—Neil Gaiman, The Ocean at the End of the Lane
“Progress in science depends on new techniques, new discoveries and new ideas—probably in that order.”
—Sydney Brenner
CHAPTER 1 THE CRISPR CRAZE
“This is CRISPR?”
Bill Whitaker, a correspondent for the 60 Minutes television show, sounds puzzled as he points to a small white plastic tube containing a few drops of a colorless liquid that might as well be water. Indeed, it mostly is water.
Holding the vial under the bright television lights is Feng Zhang, a thirtysomething scientist who has helped ignite a biological revolution.
“It has CRISPR in it,” Zhang says helpfully.1
The interview is being filmed in Zhang’s laboratory at the Broad Institute in Cambridge, Massachusetts, one of the most elite biomedical research centers in the country. The Broad (rhymes with road) is named after philanthropist Eli Broad and his wife Edythe. It jockeys for space with other ivory towers established by billionaire businessmen including the Koch brothers (cancer), publisher Pat McGovern (brain research), and medical device inventor Jack Whitehead (cell biology). When I first moved to the United States in the late 1980s, working at the Whitehead Institute on the fringe of the MIT campus, the only other sign of civilization was a Legal Seafood restaurant. Today, Kendall Square is the center of the biotech universe, as much a Boston landmark as Fenway Park. A nearby plaque proclaims this to be the “Most innovative square mile on the planet.” Few would argue.
Zhang looks, if anything, younger than his thirty-four years, with black cropped hair and a smooth cherubic face. In a lab photo with about twenty students and research fellows, you could easily mistake him for a grad student. But since 2013, Zhang has become accustomed to media requests and the intrusion of film crews. This is literally a case of déjà vu: a few months earlier he was answering the same questions in front of the same CBS cameras. But the interviewer on that occasion, Charlie Rose, had since been sacked for good reasons,I so 60 Minutes producer Nichole Marks opted to reshoot the entire segment.
Whitaker stares at the tiny tube disbelievingly. “So this is what’s revolutionizing science and biomedicine?… That’s wild!”
Even if the 60 Minutes cameras could zoom into the contents of that tiny vial between Zhang’s finger and thumb—like a scene from Fantastic Voyage—it would be hard to see what the fuss was about. But CRISPR is a very big deal—a tempest in a test tube. The term CRISPR has a precise scientific definition (more on that later) but in the space of just a few years, this obscure acronym has become a household word, both noun and occasionally verb that epitomizes the revolution in genome editing—the ability to pinpoint and alter a given DNA sequence in any organism.
But Whitaker isn’t letting this go. “So the CRISPR is not the liquid, the CRISPR is in the…?”
“It’s dissolved in the liquid,” Zhang explains patiently. “There are probably billions of molecules of CRISPR in here.”
“Billions…?”
Marks had been pondering a story on CRISPR for a year or two, visiting the Broad to meet Zhang and the institute’s founding director Eric Lander, and attending the major genome editing ethics conference in Washington, DC, in 2015. CRISPR was being trumpeted in the media as the next miracle biotechnology. But for all its medical potential, CRISPR had not yet entered the clinic, let alone cured anyone of a disease.
The tipping point for Marks came in the summer of 2017, when researchers in Oregon led by Shoukhrat Mitalipov became the first American group to successfully edit a gene in a human embryo using CRISPR. Mitalipov insisted he had no plans to use gene editing to produce actual human beings. But it was hard to ignore the possibility that, in the biological equivalent of the Doomsday Clock, we had moved a big step closer to the alarming prospect of designer babies.
The scientific possibilities of CRISPR seemingly know no bounds. By harnessing the components of a prehistoric bacterial immune system, scientists have developed a remarkable molecular cursor that can scan the 3 billion letters that make up the human genome for a specific sequence, cut it, then repair or change it. The Human Genome Project (HGP) was all about reading humankind’s genetic makeup for the first time. We identified more than 20,000 genes that make up the parts list of the human body. We catalogued mutations in fully one third of those genes that are known to give rise to a plethora of genetic diseases. We spent about $2 billion over thirteen years to spell out this rambling string of As, Cs, Ts, and Gs.II The fruits of that labor are blooming, spurring the development of precision treatments for cancer and many diseases.
But now, with CRISPR, scientists have a powerful, easy, affordable tool that puts researchers in a position to surgically rewrite the code when there’s a glitch. To “play God.” They can design and engineer the DNA sequence of organisms big and small, from viruses and bacteria to plants (crops, flowers, trees), worms, fish, rodents, dogs, monkeys—and humans. There were other genome editing technologies developed “B.C.”—before CRISPR—that have entered the clinic to treat HIV and rare genetic disorders. And there are already enhancements to CRISPR, even more precise versions called base editing and prime editing that take us closer to the Holy Grail of safe, pinpoint control of the DNA sequence.
There have been some momentous medical revolutions over the past few centuries: sanitation and clean water, anesthesia, vaccines, antibiotics, small-molecule drugs, biologics, in vitro fertilization (IVF) and prenatal diagnosis. In the basic sciences, new tools and technologies continually drive science. Tools to control neurons, map the architecture of the cell nucleus, and conduct a liquid biopsy of DNA fragments circulating in the bloodstream. But CRISPR has changed science in a profound way: the technique caught fire, its simplicity, flexibility, and affordability catching the imagination of researchers around the world in a dazzling democratization of technology.
CRISPR wasn’t the result of a dedicated applied engineering effort. Instead it is the culmination of decades of investment in basic biomedical research, supporting dozens of dedicated scientists working in unfashionable fields, conducting research for the thrill of discovery to better understand the natural world around us. As Nobel laureate Bill Kaelin noted in a piece in the Washington Post championing basic research in cancer rather than razzle-dazzle moonshots: “The CRISPR gene-editing technology that will revolutionize medicine and agriculture emerged from studies of bacteria and their resistance to viruses.”2 It is hard to envision a less trendy area of research—or it was until the CRISPR breakthrough.
What can CRISPR do? Treat cancer and thousands of genetic diseases. Simple, cheap, mobile diagnostic tools to detect outbreaks of deadly infectious diseases including the COVID-19 pandemic. Designing heartier, more nutritious strains of crops to feed the world. Creating new breeds of disease-resistant livestock and animals for organ transplantation. Conjuring the notion of “de-extinction,” a way to resurrect extinct species such as the woolly mammoth, while providing a new tool for conservationists to save endangered species. Shaping evolution to control or even eliminate the scourge of infectious diseases. And changing the human gene pool, for better or worse, by editing the DNA of human embryos in a scene straight out of a science fiction movie.
Indeed, it didn’t take long for scriptwriters and novelists to become enthralled by CRISPR. In the 2016 finale of the X-Files reboot, Mulder and Scully search for an antidote to a CRISPR bioweapon that knocks out a crucial gene in the immune system, thereby jeopardizing the human race. Jennifer Lopez was reportedly working on a pilot television show with the working title C.R.I.S.P.R.3 Billed as a police thriller set in the near future, the series would see “mentor and protégé battle for control over the human genome in a game of cat and mouse in which the future of our species may rest.” Tragically, J. Lo has yet to realize her vision of our Crispered future. Writer Neal Baer featured a CRISPR bioweapon pandemic plot line in the third season of Designated Survivor, starring Kiefer Sutherland.4