Danger Ahead

It was 40 years ago when the fears began to surge. Scientists had visions of genetically bizarre creatures running loose and snatching children from backyards. There were worries that research laboratories were brewing pathogens that could become a planetary scourge. These weren’t scenarios from horror movies.

They were some of the wide-awake nightmares of molecular biologists, biochemists and biophysicists—spawned, notes Stanford bioethicist Christopher Thomas Scott, by enormous apprehension about the possible repercussions of recombinant DNA technology. 

The ability to alter DNA molecules, even to mix genes from different species, brought speculation about huge advances in knowledge as well as terrible mutations. And ultimately, adds Scott, about what might start as a misguided lab experiment but end up “escaping into natural populations of bugs, animals and humans.” 

The upshot, after extraordinary debate and reflection by leading scientists, including Stanford biochemist Paul Berg, was the establishment of effective safety guidelines and a gradual realization that the dangers had been exaggerated. Proof that the fears had been overimagined, Berg points out, rests in part with “the creation of zillions of recombinant organisms without a single example of any untoward outcome” during the subsequent decades.

But now another alarm is blaring. New DNA-editing technology seems to blur distinctions between science fiction and reality. Some implications have a stark clarity: prospects for thwarting vicious hereditary diseases, for example, or the plausibility of “designing” the characteristics of a baby, particularly with regard to appearance. Other factors, such as the scope of the experimental risks involved, invite description in almost cosmic terms. 

“It’s fair to say this is a significant juncture for all life on Earth,” observes Stanford law professor Hank Greely, ’74, a major voice on biomedical ethics. 

That juncture amounts to this: In just the last several years, the feasibility of altering genes in both humans and nonhuman species has taken a revolutionary leap. Research has jumped from DNA stitchwork in test tubes to the editing of cells in living organisms—genome engineering “you couldn’t even sort of think about doing 10 years ago,” explains Stanford associate professor Matthew Porteus, a pediatric stem cell biologist. It’s not clear how rapidly the science will progress, and skeptics point to an array of logistical hurdles that could relegate the biggest steps to the distant future. 

But biologist David Baltimore, former president of Caltech and a 1975 Nobel laureate in Physiology or Medicine, says, “What may seem to others to be far away seems to many of us to be around the corner.”

As a result, major ethical and social issues have arisen, particularly where human germ line editing is concerned. A germ line is the egg and sperm cells, which can produce embryos; genes, which are segments of DNA, can be edited in the egg and sperm or in the embryo. Editing the embryo is more of an ethical flashpoint, but either approach involves introducing changes that are heritable—transmissible to children and subsequent generations. 

Other controversies center on the justifications for gene-based therapies and the concept of enhanced humans who might be programmed for cosmetic or functional “improvements.” Media coverage hasn’t lacked for flair, with newsstand magazine covers proclaiming “We Can Now Engineer The Human Race” and that the time has arrived for “No hunger, No pollution, No disease” (amounting to “the end of life as we know it”). Another publication pronounced an era of “Editing humanity.” In the scientific world, of course, the conversation is far more circumspect.

Nevertheless, the U.S. scientific community will grapple with gene-editing issues at a summit in Washington, D.C., during the first three days of December. With Baltimore as chair, the organizing committee plans the event as a forum for international dialogue co-hosted by the National Academy of Sciences, the Royal Society (United Kingdom) and the Chinese Academy of Sciences.

Beyond the anxiety about the boundaries of conventional research, there is a lurking dread about rogue experiments, subversively conducted for biowarfare or recklessly undertaken by individuals playing Dr. Frankenstein in their garages. Such is the temptation of the latest DNA tools because of how disruptively easy they are to use. As noted by Porteus, MD ’94, PhD ’94, minimally experienced college students can now accomplish certain kinds of lab work that used to require the resources of a giant biotech company. This particular scientific revolution, declares Greely, is about the democratization of the technology, enabling “a vast increase in who can use it and how often it will be used.” With that come the perils of unhindered and unmonitored use.

How Safe, How Fair and How Voluntary

It's not easy to boil down Greely's ideas about human enhancement through bioengineering. He applies three overarching considerations--the degree of safety, the amount of social fairness and whether there's any element of coercion--and offers this scenario: "To me, bioethics is not just ethics, it's also law and politics and pragmatic reality. I think you've got a much better argument for doing it [genetic engineering] if there's a medical necessity. And frankly, I care more if there's a medical necessity. My general bias is to let people do what they want unless there's a good reason not.... But if the government wanted to say, 'No, you can't use it for enhancing purposes, even to make an HIV-immune kid,' I'm not going to march on Washington.... I could imagine a line that says, if you really need it for medical purposes to have healthy kids, and it's safe, you can do it. And we'll pay for it. Otherwise, no. Enforcing the 'otherwise no' could be tricky. But that's a compromise position I could see working."

Porteus, who did postdoctoral training under Baltimore, thinks garage projects will likely be too limited to pose a serious worry. Baltimore is unconcerned, saying the sense of threat wilts in the face of “what it takes to really do some of this stuff.” But Greely is restless, warning that the next wave of hackers may be out to crack the biosphere.

“I am a little worried about the kid in the garage trying to modify fruit flies,” says Greely. “Or mosquitoes. Or modifying E. coli. Or turning cowpox into smallpox. And, apart from the kid in the garage, the last one, the cowpox into smallpox, that’s pretty terrifying, actually, and I don’t see any way to fix it.”

Almost certainly not in the province of garage science is the designer baby, says Scott, MLA ’05, a senior research scholar at the Stanford Center for Biomedical Ethics. Not that it couldn’t be attempted, he notes, but it would entail an exceptionally elaborate effort from a group of people. “Having said that, we need to get a policy framework in place to help jurisdictions that might face this possibility.”

The DNA-editing technology provoking so much hubbub is known as CRISPR/Cas9. The first acronym describes sequences of DNA that appear in a certain pattern: clustered regularly interspaced short palindromic repeats. Cas9 refers to a CRISPR-associated protein. A simplified synopsis of how they can work together, taken in part from the Berkeley-based Innovative Genomics Initiative, likens them to a pair of biological scissors. Researchers use pieces of ribonucleic acid—guide RNAs—to direct different versions of Cas9  to locations within the genome where it can snip out genes, which can then be replaced with engineered substitutes. The process immediately conjures hope for overcoming conditions such as Huntington’s disease, a devastating brain disorder caused by an inherited defect in a gene.

As an editing system for experimental research, CRISPR/Cas9 gets raves for its ease of use. But it’s a tool, not a therapeutic treatment. And although it’s exceptionally good at taking directions about where to cut, that does not equate to reliably delivering successful results. 

The current imperfection of the tool parallels the imperfection of genomics science. Knowing how to use CRISPR/Cas9 is one thing; knowing how to use it for intentional, predictable and safe outcomes is another. The editing technology, as powerful as it is, exists in service to an understanding of genetics, which is still replete with unknowns that can give rise to unexpected or undesirable results. Given the excitement about CRISPR/Cas9 as a research boon, those uncertainties are increasing tension over how to balance the technology’s utility with a consensus about conscientious ambitions.

Who invented what regarding CRISPR/Cas9 is difficult to fully assess. Several researchers seem to have substantial claims, and several have been widely acknowledged or credited. Among them is Jennifer Doudna, a UC-Berkeley professor of biochemistry and molecular biology who galvanized ethical debates early this year by organizing a workshop in Napa, Calif. The attendees included Greely, Baltimore and Berg, a Nobel laureate in Chemistry and a pivotal figure in the landmark 1975 Asilomar conference convened to address the swelling angst over recombinant DNA experimentation. Amid echoes of the past, the goal in Napa was to compose a compelling position statement on the bioethical issues that have been ratcheted up by gene editing. 

The group ended up publishing a short paper in the journal Science expressing its key worries: “off-target alterations” and, perhaps more ominously, “on-target events that have unintended consequences.” In other words, unwanted and harmful changes instead of beneficial and curative adjustments. The paper concluded, “At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing.”

Probably the most routinely voiced objection to human germ line editing is the absence of consent from the unborn—plus their descendents, all of whom would be exposed to unforeseeable consequences, ranging from genetic complications to social stigma. To start with, any grievous miscalculation about the procedure’s safety could cause the birth of a misengineered person. “[If] you make an embryo that way,” says Greely, “and it turns into a baby who suffers or spends 90 years in terrible disability and pain, you should rot in hell.” There could also be mutations that show up only in later generations. And how will public attitudes evolve in the long term toward people who benefit from some measure of genetic engineering?

Even presuming adequate safety, Greely takes the consent issue seriously. But he doesn’t see it as a winning argument. After all, he reasons, “None of us volunteered to be born. And what’s the one thing as parents we can guarantee? That our children will die. We can’t guarantee they’ll be happy, we can’t guarantee they’ll be healthy, we can’t guarantee they’ll have a long life. So, it’s not new to bring kids into the world without their consent.”

An illustration of DNA strands, some of which cross to create the shapes of skulls.

Berg also rejects the consent factor. “I am mindful, as we all should be, of our current level of ignorance of the potential consequences of some germ line changes in future settings,” he says. But he also wishes “that we were as considerate of future generations by our willingness to respond to the long-term genetic consequences of climate change.” And he raises the point that, already, by prolonging the lives of people with serious diseases—who might otherwise never procreate—we “thereby doom future generations to the same genetic defects.”

A more volatile concern is that germ line engineering will foster an insidious form of eugenics, a concept of selective reproduction aimed at making improvements—or so-called improvements—to the human population by controlling what qualities are heritable. Largely because of the atrocities perpetrated under Nazi ideology, eugenics is closely linked with social and racial bias. Were genetic modification to become routine, would a preference for tall children mean that short people were construed as inferior? Would class skirmishes break out over economic access to enhanced traits? And what if the “market” favored blond hair and blue eyes? 

It’s a provocative topic, hence the media focus on aspects like designer children. It’s also a highly intricate subject; Greely and Harvard geneticist George Church are among those who call attention to how gray it could be to differentiate between augmentation and a preventive measure, such as added resistance to a disease. But the general sensitivity about the issue may be overwrought: Porteus has co-authored a journal piece asserting that the scientific complexity is such that “the advent of genome-editing technology alone is insufficient to lead to applications for nontherapeutic ‘designer’ purposes,” eye color being one example.

Berg points out that most traits “are the consequence of the action of many genes; for most complex traits the genes are unknown, and those few that show up in genome-wide association studies contribute only small effects. So trying to alter almost any trait in a predictable way is far beyond our current capabilities.” 

For many scientists, the questions of basic safety loom largest. Imperfect knowledge and technique stoke the fear of doing unintended harm. Much of the dialogue is being driven by nervousness over science flying too fast and too high on its CRISPR/Cas9 wings, perhaps only to crash and burn in some disturbing way. 

To be sure, not everyone shaping the field has that mind-set. Harvard’s Church is a seminal figure in the advent of CRISPR technology. He said by email that he’s “not convinced that CRISPR is pushing this faster than previously imaginable.” As for his own sense of fear, he wrote, “My group works on safety and security for many new technologies. We not only ‘worry,’ we work hard to address even unlikely risks. Using natural pathogens is currently more threatening than engineered ones—and CRISPR-based pathogens are even less likely. We need to protect ourselves better from natural and synthetic pathogens via cost-effective vaccines, quarantines and other preventive strategies.”

Church wasn’t present at the Napa workshop but signed on as the 18th co-author of the Science piece. The group’s top recommendation took clear note of the worldwide challenge, hoping to “strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans” before more extensive discussion takes place. 

In April, strong rumors turned into a published revelation: Chinese scientists had used CRISPR/Cas9 to edit a gene in a human zygote, the earliest stage of development for an embryo. The experiment is believed to be the first ever to attempt genomic engineering on human embryos, and for some it crossed a boundary and evoked dismay. But others were unruffled, given the full context of the experiment: The Chinese team used embryos formed in vitro in a way that rendered them incapable of developing into live beings. Plus, the work was not successful—it produced an array of off-target effects. For those who accepted the use of nonviable embryos as sufficient ethical restraint, the instructive value of the research stood out.

“I don’t see any ethical issues with the Chinese experiment,” says bioethicist Scott, who is also director of the Stanford University Program on Stem Cells in Society. “As for whether the research was intellectually beneficial, that’s a bigger science policy question that is open to debate. It did show shortcomings of the approach when used in human embryos, which seem to me to be questions worth asking. But those shortcomings were shown in animal studies that preceded it. So this raises the question of whether one attempts, and whether one publishes, a paper merely to show the technical feat in human embryos or [should] instead work out the problems first in animal studies before moving into what will be socially contentious research.”

Research on human embryos in the United States is severely constrained by an assortment of laws and organizational regulations. Clinical applications—which refer to the use of treatments, including biological products, in people—are prohibited without explicit approval from the Food and Drug Administration. There have been no approvals for the implantation of genetically modified embryos (or any other germ line modification therapy). Moreover, in late April, on the heels of the news from China, the National Institutes of Health reaffirmed its policy of denying funding for the use of gene-editing technologies in any human embryos. NIH director Francis Collins also cited federal law prohibiting the use of government funding for any research in which human embryos are destroyed, without distinction between viable and nonviable.

Hoover Institution fellow Henry Miller, a physician and molecular biologist, has written that he interprets the NIH ban to apply to any institution receiving any NIH support across a wide area of related research, making germ line therapy experiments off-limits “at any U.S. academic institution.” Baltimore thinks that private funding, particularly corporate funding, might suffice, or even be robust in enabling such work, where no other governmental restrictions apply. Still, the overall research constraints are formidable, and he adds, “What’s happening in the rest of the world might be more important than what’s happening in the United States.”

Sometimes obscured by the germ line tumult is the CRISPR/Cas 9 boost to the far less contentious realms of gene therapy that involve only somatic cells (non-germ line cells). Corrective editing of genes in somatic cells would affect only the patient at hand, without any multigenerational effect. Porteus’s work, for instance, uses solely somatic cells with the goal of solving sickle-cell disease. “The idea,” he explains, “would be to remove somatic blood stem cells from a patient who has the disease, fix the mutation and give back their own cells, so that they no longer have the disease. But because we’re only modifying the blood stem cells, if they had children, they would still be passing along the disease allele [which is either of a pair of genes] to their offspring.”

“Advancing the CRISPR technology to somatic gene therapy is the way to proceed for now,” says Berg. “Aiming for that will help improve the CRISPR technology and provide experience and devise different approaches to gene modification that might very well pave the road to more adventurous undertakings.”

Whose Principles?

"Many ethical frameworks have been developed through human history, ranging from those derived from sacred texts (e.g., the New and Old Testaments, the Quran, Buddhism, the teachings of the Pope or Confucius) and from different secular lines of thought (e.g., Utilitarianism, the Golden Rule of Kant, the 'veil of ignorance' of Rawls, the theory of justice of Sandel). Hence, a clear set of ethical principles must be used and defined so as to have a constructive discussion of the societal implications of genome editing of the germ line."

From a commentary by Matthew Porteus and Christina Dann in Molecular Therapy (2015); 23(6):980-982.

The CRISPR/Cas9 landscape gets more complicated when monetary interests—patent ownership and intellectual property rights, the involvement of academic researchers in commercial companies, agricultural and industrial implications—come into play. But the hot-button headlines continued to be about human embryo editing when British scientists announced in late September that they had asked for regulatory permission to do such research for learning purposes, with no attempt to create a baby.

The Hoover Institution’s Miller, who was the founding director of the FDA’s Office of Biotechnology, is a fierce dissenter to any call for a moratorium on germ line engineering. In a recent essay, he threw a jibe at the “Napa Conference cabal” as part of a larger broadside against excessive caution that will inhibit meaningful medical progress. In an interview with Stanford, Miller emphasized the potential for eliminating “horrendous” diseases, although he warned that new medical interventions typically begin haltingly and that early breakthroughs shouldn’t be expected.

If there’s one all-encompassing argument against germ line modification, it’s probably the absence of medical necessity. Stanford was told repeatedly that the conditions that germ line editing might fix can be attacked with equivalent efficacy through other means. 

It turns out, however, to be a nuanced point. Some of those other means also raise touchy issues. A person carrying the risk of passing along Huntington’s disease can avoid that through the in vitro creation of embryos that are then culled for ones that are illness-free. The problem flares—ethically, morally, religiously, socially or politically—with any later destruction of unused embryos.

Whatever transpires at the Washington summit, Baltimore and Porteus think physicians and scientists need to make sure they’re gathering and considering input from patients and their families. Porteus figures that his emphasis on patient advocacy is, well, in his DNA, at least on his MD side. “I just think that the voice of these people who have had to live with these diseases needs to be at the table. Do they trump everything else? Of course not. But I think they have to have a voice.”

Mike Antonucci is a senior writer at Stanford.