The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

by Walter Isaacson

scientists attempting to regulate their own field: the four-day Asilomar conference of February 1975.

David Baltimore, who that year would win the Nobel Prize for his work showing that viruses containing RNA, such as coronaviruses, can insert their genetic material into the DNA of a host cell through a process known as “reverse transcription.”

Baltimore would go on to become president of Rockefeller University and then Caltech,

“The new techniques, which permit combination of genetic information from very different organisms, place us in an arena of biology with many unknowns,” they wrote. “It is this ignorance that has compelled us to conclude that it would be wise to exercise considerable caution in performing this research.” Then they described in detail the type of safeguards and restrictions that would be put on experiments.

The restrictions agreed to at Asilomar were accepted by universities and funding agencies worldwide. “This unique conference marked the beginning of an exceptional era for science and for the public discussion of science policy,” Berg wrote thirty years later. “We gained the public’s trust, for it was the very scientists who were most involved in the work and had every incentive to be left free to pursue their dream that called attention to the risks inherent in the experiments they were doing. Restrictive national legislation was avoided.”

But Chargaff’s mocking assessment pointed to another lasting legacy. Asilomar became notable for what the scientists did not discuss there. Their focus was on safety. None of them addressed the big ethical question, the one that Berg had stayed up late discussing in Sicily: How far should we go if and when methods of engineering our genes turned out to be safe?

Asilomar’s lack of focus on ethical issues bothered many religious leaders. That prompted a letter to President Jimmy Carter signed by the heads of three major religious organizations: the National Council of Churches, the Synagogue Council of America, and the U.S. Catholic Conference. “We are rapidly moving into a new era of fundamental danger triggered by the rapid growth of genetic engineering,” they wrote. “Who shall determine how human good is best served when new life forms are being engineered?”

These decisions should not be left to scientists, the trio argued. “There will always be those who believe it appropriate to ‘correct’ our mental and social structures by genetic means. This becomes more dangerous when the basic tools to do so are finally at hand. Those who would play God will be tempted as never before.”

Carter responded by appointing a presidential commission to study the issue. It came back in late 1982 with a 106-page report titled Splicing Life that ended up being inconclusive mush. It merely called for further dialogue to reach societal consensus.

The commission’s report did raise two concerns that were prescient. The first was a fear that genetic engineering was leading to increased corporate involvement in university research.

The second concern was that genetic engineering would increase inequality.

Preimplantation diagnosis involves fertilizing an egg with sperm in a Petri dish, doing tests on the resulting embryosI to determine their genetic characteristics, and then implanting into a woman’s womb the embryo with the most desired traits. It allows parents to choose the gender of their child and avoid having a child who carries a genetic disease or some other attribute the parents find undesirable.

1997 film Gattaca (the title is made up of the letters of the four DNA bases),

French Anderson, a leader in using genetic engineering to create drugs, gave a mini-sermon on the need to distinguish between treating diseases, which he proclaimed to be moral, and providing children with genetic enhancements, which he said wasn’t. Watson began to snort and stir. “No one really has the guts to say it,” he interrupted, “but if we could make better human beings by knowing how to add genes, why shouldn’t we do it?”

The title of the gathering was “Engineering the Human Germline,” and it focused on the ethics of making genetic edits that would be inherited. These “germline” edits were fundamentally different, medically and morally, from somatic-cell edits that affect only certain cells in an individual patient. The germline was a red line that scientists had been reluctant to cross. “This is the first gathering where people have talked openly about germline engineering,” Watson said approvingly. “It seems obvious that germline therapy will be much more successful than somatic-cell edits.

Lee Silver, a Princeton biologist, had just published Remaking Eden, which became a manifesto for the conference. He had coined the word “reprogenetics” to describe the use of technology to determine which genes a child would inherit.

“For the first time we as a species have the ability to self-evolve,” Silver told the group. “I mean, this is an incredible concept.” He meant the word “incredible” to be a compliment.

Watson argued. The attendees accepted that view. “No state or federal legislation to regulate germline gene therapy should be passed at this time,” organizer Gregory Stock wrote in his summation.

Stock went on to write a pro-editing manifesto, Redesigning Humans: Our Inevitable Genetic Future. “A key aspect of human nature is our ability to manipulate the world,” he argued. “To turn away from germline selection and modification without even exploring them would be to deny our essential nature and perhaps our destiny.” He emphasized that politicians should not try to interfere. “Policymakers sometimes mistakenly think that they have a voice about whether germinal technologies will come into being,” he wrote. “They do not.”

American enthusiasm for genetic engineering was a sharp contrast to the attitude in Europe, where policymakers and various commissions had increasingly turned against it, both in agriculture and in humans. The most notable expression came from a meeting convened by the Council of Europe in Oviedo, Spain, in 1997. The resulting Oviedo Convention was intended to be a legally binding treaty designed to prohibit the use of biological advances in ways that threatened human dignity. It barred genetic engineering in humans except “for preventive, diagnostic or therapeutic reasons and only where it does not aim to change the genetic make-up of a person’s descendants.” In other words, no germline editing. Twenty-nine European countries incorporated the Oviedo Convention into their laws, with Britain and Germany being notable holdouts. Even where it was not ratified it helped shape what is still a general consensus in Europe against genetic engineering.

Jesse Gelsinger The optimism among American researchers about genetic engineering was deflated in September 1999 by a tragedy that happened in Philadelphia to a sweet, handsome, and slightly rebellious eighteen-year-old high school student. Jesse Gelsinger suffered from a mild form of a disease of the liver caused by a simple genetic mutation.

Gelsinger had a massive immune response caused by the virus transporting the therapeutic gene, which resulted in a high fever followed by the breakdown of his kidneys, lungs, and other organs. In four days he was dead. Work on gene therapy ground to a halt. “We were all very much aware of what happened,” Doudna recalled.

Kass is the most influential of the country’s bioconservatives, the ethical traditionalists with a knowledge of biology who urge restraint when dealing with new genetic technologies. The son of secular Jewish immigrants, he earned a biology degree at the University of Chicago, where he was deeply influenced by its “great books” core curriculum. He got a medical degree from Chicago and a PhD in biochemistry from Harvard. With his wife, Amy, he went to Mississippi in 1965 as part of the cadre of civil rights workers registering Blacks to vote, an experience that reinforced his faith in traditional values. “In Mississippi I saw people living in perilous and meager circumstances, many of them illiterate, but sustained by religion, extended family and community attachment,” he recalled.

After reading Huxley’s Brave New World, he became more interested in “how the scientific project to master nature could, if we are not careful, lead to our dehumanization.”

“I soon shifted my career from doing science to thinking about its human meaning,” he wrote, “worrying about upholding our humanity against possible technological degradation.”

Michael Sandel, a Harvard professor

essay titled “The Case Against Perfection: What’s Wrong with Designer Children, Bionic Athletes, and Genetic Engineering,” which he published in The Atlantic in 2004.27

310-page report, Beyond Therapy, was thoughtful, vibrantly written, and filled with qualms about genetic engineering. It warned of the dangers of using technology to go beyond merely treating diseases to using it to enhance human capabilities. “There are reasons to wonder whether life will really be better if we turn to biotechnology to fulfill our deepest human desires,”

Focusing mainly on philosophical rather than safety concerns, the authors discussed what it meant to be human, to pursue happiness, to respect nature’s gifts, and to accept the given.

Gene-editing technology had enormous power to do good, but the thought of using it to make alterations in humans that would be inherited by all future generations was unnerving. “Have we created a toolbox for future Frankensteins?” she asked herself. Or perhaps even worse, would it be a tool for future Hitlers?

She had already registered the domain name HealthyBabies.com.

As a result of her Hitler dream and Sternberg’s Happy Healthy Baby story, Doudna decided in the spring of 2014 to become more engaged in the policy discussions about how CRISPR gene-editing tools should be used.

At Asilomar the discussions had been mostly about safety, but Doudna made sure that the Napa conference tackled the moral questions: Did the premium that America put on individual liberty require that decisions about gene-editing of babies be left mainly to parents? To what extent would creating gene-edited babies—and abandoning the idea that our genetic endowments came from a random natural lottery—undermine our sense of moral empathy? Was there a danger in decreasing the diversity of the human species? Or, to frame the question from a more bioliberal perspective: If the technology was available to make healthier and better babies, would it be ethically wrong not to use it?

consensus quickly developed that it would be bad to completely ban germline gene editing. The participants wanted to leave the door open. Their objective became similar to that of Asilomar: finding a path forward rather than putting on the brakes. That would become the theme of most subsequent commissions and conferences organized by scientists: it was too early to do germline editing safely, but someday it would happen, and the goal should be to provide prudent guidelines.

Baltimore warned of a development that made this Napa meeting different from the Asilomar one forty years earlier. “The big difference today is the creation of the biotechnology industry,” he told the group. “In 1975, there were no big biotechnology companies. Today, the public is concerned about commercial development, because there’s less oversight.” If the participants wanted to prevent a popular backlash against gene editing, he said, they would have to convince people to trust not only white-coated scientists but also commercially driven corporations. That could be a tough sell. Alta Charo, a bioethicist at the University of Wisconsin Law School, pointed out that the close relationship between academic researchers and commercial companies could taint the credibility of the academics. “Financial interests undermine the ‘white coat’ image of scientists today,” she said.

The group agreed that the use of CRISPR tools for non-inheritable gene editing in somatic cells was a good thing.

In the end, they decided to call for a temporary halt on germline editing in humans, at least until the safety and social issues could be further understood. “We wanted the scientific community to hit the Pause button until the societal, ethical, and philosophical implications of germline editing could be properly and thoroughly discussed—ideally at a global level,” Doudna says.

Our conference would do just that. Examine the philosophical, ethical & moral implications.

Science. It was titled “A Prudent Path Forward for Genomic Engineering and Germline Gene Modification.”

The report clearly defined what was meant by “germline editing” and why crossing that threshold would be a major ethical as well as scientific step. “It is now possible to carry out genome modification in fertilized animal eggs or embryos, thereby altering the genetic makeup of every differentiated cell in an organism and so ensuring that the changes will be passed on to the organism’s progeny,”

“The possibility of human germline engineering has long been a source of excitement and unease among the general public, especially in light of concerns about initiating a ‘slippery slope’ from disease-curing applications toward uses with less compelling or even troubling implications.”

researchers at a university in Guangzhou described how they used CRISPR-Cas9 in eighty-six non-viable zygotes (precursors to an embryo) to cut out a mutated gene that causes beta thalassemia, a deadly blood disorder like sickle-cell anemia.10 Although the embryos were never intended to be grown into babies, a line had been toed, if not crossed. For the first time, CRISPR-Cas9 had been used to make potential edits in the human germline, ones that could be inherited by future generations.

“That application of the technology needs to be on hold pending a broader societal discussion of the scientific and ethical issues.”11

Doudna and Church wrote back-to-back pieces in Nature presenting their perspectives on making inheritable gene edits. Although their positions conflicted to some extent, they reinforced the case that scientists were dealing with the issues seriously and did not require new government regulations. “Opinion on the use of human-germline engineering varies widely,” Doudna wrote. “In my view, a complete ban might prevent research that could lead to future therapies, and it is also impractical given the widespread accessibility and ease of use of CRISPR-Cas9. Instead, solid agreement on an appropriate middle ground is desirable.”13 Church was more forceful in arguing that research, even in editing the human germline, should continue. “Rather than talk about the possibility of banning alteration of the human germline, we should instead be discussing how to stimulate ways to improve its safety and efficacy,” he wrote. “Banning human-germline editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism.”

Steven Pinker. “The primary moral goal for today’s bioethics can be summarized in a single sentence,” he wrote in an op-ed for the Boston Globe. “Get out of the way.” He took a brutal swipe at the entire profession of bioethicists. “A truly ethical bioethics should not bog down research in red tape, moratoria, or threats of prosecution based on nebulous but sweeping principles such as ‘dignity,’ ‘sacredness,’ or ‘social justice,’ ” he argued. “The last thing we need is a lobby of so-called ethicists.”15

A representative from Peking University assured the audience that China had in place safeguards to prevent germline gene editing: “The manipulation of the genes of human gametes, zygotes, or embryos for the purpose of reproduction is prohibited.”

Because there were so many participants and journalists, the meeting consisted mainly of canned presentations rather than real debate.

Among the conditions the group adopted was that germline editing should not proceed until “there is broad societal consensus about the appropriateness of the proposed application.”

“broad societal consensus” was one that would be invoked often in discussions of the ethics of germline editing, as if a mantra.

it omitted one key restriction that was in the 2015 international summit report. There was no longer any mention of the need for a “broad societal consensus” before inheritable gene-editing would be permitted. Instead, the 2017 report called only for “broad ongoing participation and input by the public.” Many bioethicists were dismayed,

In Britain, the Nuffield Council, the nation’s most prestigious independent bioethics organization, produced a report in July 2018 that was even more liberal. “Genome editing has the potential to give rise to transformative technologies in the field of human reproduction,” it concluded. “So long as heritable genome editing interventions are consistent with the welfare of the future person and with social justice and solidarity, they do not contravene any categorical moral prohibition.” The Council even went so far as to diminish the distinction between using gene editing to cure diseases and using it to provide genetic enhancements. “It is possible that genome editing could be used in the future for… enhancing senses or abilities,” the guide to the report read. The report was seen, correctly, as paving the way for human germline gene editing. The headline in the Guardian was “Genetically Modified Babies Given Go Ahead by UK Ethics Body.”