Practical Plan for Managing Human Germline CRISPR

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 gene editing 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.

ABCD Plan Human Germline Modification with CRISPR.
ABCD Plan Human Germline Modification with CRISPR.

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. 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.

4 thoughts on “Practical Plan for Managing Human Germline CRISPR”

  1. anonymous stem cell repairman

    Certainly the germ cells may have less ethical baggage, but then you’re working even more with population frequencies, i.e., screening a separate population and hoping for high enough correlation in the treated group.

    I am reminded of something Renee Reijo-Pera used in her talks: something to the effect of how lucky we are that we’re the pregnancies that took, that even without IVF, successful pregnancy is a kind of rare event (I hope I’m getting that right).

    So, we couple the targeting of a population that we may or may not be able to screen later with the low frequency of successful pregnancy with relatively low homology-directed repair efficiencies of CRISPR/Cas9 in embryo/zygote (I’m still working my way through the new Hidde Plough paper; I haven’t found yet the number of injected zygotes versus number of live pups with and without modification. It must be in there somewhere…), and we probably end up with a the combined probability of winning the lottery while being attacked by a shark and also getting hit by lightning (or some other such nonsense metaphor).

  2. anonymous stem cell repairman

    The interesting thing about all this to me (as someone who works in genome engineering, specifically, with iPS/primary cells) is that there appears to be no discussion of efficiency levels. It’s still good that this discussion is happening, but let’s think what would theoretically have to be done to modify a human embryo/slash germ cell:

    1) Identify target sequence in parent(s)
    -fairly straight forward, maybe expensive
    2) Identify that same target in embryos/germ cell
    -to me, this is where it gets tricky
    -germ cells may be just throwing darts blindfolded
    -embryos would have be done with whole genome sequencing
    -this itself would have ethical concerns, vis a vis the “perfect” embryo for
    3) Apply the gene editing/engineering technology
    -Here a microinjection would be done on a huge number of embryos/germ
    -here’s where we get into the efficiency part: even if you know the target sequence and you’re working with a homogeneous population (like the Eric Olson mdx correction paper), the efficiencies for getting what you want in anything resembling a primary cell are…not good is the most charitable way of putting it

    4) Then a whole lot more screening for “corrected”

    5) Then implantation and hope it works

    To me, the cost and the low efficiency are massively prohibitive, let alone the bioethical issues around this concept.

    Can you elaborate any on those rumors of papers in peer review, Paul?

    (my guess is they’re being carried out to lock down patentability, but I could be wrong)

    1. @anonymous stem cell repairman
      Your raise excellent points. This has not been discussed enough.
      Do you edit the 1-cell embryo or the germ cells in advance of IVF? What do you think repairman?
      Either way there would be very difficult challenges both technically (how much sequencing do you do at various stages, how do you handle the timing issues, etc.?) and from a bioethical perspective.
      It will be interesting for all of us in the community to see the approaches taken by the papers in review and to discuss them in detail once published.There are many questions. Did they do a systematic carefully planned and executed study or alternatively more of a seat of the pants, let’s get this done and be first, kind of strategy?
      Just as important–will journals treat these like any other paper in terms of review or require a more thorough bioethical and perhaps even highly technical (e.g. requiring sequencing by an independent lab?) review before considering publication?
      Unfortunately I cannot comment on them further at this time except to say I expect that we’ll see several before the end of the year and probably sooner than that, and that they will spark more debate.

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