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The opening day of the human gene editing summit.

The opening day of the human gene editing summit.

National Academy of Sciences

Inside the summit on human gene editing: A reporter’s notebook

WASHINGTON, D.C.—A congressman’s warning. A mother’s heart-wrenching appeal. The long shadow of eugenics. Philosophical, ethical, and moral debates. Uncertain science and patchy regulations. And a cast that included international delegations and the three scientists widely expected to share a Nobel Prize for a new DNA-changing technology, commonly called CRISPR. All was on display—and streaming live online—at the International Summit on Human Gene Editing, which concluded yesterday here at the National Academy of Sciences (NAS).

Before several hundred people, Bill Foster (D–IL), who is the only Ph.D. physicist in the U.S. Congress, kicked off the summit on Tuesday with a reminder that gaining public acceptance of what scientists and physicians want to do with CRISPR and similar tools is critical. “For many people outside this room, including most members of Congress, CRISPR is still an unknown term,” he noted. “I believe that it’s important that the first side of CRISPR presented to the public is a positive one. CRISPR and related technologies have the potential to revolutionize the treatment of diseases but could be used in many ways not beneficial to society.”

The conference ended with the organizing committee, a mix of 12 biologists, physicians, and bioethicists, strongly endorsing the use of CRISPR and similar methods for basic research that involves altering the DNA sequences of human eggs, sperm, or embryos—work that is at the moment ineligible for federal funding in the United States and that in Germany could even get a scientist imprisoned. But the summit’s organizers concluded that actually trying to produce a human pregnancy from such modified germ cells or embryos, either through in vitro fertilization (IVF) with the sperm or eggs or the implantation of an embryo, is currently “irresponsible” because of ongoing safety concerns and a lack of societal consensus. The group’s statement, however, did not permanently rule out such gene editing of the germline, presumably to prevent the transmission of genetic disease from a parent to child. (Introducing permanent “enhancements” into the human genome was largely deemed off-limits, although a few attendees rejected that general consensus.) In fact, the missive called for revisiting the issue on a “regular basis.” “Over the years, the unthinkable has become conceivable. We’re on the cusp of a new era in human history,” California Institute of Technology in Pasadena biologist David Baltimore, chair of the summit organizing committee, told the audience.

With their statement, which did not necessarily represent unanimity among summit attendees despite some media reports to the contrary, the organizing committee became the latest group to weigh in on the myriad possibilities brought to the forefront by the molecular toolkit known as CRISPR. Shown to work just 3 years ago, CRISPR consists of a an enzyme called a nuclease and a piece of RNA that homes in on a targeted DNA sequence, enabling the enzyme to introduce precisely targeted mutations, corrections to mutations, or other alterations.

CRISPR and related tools are transforming biology, from the most basic science to the development of new crops and farm animals. But it was their potential use in humans that riveted the public and policy makers this year after a Chinese team became the first to publicly report using it to alter the DNA of human embryos (nonviable ones produced as part of IVF efforts) and a U.K. group said it wanted to do similar research in the United Kingdom. In response, NAS, U.S. National Academy of Medicine, the Royal Society, and the Chinese Academy of Sciences rushed to convene this week’s summit.

Many have compared the gathering to the 1975 gathering in Asilomar, California, where a small group of biologists debated then-new but much cruder techniques for recombining DNA sequences and famously called for a moratorium on such work until concerns over the accidental release of genetically modified organisms were resolved. Yet in his opening remarks on Tuesday, Baltimore, who was at Asilomar, was among many who sought to distinguish the two meetings. Asilomar was about the biosafety of lab experiments, he stressed, whereas this new summit was motivated by ethical issues and concerns about safety in treating human patients. CRISPR is so cheap, widespread, and easy to harness that the concept of an Asilomar-like moratorium on its use seems impractical, Baltimore added.

Sharpening CRISPR’s cuts

The summit saw complex discussions of how CRISPR works and how it could quickly be improved. Just this week, for example, a team led by Feng Zhang of the Broad Institute of Harvard and MIT, one of the pioneers of the method, published a paper in Science on engineering the nuclease part of CRISPR so that it more accurately cuts the intended DNA target. Others discussed tweaking the RNA portion of CRISPR so that it will more accurately home in on the desired sequence, reducing “off-target” effects. Zang, who shared the stage at one point with Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of the Max Planck Institute for Infection Biology in Berlin—the trio many predict will win a Nobel for development of CRISPR—also noted that even better genome-editing tools may be discovered. CRISPR was found in bacteria, which use it to cut the DNA of invading viruses, and it may not be unique. “There are likely more powerful systems still out there in nature,” he said.

Several speakers addressed the least controversial clinical use of human gene editing—employing CRISPR and its competitors on cells other than eggs, sperm, or embryos in order to treat disease. In clinical trials already underway, for example, researchers have used an older gene-editing technique, enzymes call zinc finger nucleases, in immune cells to deactivate the gene for CCR5, a surface protein that HIV latches onto in order to infect cells. HIV-infected people have subsequently received injections of these virus-resistant cells. Other plans include using CRISPR to reverse blood disorders, such as sickle cell anemia and beta thalassemia, caused by mutations in the hemoglobin gene.

A mother’s tragedy

But the meeting ranged far beyond science. Historian Daniel Kevles of Yale University gave a primer on the eugenics movement, and its popularity in the United States long before the rise of the Nazis, its most notorious enthusiasts. While arguing that state-mandated eugenics efforts were unlikely to arise again, he noted that other forces, such as commercial incentives and consumer demand for genetic enhancement, could push germline gene editing into dangerous territories.

Later, in a session on societal implications, University of Manchester philosopher John Harris and Catholic theologian Hille Haker of Loyola University Chicago in Illinois squared off over the prospect of editing the germline. Harris argued that nothing was sacred about the germline, that all forms of assisted reproduction affect future generations, and that normal reproduction is a “genetic lottery” that often produces birth defects and disease. “If sex had been invented, it would never have been permitted or licensed … it’s far too dangerous,” he joked. But Haker contended that parents with genetic disease should consider adoptions or other options instead. “There is no right to a genetically related child,” she said.

The session ended on a dramatic note when an audience member, Sarah Gray of the American Association of Tissue Banks, came to a microphone and, holding back tears, spoke of when she gave birth to a son with anencephaly, who suffered seizures for 6 days until he died. "If you have the skills and the knowledge to eliminate these diseases, then freakin' do it,” she concluded.

But whether germline editing is the best way to prevent the transmission of genetic diseases occupied much of the summit discussions. (In Gray’s specific case, it’s not clear how often anencephaly stems from inherited genetic mutations). For many at the meeting the debate came down to where they stood on the value of preimplantation genetic diagnosis (PGD), a relatively new procedure in which cells removed from IVF embryos are screened for inherited mutations and only apparently healthy embryos are implanted.

In most cases in which one or both parents have a known inheritable disease, Mendelian genetics implies that some fraction of their embryos will be free of the responsible mutation(s). With PGD those embryos could be identified and implanted. Baltimore crystallized much of the discussion over PGD in his opening remarks, asking: “Is it more ethical to edit embryos or screen a lot of embryos and throw many away.”

In some inherited diseases, however, no IVF embryos would be normal, rendering PGD useless. If both parents have cystic fibrosis, for example, any offspring would inherit the disease—it’s a so-called autosomal recessive disorder, which means an affected person has mutations in both copies of the key gene, and all children of an affected couple would also carry double mutations.

In such circumstances, gene editing of embryos, sperm, or eggs may be the only option, but that doesn’t mean it’s safe enough yet. In the Chinese human embryo experiment, CRISPR cut many nontargeted genes. Whereas many researchers at the summit expressed confidence that off-target effects could be considerably reduced, Rudolf Jaenisch of MIT stressed a less-appreciated worry: When CRISPR repairs one copy of a disease gene, it sometimes introduces mutations into the healthy copy. And Eric Lander of the Broad Institute noted that if gene editing is attempted in early stage human embryos, rather than in sperm or eggs, there’s no obvious way to verify it worked in all cells, so a mosaic embryo with some mutant tissues might still be produced.

Editing a better human

Lander also confronted an issue that haunted many of the discussions: enhancement. Could and should gene editing be used to increase disease resistance, boost cognitive skills, or otherwise improve people genetically? Lander argued that we know far too little about the human genome’s role in cognition and other traits to try to mess with it. “The conclusion is simply humility. Before we make permanent changes to the human gene pool, we should exercise considerable caution,” said Lander, who was on the summit’s organizing committee.

Exercising caution is the responsibility of scientists, but also of government regulators. In discussions of how and whether human gene editing should be regulated, most agreed that somatic cell editing—cells other than eggs, sperm, or embryos—could be handled by existing systems, such as ones designed to review traditional gene therapy work. Barbara Evans of the University of Houston Law Center in Texas noted, however, that the U.S. Food and Drug Administration will have to decide whether gene editing should be treated as a drug or a medical device, because the two categories are regulated very differently. As for germline engineering that produces human pregnancies, a pastiche of laws and regulations around the world address that issue—more than 40 countries have outlawed that option, but many others, including the United States, have not, with some restricting the practice in others ways, such as not allowing federal funding for clinical trials that involve such work. For scientists wanting to apply CRISPR in basic research on human eggs, sperm, or embryos, the landscape is equally confusing—in some places, research on spare embryos from IVF efforts is permitted, but new human embryos can’t be made just for experimentation, for example.

Clarity will be slow in coming. In their concluding statement, Baltimore and his fellow meeting organizers called for an “ongoing forum” led by the societies that convened the summit, and NAS has an established panel on human gene editing that should deliver a report next year. They and others aiming to set guidelines for the myriad uses of CRISPR and its brethren on human cells clearly have no easy task. “The ‘science’ of regulation is more precarious and uncertain than the science of gene editing,” Evans said.