Of Science, CRISPR-Cas9, and Asilomar - Stanford Law School Page 1 of 8 Of Science, CRISPR-Cas9, and Asilomar April 4, 2015 Hank Greely Comments (6) (https://law.stanford.edu/2015/04/04/of-science-crispr-cas9-and-asilomar/#comments) On Thursday, March 19, 2015 Science published (on-line) a Policy Forum (http://www.sciencemag.org/content/early/2015/03/18/science.aab1028.full) entitled A Prudent Path Forward for Genomic Engineering and Germline Gene Modification. The piece had 18 authors, including David Baltimore, Paul Berg, Alta Charo, George Church, George Daley, Jennifer Doudna, Ed Penhoet, Keith Yamamoto, and (as, with Alta, one of only two non- scientists and definitely as one of the lesser lights) me. The Policy Forum recommended that steps be taken to “strongly discourage…any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations.” A bit more than forty years earlier, on Monday morning, February 27, 1975, David Baltimore opened the famous Asilomar conference on recombinant DNA. That conference had been called after a letter in Science from the leaders in the field called for a moratorium on recombinant DNA research until important safety issues could be worked out. The three and a half days of the Asilomar meeting produced safety guidelines which led the group to lift their (totally informal and non- binding) moratorium – and ultimately led the NIH Recombinant Activities Committee; to federal (and foreign) biosafety regulations; in some tellings the wildly successful application of recombinant DNA techniques to research and medicine; and, undoubtedly, the most famous story in modern scientific self-regulation. (An excellent, non-speculative, memoir of the Asilomar meeting by George Frederickson, head of the Institute of Medicine at the time of Asilomar and director of NIH a few months later, can be found here (http://www.ncbi.nlm.nih.gov/books/NBK234217/%20).) The roughly 1400 words of the recent Science Policy Forum include the name “Asilomar” exactly once, in passing, even though two of its signers (and vocal advocates), David Baltimore and Paul Berg, were among the five organizers of the Asilomar meeting. They also include only limited discussion the statement’s origin and, more importantly, of its meaning. I was not one of the organizers of the meeting that led to the Policy Forum, though I did attend and participate in the meeting. Neither did I draft or wield a decisive editorial pen in the writing of the document, though I did have several opportunities to offer comments, which I did. (Some of them, I think, made it into the piece.) I can’t read the minds of the other authors, some of whom didn’t attend the meeting, but I can tell you a bit about my thinking, both on the document and on the underlying issues raised by advances in genomic editing. A Little Background on the Document On October 2, 2014, I got an email entitled “Invitation: Bioethics Workshop.” It came from Jennifer Doudna’s email account but was signed by Doudna, Mike Botchan, Jacob Corn, Ed Penhoet, and Jonathan Weissman (all of whom attended the meeting and signed the document). It also has a list of thirteen invitees, eight of whom ended up attending the meeting and signing the document. It invited me to a full day workshop on Saturday, January 24 in Napa Valley “to discuss the bioethical issues raised by the explosion in new genomic editing methods.” With some qualifications for calendar uncertainties, I said “yes!” https://law.stanford.edu/2015/04/04/of-science-crispr-cas9-and-asilomar/ 15-Dec-15 Of Science, CRISPR-Cas9, and Asilomar - Stanford Law School Page 2 of 8 Coincidentally, I was flying home from Dulles airport in Washington, D.C. in late October and ended up sitting next to Mike Botchan. We didn’t know each other, but, after some conversation that established he was a molecular biologist (he was carrying around a new molecular biology textbook) and I was a law professor who worked on bioscience issues (I recognized that it was a molecular biology textbook and knew some of the authors), he surprised me by asking “Is your name Henry Greely?” We spent the next several hours happily talking about a wide range of issues in biosciences, including but not limited to genomic editing. Also, at some point someone decided that Alta Charo and I should do an overview of the legal and regulatory framework, so the two of us corresponded and talked about dividing up that territory; otherwise, I arrived at the meeting without a lot more information about it. I have a nagging feeling that, at the meeting, we agreed the discussions would be confidential, so I won’t go into details. I don’t think my colleagues will be too upset if I let slip that the conversation on January 24 was lively – and, for me at least, great fun. Well before the end of the day, a consensus seemed to be emerging, one part of which was to move from “emerging” to “written down.” I got my first draft ((I think) of such a document on February 6 from Jennifer Doudna and, after quite a few revised versions (each with opportunities to comment), the final version was published on March 19. Changes were not usually discussed collectively, but most of the time they were understandable and unobjectionable, including the change to add a few authors who agreed with the document but had not attended the January meeting. By the way, thanks to California’s truly impressive drought, January 24 in Napa was warm, clear, and gorgeous, as was the 25th. The Carneros region doesn’t have the incredible natural beauty of Asilomar – though it is beautiful – but the weather was unbeatable. How I Interpret the Document All documents are ambiguous (at least, once lawyers read them). That’s particularly true of a collective writing enterprise done largely at a distance. I think there are three non-trivial possible ambiguities in this one. I will give my take on them, though without guaranteeing that all, or any, of my co-authors agree. First, what does the document seek to “strongly discourage”? [A]ny attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations. I read that as clearly encompassing “making babies” and to include “making babies” for enhancement purposes as well as disease prevention purposes. The “clinical application” there, I am confident, is in contradistinction to “research uses”, not to “non-clinical babymaking applications.” I think it just as clearly does not prohibit research on cells, cell lines, and tissues, even cells, cell lines, and tissues that could become part of the germline, such as human embryonic cell lines (hESCs), human induced pluripotent cell lines (hiPSCs), various more direct egg and sperm precursor cells, and even human eggs and sperm. To me, it is putting the modification into the germ line of what is or is intended to become a living human being that is our focus. (That is also what is widely banned, which the lawyers in the group argued should be – and was – noted in the recommendation.) This does still leave open a question about ex vivo human embryos. Some people – including some reasonable people – consider them human beings. Other people – also including some reasonable people – do not, either before implantation or at some point between implantation and just after birth. My own view is that ex vivo embryos are not human beings and so the recommendation does not apply to them, though I would, personally, at this point still discourage researchers from experimenting on them without substantial societal discussion. Second, is this only about human germline genomic modification? The paper, mirroring many of the authors, focuses almost exclusively on those issues, but only almost. There is a nod at the beginning to the fact that “in other organisms it provides methods to reshape the biosphere for the benefit of the environment and human societies.” As noted below, I think the implications of non-human uses are more pressing than human uses, but it is fair to say I did not win that argument. – at https://law.stanford.edu/2015/04/04/of-science-crispr-cas9-and-asilomar/ 15-Dec-15 Of Science, CRISPR-Cas9, and Asilomar - Stanford Law School Page 3 of 8 least in this paper (but I am stubborn). Issues around somatic cell genomic engineering are raised more directly, but, for my taste, are somewhat downplayed in this paper. Those uses, especially if they move beyond treatment to enhancement, will raise concerns. Third, is this only about CRISPR-Cas9? That’s the easiest one to answer: no. It’s about recent and likely future advances in genome engineering. CRISPR-Cas9 is the current leader in truly revolutionizing the field by making such editing cheaper, faster, and more accurate. It is an amazing and deeply important accomplishment. And it is, understandably, the focus in a paper from this group. But should some other genome engineering technology end up supplanting (or even supplementing) CRISPR-Cas9, the issues discussed in this paper will apply, at least a priori, with equal force. How I (Currently) See the Issues So in this section I’m constrained neither by confidentiality nor by my lack of knowledge of other people’s thoughts. And as I am only mildly constrained by prudence, I’ll give you my current thoughts on the issues raised by much more effective genomic engineering, in three tranches: human germline genomic modification, human non-germline genomic modification, and non-human genomic modification.