March 14, 2016
THE CRISPR CONUNDRUM
A powerful new genetic technique comes with possibly grave dangers
JOHN J. MILLER
Pasadena, Calif. — ‘I’ve seen revolution after revolution in biology,” says David Baltimore, a 77-year-old scientist who has had one of the brightest careers in his field. “This one is a big deal.”
He’s talking about CRISPR, which may sound like a drawer in your refrigerator but in fact refers to a new gene-editing technique whose acronym could become its own word, as familiar in the future as “radar” and “laser” are today. Its full name is gibberish to most people: “clustered regularly interspaced short palindromic repeats.” Its possible effects, though, are easy to understand. In December, Science hailed CRISPR as its “breakthrough of the year,” announcing that it promises to do everything from wiping out diseases to creating super crops. “In short,” said Science, “it’s only slightly hyperbolic to say that if scientists can dream of a genetic manipulation, CRISPR can now make it happen.”
Yet these dreams could turn to nightmares if they involve the genetic manipulation of people. “That’s an obvious application of the technology,” says Baltimore. It raises the specter of Dr. Frankenstein’s wild experiments and the eugenic goal of designer babies. In an article on CRISPR last year, MIT Technology Review wrote of labs in which “man rebuilds creation to suit himself” and warned of “a path toward a dystopia of superpeople.” From these accounts, it would seem that Aldous Huxley’s creepy totalitarian vision in Brave New World looms as never before.
For much of the last year, Baltimore has devoted himself to organizing his fellow scientists in an ad hoc campaign to fend off these dark possibilities. It culminated in December, when he convened a major conference for the National Academy of Sciences (NAS). Baltimore and his allies urged researchers around the world not to proceed “in purposefully altering human evolution.” At the same time, they believe that CRISPR may hold the valuable potential to fight hereditary diseases, so they stopped short of calling for the broader moratorium that some have demanded.
A respected scientist who is also a veteran of political rumbles, Baltimore may be the ideal person to direct this effort. The native New Yorker was a prodigy who knew from boyhood that he would spend his life in science. “I wanted to learn about the world, to live on the edge of knowledge,” he says. As an undergraduate at Swarthmore, he developed an interest in molecular biology. Because Swarthmore didn’t offer any courses on the subject in the 1950s, he designed and taught his own.
He earned his doctorate at 26, worked at the Salk Institute in California, and then joined the faculty of MIT. The Nobel Prize in Medicine commonly caps off careers, going to people as they near the end of their professional lives. Baltimore won it in 1975, when he was just 37, for work that he had finished five years earlier. Baltimore and two others shared that year’s award “for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell.” By the 1980s, he was not just a first-rate researcher but also a builder and leader of institutions. He launched the Whitehead Institute for Biomedical Research, in Massachusetts, and went on to be appointed president of Rockefeller University, in New York City.
Around this time, Representative John Dingell (D., Mich.) dragged Baltimore in front of his congressional committee, which oversaw federal science grants. Baltimore stood accused of covering up the alleged scientific fraud of a colleague. “The Baltimore case is reminiscent of the Watergate scandal,” glowered an editorial in the New York Times. Baltimore resigned from Rockefeller’s presidency, but he refused to admit wrongdoing — and in 1996, after a decade of adversity and legal bills, a special panel exonerated him. “When it’s time to hold a bridge, I want David Baltimore in my foxhole,” wrote Paul Gigot of the Wall Street Journal, who covered the ordeal. His reputation restored, Baltimore went on to serve as president of the California Institute of Technology for nearly a decade. Today he’s a professor on its faculty, working on the third floor of a laboratory building, in a small office he has decorated with the modern art of Damien Hirst and Michael Kenna.
Baltimore first learned of CRISPR about three years ago, in conversations with other molecular biologists. “I saw its importance right away,” he says. Although much of the groundbreaking work had been done in mice, he knew its lessons could apply to humans. One basic and uncontroversial type of therapy would involve somatic cells, which are the ordinary cells of the body. Editing these would affect only the person whose body contains them. Germline cells, however, are another matter. These are the egg and sperm cells that generate offspring — and editing them with CRISPR would shape human inheritance.
Instead of the future, Baltimore’s thoughts turned to the past — specifically, to a 1975 conference that usually goes by the shorthand name of “Asilomar,” after the facility near Monterey, Calif., that hosted it. Back then, researchers were just learning about the gene-splicing power of recombinant DNA, as well as confronting widespread concerns about mad scientists’ hatching deadly plagues in their test tubes. If the literary touchstone of CRISPR is Brave New World, then for Asilomar it was Michael Crichton’s popular 1969 novel The Andromeda Strain.
With several others, Baltimore called on scientists to police themselves, building public trust through transparency and allowing regulators time to develop sensible policies. Yet Baltimore says he always knew scientists would have to confront the challenges posed by Huxley’s novel, which he had read as a teen. “The history of our field teaches that the inconceivable becomes conceivable,” says Baltimore. “At Asilomar, we had identified the genetic modification of humans as the biggest coming issue. We just didn’t know when it would come.”
When it came in the form of CRISPR, Baltimore hesitated to throw together a new Asilomar conference. “I thought younger people might do it,” he says. One of those younger people was Jennifer Doudna, a geneticist at UC Berkeley who had helped discover CRISPR. Through a mutual friend — the scientist Michael Botchan, also of Berkeley — she contacted Baltimore and invited him and a handful of others to a small meeting at a hotel in Napa Valley early in 2015. Their group discussed the implications of CRISPR and began to draft a statement, which appeared in the April 3 issue of Science. It spoke of “the promise of curing genetic disease” but also warned of “unknown risks to human health and well-being.” Then it put forth a proposal: “We recommend that steps be taken to strongly discourage . . . any attempts at germline genome modification for clinical applications in humans.”
The statement listed 18 authors, with Baltimore at the top. “I thought Doudna should have been the first signer,” says Baltimore. Yet Doudna insisted on an alphabetical ordering, which had the perhaps intended effect of making Baltimore look like the leader. Soon he started to act like one. With fellow Nobel laureate Paul Berg of Stanford, he wrote an op-ed for the Wall Street Journal: “Let’s Hit ‘Pause’ Before Altering Humankind.”
Days later, as if on cue, scientists at Sun Yat-sen University in China published the results of a controversial study in which they used CRISPR to alter the genome of human embryos. The research, meant to investigate the possibilities of CRISPR, was performed on selected embryos that had a chromosomal defect that rendered them unviable. The Chinese research revealed that CRISPR, despite its potential, is still a young technology that often doesn’t work properly, leaving it a long way from practical applications in people. Yet the event demonstrated that Baltimore’s concerns had moved out of the realm of science fiction and into scientific reality. “There are no borders around this technology,” says Baltimore.
Before the month was over, Francis S. Collins, director of the National Institutes of Health, pledged not to “fund any use of gene-editing technologies in human embryos,” calling it “a line that should not be crossed.” A few weeks later, John P. Holdren, President Obama’s chief science adviser, declared: “The administration believes that altering the human germline for clinical purposes is a line that should not be crossed at this time.”
In the debates over gene editing, “lines that shouldn’t be crossed” is everyone’s favorite metaphor. Where would Baltimore draw them? “There may be things we should just say no to, but until I have a precise proposal in front of me, I don’t know what those limits are,” he says. “Right now, we need an international, voluntary consensus, from a highly respected process.” He thinks it would be a mistake to rule out anything — and wise to proceed with extreme caution.
Baltimore had hoped that the NAS might sponsor the equivalent of a new Asilomar conference. When the NAS did and asked him to lead it, he reluctantly agreed. In December, an international group gathered in Washington, D.C., under the aegis of the NAS as well as the Royal Society of London and, notably, the Chinese Academy of Sciences. “The overriding question is when, if ever, we will want to use gene editing to change human inheritance,” said Baltimore, as he opened the deliberations.
“We did not answer the question — that’s still in front of us,” says Baltimore now. “To answer it, we would have had to make a lot of assumptions and decisions that we didn’t want to make. We wanted to open a discussion, not close it.” Yet he also intended the conversations to reflect certain perspectives. Speakers included Yale historian Daniel J. Kevles, author of In the Name of Eugenics, the definitive account of the movement to improve humanity through supposedly better breeding. “I wanted him to remind us of the historical context,” says Baltimore. “People may not know how popular eugenics once was, when some of the best scientists believed in it. Just because we can do it with more foresight and precision today doesn’t mean it’s a good thing.”
As the conference closed, Baltimore released a new statement that tried to balance the fear of eugenics with the hope that CRISPR could improve the human condition: “It would be irresponsible to proceed” with germline modification without first having worked out basic questions of safety, or having achieved a “broad societal consensus” about the application. “At present, these criteria have not been met.” In the future, though, that could change: “As scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.” The statement carries no legal or regulatory authority. “It’s an act of moral suasion,” says Baltimore. “It worked at Asilomar and it can work here.”
Some complain that it doesn’t go far enough. In May, Robert Pollack of Columbia University wrote to Science: “I do not think anything short of a complete and total ban on human germline modification will do.” He warned of “the beginning of the end of the simplest notion of each of us being ‘endowed by our Creator with certain inalienable rights.’” Marcy Darnovsky of the Center for Genetics and Society accused Baltimore of having “kicked the can down the road” and called on the United States to outlaw germline editing.
Gene editing makes a hash of ordinary political labels. Pollack calls himself liberal and Darnovsky calls herself progressive, but they also might be labeled genetic reactionaries who seek to halt innovation. They’re opposed by genetic radicals such as John Harris of the University of Manchester and Julian Savulescu of Oxford University, who argue that the genetic enhancement of the human species is a moral obligation. Their school of thought is sometimes dubbed “transhumanism.”
Baltimore, who is a liberal in the conventional sense, prefers what might be called, in this context, a conservative approach. “We didn’t want to ban anything or make permanent decisions about anything,” he says. “If we had banned research into recombinant DNA in the 1970s, we wouldn’t have modern biology — and that means we wouldn’t have all of the treatments and drugs that have helped us fight cancer and heart disease, increase lifespans, and improve the quality of life for so many people.”
CRISPR may yet do the same, allowing scientists to reach inside the human genome and cure diseases before they’re passed on to new generations. “If we could keep a child from inheriting Huntington’s disease, for instance, would we want to do that?” asks Baltimore. “Maybe we would. At the very least, we should talk about it.”
What about another kind of gene editing, which aims not to alleviate suffering but to offer voluntary enhancements? “When people talk about altering genes to make children taller or smarter, they’re talking about whole sets of genes that work together. We don’t even know how to define intelligence, let alone how to increase it through genetic therapy,” says Baltimore. Selecting for eye color might be easier. Should parents pick brown or blue for their kids? This gives him pause. “If everybody wanted blue-eyed children, we’d lose some of the beauty of the human race.”
Before CRISPR allows these choices, it will force us to consider other questions that are perhaps only slightly less vexing. One current idea involves using CRISPR to refashion mosquitoes so that they cannot spread malaria or the Zika virus and then releasing these genetically modified insects into the wild, reshaping the species in a way that holds obvious benefits for people in the developing world but also poses unknown risks for ecosystems.
Eventually, though, the questions will turn back to whether and how we’ll use genetic technologies on people. “Brave New World is not a novel about science,” says Baltimore. “It’s a novel about politics and the choices we make.” He thinks we still have a bit more time to contemplate gene editing, as technologies mature. “I don’t think it’s a problem we’ll have to worry about for 50 years. I leave it to people in the next generation to think this through. When they do, I hope they’ll be glad we started this conversation now. The future has a way of arriving quickly.”