CRISPR germline editing reverberates through biotech communityCRISPR, crispr genome editing system | CRISPR, crispr genome editing system
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Jennifer Doudna, Professor of Chemistry..........

The organizers of a recent meeting in Napa, California, to consider the broad societal implications of clustered, regularly interspaced, short palindromic repeats (CRISPR) genome editing have succeeded in their primary goal of stimulating public debate on the ethical issues raised by the technology. Although the event, held on January 24, took place behind closed doors, a subsequent commentary from its leading participants—plus two influential non-attendees, George Church of Harvard Medical School in Boston, and Martin Jinek of the University of Zurich—prompted widespread media coverage (Science 348, 36–38, 2015). The group has called for a broadly based discussion of the potential merits and risks of the technology and a global moratorium on germline applications, until such time, if ever, responsible uses can be identified.

But the declaration, along with a high-profile commentary in The Wall Street Journal on April 9 from David Baltimore and Paul Berg, two veterans of the 1970s debates on genetic engineering, has already altered the social context in which new developments in the field will be received. Any scientist or organization that crosses the ethical Rubicon by conducting human germline engineering experiments will now face a considerable level of opprobrium. “I doubt the unsanctioned use will happen soon,” says Nobel laureate Craig Mello of the University of Massachusetts Medical School, in Worcester, and a scientific founder of Basel-based CRISPR Therapeutics. “It’s not something that’s going to be easy, cost-effective or safe, given existing technology.”

The Napa event was by no means representative of all the main players in CRISPR-Cas9, however, which leaves its main organizer, the Innovative Genomics Initiative at the University of California, Berkeley, open to criticism that it is attempting to set the agenda without first building a broad front within the scientific community and beyond. “I do think it’s a discussion the community should have—not just the West Coast community,” says Rodger Novak, CEO and co-founder CRISPR Therapeutics, whose scientific founder, Emmanuelle Charpentier, is, along with Berkeley’s Jennifer Doudna, co-inventor of the technology. At the same time, there is no evidence of a rift opening up between those who attended and those who did not. “I don’t feel slighted in any way,” says Mello. “Anything that raises awareness is important.”

The cluster of companies working with CRISPR-Cas9 shares a common goal in ensuring that the technology gains public and regulatory acceptance and avoids the kind of backlash that would halt its development. All of them are proceeding cautiously. “The promise is so exciting, nobody wants to take the step that would undermine that promise,” says Katrine Bosley, CEO of Cambridge, Massachusetts–based Editas Medicine. Although individual companies are keeping details of their development programs under wraps for now, the present focus is on therapies that target somatic cells, most likely in ex vivo settings initially. “Germline, from an industry perspective right now, is a no,” says Novak. Nessan Bermingham, CEO of Cambridge-based Intellia Therapeutics, echoes the point. “We are not doing any germline modification—it is not in our business plan, nor is there any [such] plan at all.” Clinical trials involving therapies based on CRISPR-Cas9 have not yet started, but the research effort is moving ahead quickly. “I would be disappointed if we didn’t see something in the clinic three years from now,” says Novak. It could happen even sooner.

Whether CRISPR-Cas9 should be singled out for special attention is open to debate. It is not the first genome editing technology to emerge. Meganucleases, zinc finger nucleases (ZFNs) and transcription activator–like effector nucleases (TALENs) all preceded it. Sangamo Biosciences, of Seattle, is conducting trials of a ZFN-based therapy in HIV patients at present. What’s more, together with other researchers, Ed Lanphier and Fyodor Urnov from Sangamo authored a Comment in Nature (Nature 519, 410-411, 2015)calling for a moratorium on genome editing of the human germline. What distinguishes CRISPR-Cas9 from the earlier technologies is its accessibility, its ease of use and its low cost. Germline engineering with the technology, although not trivial, is feasible in a well-equipped molecular biology laboratory. “Something that was pretty much theoretical before now is now facing us,” says Bosley.

Policing the use of the technology is practically impossible. “One cannot control what’s happening in China, for example,” says Intellia’s Bermingham. Rumors are swirling through the research community that at least one laboratory may already have conducted human germline experiments—and that papers describing the process have been submitted to journals or published.

André Choulika, CEO and founder of Paris-based genome editing firm Cellectis is not convinced that the advent of CRISPR-Cas9 creates any new problems, however. “CRISPR is essentially a revolution because it makes gene editing accessible to any researcher—that’s all,” he says. Cellectis plans to complete an investigational new drug filing this year of allogeneic chimeric antigen receptor T-cells engineered using TALENs. “I think you could do germline changes with zinc finger nucleases, TALENs or meganucleases,” he says. The current explosive uptake of CRISPR-Cas9 in academic laboratories will not necessarily be replicated in clinical settings, he argues. “Once you want to push the technology into therapeutic applications—you want to be super-specific, you don’t want off-target effects—then it becomes far more challenging.” Ethical discussions, he suggests, are best left to those who are qualified to engage in them. “We are scientists, not philosophers.”

The Napa meeting has obvious resonances with the historic 1975 Asilomar conference on recombinant DNA, which set the agenda for managing the then poorly understood risks associated with genetic engineering. Paul Berg from Stanford University and David Baltimore, at Caltech in Pasadena, embodied that link by attending the Napa meeting and lending their names to the present campaign to prevent germline experiments. Science historian Susan Wright, who is currently based at the University of California, Santa Cruz, is author of Molecular Politics (Univ. of Chicago Press, 1994), a detailed account of the development of genetic engineering policy in the US and the UK. She is critical of any interpretation of the stance taken at the Asilomar meeting as “a noble act of self-sacrifice.” Its real focus, she says, was to shape consensus around how the technology would be used.

Forty years on, industry interests are more powerful, but the ethical stakes are higher than ever, and the uncertainty surrounding the long-term applications of the technology is genuine. The prospect of rogue laboratories operating in unregulated jurisdictions is not difficult to imagine. “We live in a world where female fetuses are routinely aborted, because the societies where that happens place a higher value on males,” says Ron Cohen, CEO of Acorda Therapeutics, of Ardsley, New York, and vice chair of the Biotechnology Industry Organization of Washington, DC (BIO)’s health section, who stresses he was speaking in a personal capacity. BIO is still formulating a policy on the area. For now, it states that “it is imperative” that the scientific community joins in an “open public discourse” to consider the responsible use of the technology.

In the meantime, the companies that are actively engaged with the technology have their hands full of routine work focused on establishing the safety profile of the technology in noncontroversial settings. “A large part of the work that’s been done has been documenting how frequently the off-target events occur,” Mello says. Different ways of monitoring and minimizing these events have started to emerge, not all of which have been published as yet. “I’m aware of several that are promising,” Mello says.

In the long term though, there is a possibility of germline applications (Box 1).  Would it be unethical not to fix something if you could?” he asks. “If it were very safe, wouldn’t it be wrong not to?” But it will take a very long time—and significant research on CRISPR-Cas9 and on disease biology—to be in a position even to contemplate those questions.

Cormac Sheridan, Dublin

Box 1. OvaScience IVF offerings stuck in regulatory limbo

Some companies working on infertility treatments have already started combining their platforms with genome engineering approaches. In December 2013, OvaScience a Cambridge, Massachusetts–based biotech working on next-generation in vitro fertilization technologies formed a joint venture with synthetic biology company Intrexon of Germantown, Maryland. Under the OvaXon Joint Venture the companies agreed to combine OvaScience’s EggPC (egg precursor cells: immature egg cells found inside the protective ovarian lining) platform with Intrexons’s genome engineering capabilities to prevent inherited diseases in humans, such as mitochondrial and other genetic disorders.

In its advertised offerings for fertility clinics, OvaScience is not employing CRISPR-Cas9—or any other form of genetic engineering—at present. Even so, the company has hit regulatory barriers in its efforts to translate controversial new insights on oocyte biology into fertility treatments.

The company was founded in 2011 to commercialize the research of co-founder Jonathan Tilly, then of Harvard Medical School, who is now chair of the biology department at Northeastern University in Boston. Over a decade ago, Tilly and colleagues identified putative immature egg precursor cells in the ovaries of juvenile and adult mice, a finding at odds with a central dogma of mammalian biology—that the supply of eggs is fixed at birth. (Nature 428, 145–150, 2004). The science remains disputed, but Tilly’s group and others have since reported the same observations in humans (Reprod. Sci. 20, 7–15, 2013). Moreover, OvaScience plans to roll out a treatment based on this concept to women undergoing in vitro fertilization (IVF) later this year. It aims to boost women’s egg reserves by transferring egg precursors—oogonial stem cells—from the lining of the ovary to its interior, where maturation to a viable egg cell can take place. The procedure, dubbed OvaPrime, will not be available in the US, however.

OvaScience’s initial offering, Augment—a process intended to improve the energy status of eggs used in IVF procedures by supplementing them with mitochondria derived from oogonial stem cells—has already run into a regulatory barrier. In 2013, the US Food and Drug Administration (FDA) informed the company it needed to file an investigational new drug application for the procedure, whereas OvaScience claims Augment is eligible for use as a 361 HCT/P, meaning it is covered by the FDA’s Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s) Product List and Section 361 of the Public Health Service Act.  Randomized clinical trials are not the norm in the fertility sector. “People are attempting to apply a high level of scientific rigor to an area that is not accustomed to it,” says Andrew Fein, analyst at HC Wainwright & Co. in New York.  

In the meantime, Augment is available in four territories only, Canada, Dubai, the UK and Turkey. As Nature Biotechnology went to press, the first baby conceived through the Augment process was due to be born. “The way the company foresees this playing out is after a few years of positive experience ex-US—US-based women will ask or essentially lobby the FDA for access to this technology,” Fein says. The example of egg freezing offers a precedent. “Demand in the US dictated its availability in the US,” he says.

David Sinclair, another scientific founder of OvaScience, alluded to the potential of CRISPR-Cas9 in germline engineering at an investor presentation, Fein says, but it is not part of the company’s research agenda at present. “They have enough headaches at this point without adding fuel to the fire.”

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