A longer version of this story previously appeared on the website Statnews.com.
As the dish of steamed chicken feet clattered onto the table, an impish toddler drummed with her chopsticks. Nobody in the noisy restaurant in Boston’s Chinatown last fall gave a second glance at the man dressed in a polo shirt and jeans enjoying dim sum with his little girl, wife, and mother.
No one could have guessed that Feng Zhang, at 34, is widely considered the most transformative biologist of his generation, a double threat to win a Nobel Prize. Or that his discoveries could bring cures for some of the greatest causes of human suffering, from autism and schizophrenia to cancer and blindness. Or that he has touched off a global furor over the possibility that a genetics tool he developed could usher in a dystopian age of designer babies.
At that moment, Zhang was simply a young father, husband, and son struggling to explain what drives him and why it isn’t unusual for him to arrive home from his lab at 1, 2, or even 3 in the morning.
He thinks it’s important, he told a reporter he had invited to join him for brunch. He enjoys it, he wants to carry on the work of mentors who invested in him, he . . . “The autumn leaves,” his mother, Shujun Zhou, piped up.
Zhang was 11 when he and his mother left China and settled in Des Moines. A few years later, when he was in high school, she often waited in her car for hours while he worked late in a gene therapy lab. Driving home in the gathering dark one autumn evening, mother and son were struck by the sight of falling leaves, dead and dying after lifespans measured in mere months. They spoke about how little time anyone has, she recalled, and how easy it is for a life to disappear without the slightest trace that it had ever been. “It just seemed important to me to try my best to make a difference,” Zhang said.
As much as anyone in science, he already has.
From interviews with Zhang, his mentors, and the young scientists in his lab, there emerged a portrait of a mild-mannered researcher with a brash vision, a striver with an immigrant’s ambition to scale the greatest heights in his adopted land, and a biologist who is impatient with the plodding ways of his craft.
Colleagues note his ability to identify promising ideas early, to stoke the creative fires of junior lab members, and to resist the temptation to pursue likely-to-succeed but incremental advances and instead to take risks. When a member of his lab proposes a project, Zhang asks: Will it be a “hack,” clever but inconsequential, or an innovation?
Zhang vaulted into the front ranks of the world’s biologists for discovering how to edit the genomes of plants and animals — including humans — quickly, easily, and efficiently. Called CRISPR-Cas9, the tool is already being used in labs to make human cells impervious to HIV; cure mice of muscular dystrophy, cataracts, and a hereditary liver disease; and improve crops. It quickly spawned three companies with hundreds of millions of dollars in venture financing and opened a new era in molecular biology.
It’s “changing how we do science,” said MIT biologist Phillip Sharp, who shared the 1993 Nobel Prize in Medicine.
The gene editing tool is so powerful that science organizations from around the world, convening a global forum last December, explicitly recommended that it not be used to change the DNA of embryos except for research purposes — that is, in embryos that will never be born.
Exactly how much credit Zhang deserves for the development of CRISPR is the focus of a bitter patent fight, but if he and the Broad Institute prevail, he stands to become the latest of MIT’s wealthy scientist-entrepreneurs. A genome-editing company he cofounded, Editas Medicine, went public in February.
From Iowa to Harvard
It’s a future Zhang could never have imagined as a child in Iowa. After arriving from China, he and his mother initially got by on what she earned in menial jobs such as a motel housekeeper — though she was a computer engineer. His father, an administrator at a science and technology university, did not join them for several years.
Then his life changed thanks to the most mundane of experiences. Zhang went to the movies.
In Des Moines, middle-school biology class meant dissecting frogs stinking of formaldehyde. But Zhang was rescued by a Saturday enrichment program in molecular biology, where the instructors, not being fools, figured that a reasonable way to keep a bunch of teenagers engaged was to show them “Jurassic Park.”
“Both of my parents work in computer science, so I was always interested in programming,” Zhang recalled. The 1993 film, in which hubristic researchers merged dinosaur and frog DNA to bring back the extinct reptiles, “told me that biology might also be a programmable system.”
He got his first chance to program a living thing in 1995, as a sophomore at Theodore Roosevelt High School. Volunteering after school in a gene therapy lab at nearby Methodist Hospital, he engineered human melanoma cells, growing in a lab dish, to express genes from jellyfish, and the eerie emerald light emanating from the cells was proof. “They glowed!” Zhang recalled with an excitement he retains 20 years later.
It wasn’t resurrecting dinosaurs, but it showed him that an organism’s genetic instructions could be overwritten to change its characteristics, just as his parents wrote computer code.
Attending Harvard on a full scholarship, Zhang was a bit of a Julia Child in the lab, able to get wondrous results but prone to the laboratory version of dropping turkeys onto the floor. In organic chemistry, he forgot that putting acid into a certain hot reaction is a no-no. “Everything foamed up and exploded inside the chemical hood,” he recalled. He and his partner fled.
Another experience had a more lasting impact. When a close friend and fellow student developed major depressive disorder, Zhang spent hours trying to help and making sure he was not suicidal. The friend was so deep in the abyss of depression as to be unreachable, however, and had to take a year off from Harvard. Zhang dedicated himself to developing better treatments for mental illness.
After graduating from Harvard in June 2004 and earning his Ph.D. at Stanford, Zhang received a position at Harvard’s Society of Fellows, but it didn’t come with a lab. He begged and borrowed space in labs of senior scientists to pursue gene editing. He began with the then-leading technique, in which proteins studded with structures called “zinc fingers” recognize a specific DNA sequence and cut it. Cells naturally repair such cuts and, if foreign DNA has also been slipped into the cell, incorporate the substitute DNA. Presto: an edited genome. The trouble is, zinc fingers are “remarkably difficult to work with,” Zhang said.
Scientists unveiled another gene-editing technique, called TALEs, in 2009. But TALEs, like zinc fingers, are difficult-to-make proteins. “I was teaching students to build TALEs, and it would take three months before they could even use it,” Zhang recalled. “I thought there must be better ways.”
What is CRISPR?
In early 2011, after being hired by both MIT and the Broad, Zhang was listening to a visiting scientist tell a meeting of the Broad’s advisory board about his research on bacterial genomes containing an immune system called CRISPR. “I was sitting in the back of the room and my mind had been drifting,” Zhang recalled, but the odd acronym sparked his curiosity.
“I had no idea what CRISPR was, but I looked it up on Google and became really excited. Fortunately, the field was young and there were not a lot of papers to read.” He spent much of a scientific meeting in Miami a few days later holed up in his hotel room poring over CRISPR papers.
What he learned was that CRISPR — Clustered Regularly Interspaced Short Palindromic Repeats — had been discovered by microbiologists in bacteria, where they defend against viruses. The CRISPR system consists of a search-and-destroy duo: Genetic material called RNA homes in on a specific stretch of DNA; an enzyme called Cas9 cuts that DNA. He e-mailed graduate student Le Cong: “This could be really big.”
Back in Cambridge, Cong “immediately recognized why Feng was excited,” he said. TALEs had driven them crazy, as they laboriously synthesized protein after protein only to find that it wouldn’t focus on the stretch of DNA they wanted. But CRISPR used RNA, not proteins, to recognize specific DNA sequences in a genome. If synthesizing proteins is as complicated as making a roller coaster out of K’nex, then constructing RNAs is as simple as stringing beads on thread.
Instead of warming up by studying CRISPR in bacteria, as other scientists were, the duo jumped to human and mouse cells, figuring that only if CRISPR worked in these higher-order cells would it be medically important. On a whiteboard in his office, Zhang listed individual experiments they would need to do and split them up.
“It was initially Feng and myself, and we were working like crazy,” Cong said. The scientists spent months testing Cas9 enzymes, in particular monitoring whether they got to the nuclei of human cells, where the genes reside. Bacteria, where the CRISPR system originated, do not have nuclei, so there was no guarantee it would work in cells that do. “We wanted to show that CRISPR was better than TALEs, that it was revolutionary and the system of choice for genome editing,” Cong said.
They often worked until 11 p.m. or later — Zhang had classes to teach and couldn’t start his experiments until late afternoon. They took breaks for ramen noodles, Chinese take-out or burritos, and, once, to crash a party at Zhang’s apartment complex and try their first tequila shots. (Only one each; they returned to the lab that night, too.)
By the spring of 2012, they had enough data for a paper, Zhang said. But it would have been only a so-so paper. “I didn’t want to submit the paper just because the result was publishable,” he said. “I want to wait until we have a paper that can make a significant difference, not just to be first with something.”
“We thought we had the luxury of time,” Cong recalled. “We didn’t know about the competition.”
No time to wait
But competition there was. In June 2012, scientists led by Emmanuelle Charpentier, then at Umea University in Sweden, and Jennifer Doudna of the University of California, Berkeley, reported using CRISPR-Cas9 to cut target DNA sequences in test tubes, raising the “potential . . . for RNA-programmable genome editing,” they wrote in the journal Science.
Zhang didn’t feel he had been scooped, he said: Many biochemical tricks work in test tubes but fail in human cells. Before the Charpentier-Doudna paper was published, Cong recalled, they had come up with “a completely independent and different way of using Cas9 for genome editing than the strategy proposed” in that June paper: “We had these details figured out before [it] was published,” Cong said.
Moreover, when they read their rivals’ paper, Cong said, they saw that it described the use of two molecules that were “very different” from the CRISPR-Cas9 system Zhang’s team had designed and lacked “critical components” for making the genome-editing system work in living cells as opposed to test tubes.
The team pressed on through late summer, amassing data showing their system could edit several genes inside human and mouse cells at once. During the final sprint, Zhang recruited additional members of his growing lab, an approach his colleagues compare to that at tech start-ups: He recognizes a killer app and throws bodies into the fray like a general calling up infantry. “We”— a word Zhang emphasized — “showed we could edit the human genome.”
He sent the paper to Science on Oct. 5. It was published online in early January 2013, along with a similar paper from the lab of Harvard’s George Church. Asked if he knew his old mentor was also in the CRISPR race, Zhang said he had no idea.
Zhang has received some bad press because MIT paid a $70 fee for accelerated review when it applied for a CRISPR patent. That has been portrayed by rivals as somehow jumping the line, since the Doudna-Charpentier patent application was submitted months earlier. MIT received a key patent for the use of CRISPR to edit plant and animal genomes, with Zhang listed as inventor, in April 2014.
Berkeley has appealed that decision, and the patent office began hearing the appeal this year. The university contends that Doudna and Charpentier achieved the key CRISPR breakthroughs and that Zhang’s success in animal cells was just an extension of their work.
More than anything, what stands out about Zhang is his productivity. Since his breakthrough CRISPR paper in 2013, he has had 46 more publications. His lab hums into the night, with Zhang often right there beside his junior colleagues, happily pipetting. “He comes back after eating dinner with his family” — his wife, his toddler daughter, and his parents squeeze into an apartment about a mile from the Broad — “because he genuinely can’t wait until morning to know the answer” from the experiment his team is running, said postdoctoral fellow Naomi Habib. “He leads by example. He doesn’t measure people’s hours, but infects us with his passion.”
Zhang gives credit to other scientists, even those on the bottom rungs of the lab hierarchy. When he and colleagues engineered a new CRISPR-related protein in 2014, he named it SAM — ostensibly for “synergistic activation mediators,” but really for the initials of three students who did the work. “We had to come up with a fancy name to please the reviewers,” Zhang said, “but SAM was really for them.”
Although Zhang is known for CRISPR, he views that as only a means to his true goal: using genetics to understand and, ultimately, treat diseases of the mind. Half his lab is focused on brain research. It’s the possibility of making a real difference in autism, depression, schizophrenia, and other serious disorders that drives him, Zhang said. All the things such illnesses take away, he said — the ability to feel joy, to make meaningful social connections, to think clearly and deeply — are “a very essential part of being human.”