I. My editorial accompanying the hemochromatosis gene paper was entitled Definitely Maybe, a clever nod I thought to Oasis’s debut album and the line Kirstie Alley exhaled in Cheers after Ted Danson first plants a kiss on her. It was criminally edited to “A Definite Maybe.” (I’m still upset 25 years later.)
II. While Lander was playing at plate tectonics, he could have scratched off the UK as well. For a country that has contributed so much to our understanding of evolution and molecular biology—Darwin, Fleming, Crick, Rosalind Franklin, Sydney Brenner, Fred Sanger, Alec Jeffreys, Paul Nurse, and more—the origins of the CRISPR revolution surprisingly sidestepped the UK.
III. Some commentators also accused Lander of diminishing the contributions of the women at the center of the CRISPR story in favor of their male rivals. This was silly; Lander has mentored many superb female scientists, including Stacey Gabriel, Jill Mesirov, Pardis Sabeti, Anne Carpenter, and Aviv Regev, who in 2020 was recruited to lead R&D at Genentech.
IV. Zhang used cultured 293 cells, a kidney cell line.
V. There is an exception: if you die but nobody on the Nobel selection committee knows at the time of the announcement, you may still be awarded the Prize on a technicality. This happened to Ralph Steinman in 2011, who passed away three days before the winners were revealed.
VI. SHERLOCK stands for Specific Hypersensitive Enzymatic Reporter unLOCKing.
PART II
“I hold that while a man exists, it is his duty to improve not only his own condition, but to assist in ameliorating mankind.”
—Abraham Lincoln
“The advance of genetic engineering makes it quite conceivable that we will begin to design our own evolutionary progress.”
—Isaac Asimov
“Your scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.”
—Ian Malcolm, Jurassic Park
CHAPTER 8 GENOME EDITING B.C.
“If I had a ruble for every time I’ve heard about the promise of gene editing, I’d be an oligarch!” declares Fyodor Urnov. “What hypothetical promise? It’s been in the clinic for nearly a decade!”1 Urnov should know: for more than a decade, he was one of the molecular musketeers at a biotech company called Sangamo that took the lead in developing genome editing and brought it to the clinic, developing a therapy for HIV. It wasn’t an unequivocal success by any means, but it opened the door for CRISPR and an avalanche of new therapies, some of which might turn into cures.
Now back in academia working with Doudna at the Innovative Genomics Institute, Urnov is all in on CRISPR, allied with the biggest name in the field. “I’m happy Jennifer Lopez is doing a TV show [on CRISPR], but what the other Jennifer is doing is a lot more interesting,” he joked the first time I heard him give a lecture in 2018. He speaks fast and enunciates crisply in a vestigial Russian accent mellowed by more than two decades on the West Coast. If there is a guru in the world of genome editing, Urnov is the man. But before we consider what CRISPR means for humankind now and in the future, I first need to tell a bit more of the back story regarding CRISPR.
Genome editing did not burst onto the scene fully formed like Athena, with what Urnov termed the “immortal” Charpentier-Doudna CRISPR discovery in 2012. In fact, the year before, the journal Nature Methods declared gene editing its “Method of the Year” based on the promise of two forerunners of CRISPR—zinc finger nucleases (ZFNs) and TALENs.2 Although expensive and difficult to deploy, the technologies entered the clinic years ahead of CRISPR—ZFNs developed commercially by Sangamo, and TALENs championed by Paris-based Cellectis.
If Doudna and Charpentier’s teamwork in 2012 is the pillar for genome editing in the modern era, the New Testament if you will, then Urnov brands the era leading up to that moment as “Genome editing B.C.”—before CRISPR.
Few Nobel laureates have a more remarkable personal story than Mario Capecchi. Creativity and success in science requires “the abrasive juxtaposition of unique sets of life experiences that are too complex to pre-orchestrate.”3 Remarkably, Capecchi survived outrageous odds during World War II to become the first scientist to conduct a form of gene editing in mammalian cells. Capecchi was born in Verona in October 1937 as fascism flared across Italy. His father, an officer in the Italian air force, had an affair with a beautiful poet who lectured at the Sorbonne in Paris. After Capecchi’s birth, “my mother wisely chose not to marry him.”4 As a bohemian, she staunchly opposed fascism and took her baby to the Italian Alps. But in 1941, Capecchi recalls the Gestapo arriving in Tyrol and arresting his mother, who was incarcerated in Dachau, Germany.
For a year, Capecchi lived with a neighboring family, living on homemade bread; he remembers jumping naked in barrels of freshly picked grapes. But when the money Capecchi’s mother had provided ran out, he was left to fend for himself. Only four years old, Capecchi headed south, “sometimes living in the streets, sometimes joining gangs of other homeless children, sometimes living in orphanages and most of the time being hungry.” Many memories of that period “are brutal beyond description.” After the liberation of Dachau in 1945, Capecchi’s mother returned to Italy to search for her son. Miraculously she found him in a hospital in Reggio Emilia, where he was being treated for malnourishment. In Rome, Capecchi had his first bath in six years. Later, the Capecchis sailed to America. “I was expecting to see roads paved with gold,” he wrote. “I found much more: an opportunity.” Capecchi settled with his Uncle Edward, a physicist, just outside Philadelphia, He reveled in wrestling and still has the physique to prove it.
After graduating from Antioch College, Capecchi interviewed at Harvard with Jim Watson. When he asked Watson where he should conduct his PhD, Watson snorted: “You’d be crazy to go anywhere else.” Capecchi joined the effort to defragment the genetic code. Capecchi admired Watson’s bravado and stark honesty, as well as a sense of justice. “He taught us not to bother with small questions, for such pursuits were likely to produce small answers,” he said. A few years later, Capecchi set up his own group at the University of Utah. By microinjecting DNA into the nucleus of living cells, he developed a method to swap a gene for a near-identical copy. In the early 1980s, an NIH panel rejected Capecchi’s proposal, but he’d overcome tougher odds than that.
Capecchi’s groundbreaking work, along with Oliver Smithies, a British geneticist then at the University of Wisconsin, and Martin Evans, provided researchers with a means to “knock out” a mouse gene using homologous recombination. By inactivating a gene in embryonic stem cells and then injecting those modified cells to create a chimeric embryo, scientists could do in small, furry mammals what they’d been able to do routinely in yeast and bacteria for decades. The technique was demanding, inefficient, and took months to perform, but the ability to create an animal model lacking a key gene was a godsend for geneticists and developmental biologists. Like a genetics gold rush, the journals were flooded with papers reporting what happened when one mouse gene after another was muted, many providing critical models of human genetic diseases. And it earned Capecchi, Evans, and Smithies the Nobel Prize in Physiology or Medicine in 2007.