Heroes and Villains: CRISPR Debate Opens 2019 World Science Festival

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The co-founder of the World Science Festival, Brian Greene, opened the 2019 festival in New York on Tuesday evening by noting the capacity of our species to take hold of a process that was driven by random chance for four billion years. That process, of course, is the microbial immune system known as CRISPR, which has been adapted since 2012 to become a powerful and highly accessible genome editing tool.

In front of a capacity crowd at the Simons Foundation headquarters in New York, CRISPR pioneer Jennifer Doudna PhD (University of California Berkeley), bioethicist William Hurlbut MD PhD (Stanford University), and futurist/author Jamie Metzl PhD discussed the medical and ethical ramifications of CRISPR-based genome editing.* Much of the debate focused on the actions of He Jiankui, the Chinese scientist who stunned the world last November by overseeing the births of gene-edited twins.

Most scientists go into science “because we don’t seek the limelight, we don’t court public attention,” Doudna said. At least that was her frame of mind until reporters started calling her in 2014 about reports of genome editing in monkey embryos using CRISPR, forcing her to contemplate the ethics of her research tool. “If people are doing this in monkeys, they’ll do it in human embryos,” she realized. While she didn’t particularly want to get involved in this discussion, she concluded it would be irresponsible not to do so.

Doudna said she welcomed the recent creation of two separate commissions under the auspices of the World Health Organization (WHO) and the National Academies of Science and Medicine, to make recommendations regarding the medical and ethical application of genome editing in human embryos. “We may need the UN [United Nations] to get involved as well,” Doudna said.

No JK

Stanford’s Hurlbut was one of a select group of American scientists who was made aware of He Jiankui’s (also known as JK) interest in performing genome editing on human embryos. (JK performed a 12-month postdoc with Stanford professor Stephen Quake PhD in 2013 before returning to Shenzhen, China.) Hurlbut recalled first meeting JK at a conference in January 2017. Two months later, they met for lunch, the first of several lengthy discussions.

While not condoning JK’s experiments or understanding why he was pushing so fast, Hurlbut said there were mitigating circumstances. JK was under a lot of pressure in the competitive environment he faced in China — “Shenzhen speed”, Hurlbut called it. A very intense person, JK felt he had to move forward “because there’s so much suffering in the world.” But JK relied too much on his own judgment, taking little advice from those in whom he had confided.

JK’s announcement was met with near universal condemnation, but not everyone disapproved. Hurlbut displayed a striking email that JK had received on December 5, 2018, one week after the revelation of the twins’ birth, from an employee of a fertility clinic in Dubai:

“Congratulations on your recent achievement of the first gene editing baby delivered by your application!” the email began. “Our embryologist is interested in partaking in a course regarding CRISPR gene editing for Embryology Lab Application (sic). Does your facility offer this type of course?”

“The biggest problem isn’t JK,” Hurlbut continued. “He wasn’t just seeking fame and fortune (many scientists do this). He was very well intended. People will be amazed what he wanted to happen. He needed to stay in conversation, be more transparent. It needed to be adjudicated by the deepest wisdom of the human species.”

Asked if he is still in contact with JK (they were in regular phone contact in January 2019), Hurlbut said: “I’m not at liberty to say what the situation is, but I’m worried about him. I hope he doesn’t suffer more opprobrium than he deserves… He did not do what he did alone. It wasn’t in secret. It was in line with what people do, it was the seriousness of it.”

But Metzl, who has just published a book called Hacking Darwin and sits on the WHO genome editing panel, disputed Hurlbut’s sympathetic characterization.

“I think JK is a villain,” Metzl said. “The first step of germline editing needed to be defensible, transparent, but to do that in a ‘race for glory’?” The experiment might have been defensible “if the first step had been well thought out, with a careful target, to eliminate a deadly risk.” JK has harmed us, Metzl said, “but he’s raised the alarm.”

Future regulations “can’t be just up to the scientists.” Every country needs a robust regulatory infrastructure, Metzl said, holding up the UK as a gold standard. But how do we think about global regulations? “It’s very difficult to get international consensus – look at climate change,” he said. The WHO committee has already issued a call for a global registry of genome editing trials, to make international efforts as transparent as possible. “Then we have to try to build norms.”

Shutdown

Doudna, who first called for a moratorium (in everything but name) on germline editing in Spring 2015, shrugged at the latest twin calls for a moratorium (here and here). “To call for another moratorium is a bit ineffectual,” she said. “It would be better to invite a more open discussion. There will be opportunities… to learn from this experience. I’d rather not see that conversation shut down.”

While research on embryos will continue, Doudna stressed “the technology is not suitable right now for use in embryos. It’s just not ready.”

On a brighter note, the prospects for somatic gene editing are bright. There will soon be clinical trials for diseases such as sickle-cell disease. “Hopefully they do no harm first and are beneficial to patients,” she said. “Then we’ll start to see monogenic diseases treated using genome editing.”

Ex vivo gene therapy “is almost there, very feasible,” she said. “In vivo [gene] delivery is a lot harder to be sure it’s done right and safely. In the end, that will be the more powerful way to do gene editing.”

CRISPR has evolved to be a pretty good tool, Doudna said, but it’s not perfect. “If it makes a mistake in a bacterium, it kills the bacterium. But there is potential to make mistakes.” Progress is being made in addressing technological concerns such as off-target effects, for example by limiting the time Cas9 spends in cells, careful target site selection, and evolving versions of Cas9 with increased accuracy.

But she pushed back on the plausibility of designer babies or super soldiers. “Genes don’t have a single role, so we have to be thoughtful how to manipulate them,” she said. The sort of traits people like to fantasize about “all result from hundreds or thousands of genes. We don’t know what those are. The reality of doing that kind of manipulation is a long way off.”

Asked about the prospect of enhancing soldiers for greater memory or endurance, Doudna patiently pushed back. “I think that’s in the future, maybe, but not anytime soon. There are easier ways to improving armies than CRISPR right now.”

Debating the future of the gene editing field with a large pool of stakeholders was essential. “I’ve seen increasing distrust of scientists,” Doudna said in closing. “The more we can get scientists to engage the better. I’d love to see science become more integral to society.”

*CRISPR in Context: The New World of Human Genetic Engineering. World Science Festival, New York; May 28, 2019.

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