f there was one misstep that doomed the long and bitter fight by the University of California to wrest key CRISPR patents from the Broad Institute, it was star UC Berkeley scientist Jennifer Doudna’s habit of being scientifically cautious, realistic, and averse to overpromising.
A biochemist who co-led a breakthrough 2012 study of CRISPR-Cas9, Doudna repeatedly emphasized in interviews the challenges of repurposing the molecular system, which bacteria use to fend off viruses, to edit human genomes. The U.S. patent office, in a February ruling that let the Broad keep its CRISPR patents (for now), relied heavily on those statements — “We weren’t sure if CRISPR/Cas9 would work in … animal cells,” for example — to conclude that when scientists at the Broad CRISPR’d human cells in 2013, it was a non-obvious advance and therefore deserving of patents.
So it’s striking that the careful, measured Doudna who said CRISPR’ing human cells and thereby curing devastating diseases would be a challenge is hardly in evidence in “A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution,” the new book she co-authored with her former student Samuel Sternberg. It goes on sale Tuesday.
This Doudna doesn’t hold back. We are “on the cusp of a new age in genetic engineering and biological mastery,” she and Sternberg write, dangling the prospect of “life-changing treatments” and “lifesaving cures.” She says she is “not kidding” that CRISPR could bring about “woolly mammoths, winged lizards, and unicorns. … It won’t be long before CRISPR allows us to bend nature to our will.”
The hyperbole contrasts with CRISPR’s stumbles, including altering parts of genomes (in lab studies, not patients yet) it wasn’t supposed to. “I don’t think we’ll have a version of CRISPR that’s 100 percent perfect, so it comes down to a risk-benefit analysis,” Sternberg, a biochemist at Caribou Biosciences (which Doudna co-founded), said in an interview. “There has been phenomenal progress in understanding off-target effects; I think it’s a solvable problem. … We have every reason to be optimistic but I hope we avoided overhyping and didn’t give the impression that there would be windfall of cures in the next couple of years.”
This is not a tell-all. The farthest Doudna goes in addressing the patent fight — a “disheartening twist” — is to say that because of such rivalries she experienced “the gamut of human relationships, from deep friendships to disturbing betrayals.” She doesn’t name the betrayers.
An early review chastised Doudna for presenting herself as “so flawless” the book “seems more concealing than revealing,” not “insightful [and] candid.”
So what she does choose to reveal is fascinating, especially about her collaboration with Emmanuelle Charpentier. The two are so closely linked that all the prizes they’ve won for CRISPR, they’ve won together; among CRISPR watchers “DoudnaandCharpentier” is virtually a macro.
But the book’s account of their breakthrough experiment showing that CRISPR could be programmed to edit a precise spot in a genome leaves a different impression. We read that “Martin [Jinek, Doudna’s postdoctoral fellow] showed” and “Martin labored tirelessly,” “Martin and I brainstormed” and “designed an experiment,” and when “Martin walked me through the data,” Doudna knew “we’d done it.”
That work was described in the 2012 paper, which is widely recognized — by prize committees, the European Patent Office, and many scientists — as the Bastille moment for the CRISPR revolution. It identified the three crucial molecules in the CRISPR system — one to cut, one to guide the cutting enzyme to its target DNA, one to activate the cutting enzyme — that produced a programmable DNA-cutting machine. “We had built the means to rewrite the code of life,” Doudna and Sternberg write. “Nothing after that would ever be the same.”
Although Doudna and her collaborators didn’t actually change genomes in cells — their CRISPR molecules altered cell-free DNA in test tubes — that was an obvious next step. How difficult a next step was the core dispute in the patent fight and one that she repeatedly cautioned was no slam dunk. But “Crack in Creation” says that doing so “was immediately clear to us,” and “there were good reasons to expect success.”
That contrasts with her cautious statements, cited by the patent office, at the time. When Feng Zhang of the Broad Institute and George Church of Harvard used CRISPR to edit genes, it was “just as we had proposed in 2012,” according to the book. She was elated that her 2012 work “inspired others to pursue a line of experimentation similar to our own.”
Doudna became a public scientist — she’s given a TED talk and will appear on “Sunday Night with Megyn Kelly” — because of her research, but also because she was instrumental in getting the scientific community to focus on ethical issues it raises, especially about editing embryos in a way that would be inherited by future generations (“germline” editing). She writes that she had nightmares that a man asking her about this was Hitler and that she “began to feel a bit like Dr. Frankenstein.”
Her own moral journey is intriguing. She feels germline editing can be safe, and the “it’s unnatural!” argument “doesn’t carry much weight with me anymore,” she writes. “It seems to me that we’d be justified in using” CRISPR to eliminate genes that cause untold suffering, such as those for Huntington’s disease. “When I think about the pain that genetic diseases cause families, the stakes are simply too high to exclude the possibility of eventually using germline editing,” as an expert panel also concluded.
Doudna acknowledges, however, that “it’s difficult to see how we’d do it equitably,” especially when the line between therapy and enhancement is paper thin: Some families might purchase a genetic legacy that gives them less need for sleep, greater endurance, extra-strong bones, leaner or larger muscles, lower risk of diabetes and Alzheimer’s, even less armpit odor — while other families muddle through with the genes nature gave them.
That threatens to “transcribe our societies’ financial inequality into our genetic code,” Doudna writes.
Her solution? “Redoubl[ing] our commitment to building a society in which all humans are respected and treated equally, regardless of their genetic makeup.”
Update, June 14: Doudna, whose office cancelled an interview with STAT before this story ran, said in an email that “positioning Martin Jinek’s role to your readers as above the work of Emmanuelle Charpentier is incorrect and unfair. Our work was conducted closely with Emmanuelle, whose contributions and insights including the role of tracrRNA in the DNA targeting complex were a key aspect of the development of CRISPR-Cas as a gene editing technology.”