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.

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