MARK WAS HERE NIH
In his sophomore year, Zhang got his first intoxicating taste of scientific research, volunteering in a gene therapy lab at the Iowa Methodist Medical Center. He used a virus to ferry a jellyfish gene encoding a green fluorescent protein into human cancer cells. The magical glow that emanated from those cells was early proof that Zhang had green fingers at the bench. His mentor, John Levy, gave Zhang some words to live by: “Try to do something on the sexy side of practical.”2 From this point on, Zhang’s future in biological research was pretty much assured. Pilkington observed: “Not everybody is able to fail twenty experiments and then get up and then come up with something brilliant.”3
At nineteen, Zhang placed third in the prestigious Intel Science Talent Search competition, winning a $50,000 scholarship. His mother accompanied him through to the finals, exhorting her son, “Zhan zhi!” (“Stand up straight!”). He excelled at Harvard, matriculating the year before Mark Zuckerberg, earning a degree in chemistry (“the central science”) and physics. Zhang wanted a grounding in the fundamentals that he could apply as he saw fit. Eager to experience Silicon Valley, Zhang moved to Stanford for his PhD. His first choice supervisor, Nobel laureate Steven Chu, had moved on; camped out in Chu’s former office was a new faculty member, Karl Deisseroth.
A psychiatrist by training, Deisseroth had treated many patients with schizophrenia and depression, but was frustrated at how poorly we understand those diseases. He was developing a new technique called optogenetics for studying neuronal activity and neurological diseases. Deisseroth’s brainstorm was to introduce a light-sensitive protein called an opsin into a rodent neuron, affording him the ability to trigger and control its activity.II
Zhang’s initial task, building on his familiarity with gene therapy, was to introduce the opsin gene, which was derived from a pond-dwelling green algae, into single rat neurons on a tissue culture plate using a recombinant virus. When triggered by light, the newly transfected neurons would emit an electrical signal. Over the next few years, Deisseroth, Zhang, and another grad student, Ed Boyden, progressed from neurons in a dish to rats in a maze. When a New York Times reporter visited the lab one Sunday, Zhang had prepared a show-stopping experiment: inside a white plastic tub was a solitary transgenic brown mouse expressing the opsin gene in a particular type of neuron. Zhang inserted a small metal tube into the mouse’s head, into which he threaded a tiny fiber optic cable. When he flicked on the light switch, the mouse suddenly started spinning in circles; switched off, the mouse stopped moving.4 Optogenetics was ready for the big time: a tool to study brain function far more precisely than sticking electrodes into the brain or taking blurry MRI pictures.
“This is one of those things that only comes around every five or ten years,” Deisseroth told his student.5 And he was right: Deisseroth won the Breakthrough Prize in 2015 and helped lay the foundation for President Barack Obama’s $300-million BRAIN Initiative. Deisseroth credited Zhang’s skills as “absolutely essential to the creation of optogenetics.”6 Not too many PhD students get to see their handiwork featured in the Times or win a share of a major scientific prize. It was a sign of things to come.
Still in his twenties, Zhang returned to Boston in 2010 and joined the lab of George Church as a Harvard junior fellow. For a gifted scientist intent on developing new tools for studying genetics and the brain, there could be no more inspiring training ground. For twenty-five years, Church had been a driving force in genomics, pursuing the kind of bold, fearless research that appealed to a talent like Zhang. Church and his dozens of students developed new sequencing technology for reading DNA but was increasingly interested in writing entire genomes. In collaboration with stem cell researcher Paola Arlotta, Zhang and a new PhD student, Le Cong, threw themselves into the emerging field of gene editing. The idea was to develop a method to improve the creation of sequence-specific TALENs to target genes and modulate gene activity.7 Joining them in a corner of the Wyss Institute were two other postdocs, Prashant Mali and Kevin Esvelt.
Born in Beijing, Le Cong shared Zhang’s love of engineering. He enjoyed tinkering with radio sets and designing computer games as a child. While studying electronic engineering at Tsinghua University, Le Cong’s interests turned to medicine after the death of some close relatives. “We’ve made so much progress in modern medicine, but there’s so much we don’t know,” he told me.8 Even simple diseases such as type 1 diabetes can take people’s lives.
Arriving at Harvard on a fellowship, Le Cong quickly bonded with Zhang and was swept up by the infectious lab chatter about the genomics revolution. He wanted to develop tools to engineer the human genome to model brain diseases such as autism, schizophrenia, and bipolar disorder. Although officially Church’s student, Le Cong says that in January 2010, “Feng became my advisor and mentor. We were the only folks interested in working on new tools in gene editing.” It was difficult work: the techniques to synthesize bacterial chromosomes were still rudimentary, and extrapolating to larger mammalian genomes would be even harder.
Across the Charles River in Cambridge, Bob Desimone, the director of the McGovern Institute for Brain Research at MIT, was looking for new faculty. The institute was established by the late Pat McGovern, who had dropped out of MIT to start a publishing company in his basement. That company evolved into IDG (International Data Group), the global publisher of Computerworld, MacWorld, and Bio-IT World. McGovern became a billionaire but ran his enterprise with the warm touch of a family-run business.III McGovern and his wife Lore proudly donated $350 million to create the eponymous institute.
The faculty search wasn’t going particularly well until Zhang’s name came up. His research credentials were impeccable, the only question was whether his flourishing interest in genome manipulation would be the right fit. Desimone asked MIT’s top stem cell researcher, Rudy Jaenisch, to assess the candidate. Jaenisch’s verdict: “He’s certainly very clever. If he can do 10 percent of what he’s proposing, he’s going to be a star.”
Zhang joined the McGovern Institute in January 2011 with a joint appointment at the nearby Broad Institute. His goal was to continue developing TALENs and other systems to engineer genome mutations to model and devise treatments for autism, Alzheimer’s disease, and schizophrenia. Zhang concedes he might have had a slight case of Imposter Syndrome, but it didn’t linger. Le Cong decided to hitch a ride as well. “We’d been working colleagues, it was wonderful to continue our relationship,” he said. Even though he was still technically Church’s graduate student, they shared a taxi over the Harvard Bridge to start their new adventure at MIT.
In early February, 2011, Zhang paid a return visit to Harvard Medical School. The Broad Institute’s annual Board of Scientific Counselors meeting was at the Joseph Martin Auditorium, a block from Zhang’s old lab. A lecture from a most unlikely source was about to change his life.
Michael Gilmore is an expert on antibiotic resistance in bacteria. In 2007, while at a microbiology conference in Pisa, Italy, he was impressed by a poster presented by Danisco on the link between phage immunity and DNA repeats with a weird name: CRISPR. Gilmore wanted one of his new postdocs to study CRISPR. One promising candidate, Luciano Marraffini, opted instead for a position in Chicago. In stepped Kelli Palmer who, with colleagues at the Broad Institute, began comparing the sequences of multidrug-resistant strains of bacteria with older strains. She made a striking observation: genomes from multidrug-resistant clinical strains dating back to the 1970s were larger and generally lacked CRISPR. By comparison, the other isolates still possessed CRISPR.