk here is that a moratorium on clinical use also might in theory discourage some potentially valuable pre-clinical research as well. In other words, some researchers may adopt the mindset that if they cannot get to their ultimate goal of making clinical impact, why do the preclinical studies? I expect that many researchers would instead go ahead and do the preclinical work with the expectation that a clinical moratorium could be lifted and in fact their own preclinical work might help build a case for moving beyond a moratorium.

I agree strongly with Hinxton on the need for continuation of basic science on CRISPR and other gene editing technologies limited to the lab. In my view, we should have a nuanced policy though, whereby we support continuation of gene editing research in human cells and even in some cases human embryos in the lab under specific conditions (see again my ABCD plan for details), but in which we also put an unambiguous hold on clinical applications at this time.

In the absence of a framework that includes a clinical moratorium, we probably do not have the luxury of a reasonably long time frame (e.g. measured in a few years) for open discussion to sort things out carefully. To be clear, open and diverse discussion is crucial, but we just do not have a whole lot of time to do it as things stand today. Why? In the mean time absent a moratorium, I believe that some will go ahead and do clinical experiments on human germline editing. This would not only put individual research subjects at risk, but also pose dangers in terms of public trust and support to the wider scientific community. In a relatively permissive environment lacking a clinical moratorium, one or two instances of rogue researchers clinically using gene editing in a heritable manner could end up leading to a backlash in which even in vitro gene editing research is stymied.

Where’s the Beef? Why I Disagree with Pinker On CRISPR

Steve PinkerProfessor Steven Pinker of Harvard has been making the case recently that when it comes to novel biotechnologies such as CRISPR-Cas9 that bioethics should just get out of the way. Further, he has argued that we do not need a moratorium on clinical use of CRISPR-Cas9 for human genetic modification. In fact, he says that such a moratorium would be harmful.

I think he’s wrong about that. I’m not a bioethicist so rather than talk primarily about his views on bioethics, I’m going to focus instead on a scientist’s perspective on the key issues.

I respect Pinker’s intellect. In addition, I share his goal of stimulating dialogue on innovative biotechnologies. Sometimes being provocative is the best way to stimulate much-needed discussion.

I invited Pinker to do an interview on this blog last week, which you can read here. In that conversation he goes into much more depth on his view of human genetic modification via CRISPR, a possible moratorium on such efforts (which again he strongly opposes), and bioethics. It’s a fascinating read even if you disagree with him.

His is a wonderful, bright writing style and I appreciate his inventive neologisms like the new words bioethocrats and moratoristas even if admittedly (we need thick skins to weigh into science politics) they tend toward the pejorative and arguably are divisive.

The real Achilles heel of his argument on human germline modification is the lack of hard science behind it. As a spin on “where’s the beef?” we might ask Pinker, “where’s the data?” In fact, his main assertions are not backed up with data, but rather with assumptions, predictions and clever use of words. Most scientists that I know aren’t convinced by this kind of argument because there’s not much if any data behind it. The arguments are not scientific, but more philosophical and speculative.

For instance, his super cheery vision on biotech and in particular clinical use of CRISPR puts him at odds with leaders in the gene editing field including scholarly scientists such as Jennifer Doudna. Doudna and other prominent scientists have publicly voiced concerns over the potential for misuse of and unintended consequences from CRISPR-Cas9.

Doudna and fellow scientists such as Nobel Laureates David Baltimore and Paul Berg correctly see there being great potential for good in CRISPR-Cas9 and I totally agree on that, but Doudna, even as a discoverer of CRISPR-Cas9, doesn’t view this technology as being free from complications or bioethical issues. Of course she’s right about that too. Even geneticist and CRISPR-Cas9 innovator George Church, who has been relatively more enthusiastic about the possible future role for heritable human modification via CRISPR, has raised some concerns at times about this technology including safety and possible weaponization. Those issues plus many others including commercialization and potential conflicts of interest, are precisely where we scientists need the expertise of bioethicists. But really what the scientists like to focus on is data and that’s one major thing lacking from Pinker’s argument.

Biotechnology is neither as simple nor as positive as over-exuberant technophiles would have us believe. In the real world of science, things are complicated. Experiments are rarely black and white in this arena where grey dominates. We might say, “Data is king” and data are glaringly absent from the writings of those promoting human genetic modification. For instance, Pinker hasn’t presented data to back up his sweeping assertions that (A) we can do a risk-benefit calculation for innovative biotechnologies such as CRISPR-Cas9 and that (B) as a result we can confidently predict that benefits will greatly outweigh risks. He’s engaging largely in wishful thinking. I pressed him on this point in my interview and I don’t believe he answered that question convincingly. In addition, Pinker is far too optimistic about the protections in place for individuals or future individuals who might be genetically modified and harmed in the process.

As a scientist and an admitted datacrat, I have to look skeptically on this kind of breathless optimism in the process of policy formation. The fact that the CRISPR-Cas9 data we have so far is at least somewhat concerning on certain levels is certainly relevant here as well and concretely supports a moratorium. These data include the evidence of substantial off-target activity of CRISPR at times, that CRISPR can also make the “wrong” genetic modification in the “right” place too, the fact that CRISPR technology is new and rapidly improving giving a sound, data-based basis for predicting that even in a few years CRISPR-Cas9 will be a dramatically better tool than it is today, the reality that the first paper reporting CRISPR editing of a human embryo used a suboptimal form of the technology (i.e. human judgment is not perfect even in science), and more.

We can argue about philosophy and debate about future visions. We can battle with words. In the end, our decisions need to be in large part driven by data and even by the absence of data. For example, scientists can say, “we need to know XYZ before we can proceed, but we just don’t know that yet”. More data is definitely needed before we can confidently make predictions about CRISPR’s use in humans.

Further, bioethicists have a key, positive role to play here in community discussion and policy formulation even as we take the appropriate time to accumulate more data. I would hazard to guess that most scientists (and I include myself in that) wouldn’t want bioethicists to completely run the show on this, but at the same time we realize that we need some bioethics expertise around the table. That certainly was the case for the Napa meeting on CRISPR. I’m confident that the organizers of the upcoming NAS meeting on human germline modification share this view too so I’m not going to belabor that point.

The bottom line is that the keys to a constructive path forward on CRISPR-Cas9 and evaluation of potential human genetic modification overall will be more data as well as balance in discussion and policy making. We haven’t had time for that yet so at least a temporary clinical moratorium is the wise way to proceed.