The code breaker, p.15
The Code Breaker, page 15
They did a lot of hands-on experiments, including one that transformed bacteria to make them resistant to antibiotics. They also watched the 1993 movie Jurassic Park, in which scientists bring dinosaurs back from extinction by combining their DNA with that of frogs. “I was excited to discover that animals could be a programmable system,” he says. “That meant human genetic coding could be programmable as well.” It was more exciting than Linux.
With his corn-fed eagerness to learn and discover, Zhang became an example of the impact that gifted and talented programs can have on turning American kids into world-class scientists. The U.S. Department of Education had just published, in 1993, a study called “A Case for Developing America’s Talent,” which led to funding for local school districts “to challenge our top performing students to greater heights.” Those were the days when people took very seriously, even if it meant spending tax dollars, the aim of creating a world-class education system, one that would keep America the world leader in innovation. In Des Moines, this included a program called STING (Science/Technology Investigations: The Next Generation), which tapped a small group of talented and motivated students to do original projects and work at local hospitals or research institutions.
Zhang’s Saturday teacher helped him get selected to spend his afternoons and free time at the gene therapy lab of Methodist Hospital in Des Moines. As a high school student, he worked under a psychologically intense but very personable molecular biologist named John Levy, who explained over tea each day the work he was doing and assigned Zhang to increasingly more sophisticated experiments. On some days Zhang would arrive right after school and work until eight in the evening. “My dear mother would drive each day to pick me up and then sit in the parking lot until I was finished,” he says.
His first major experiment involved a fundamental tool in molecular biology: a gene from jellyfish that produces green fluorescent protein, which glows when exposed to ultraviolet light and thus can be used as a marker in cell experiments. Levy first made sure Zhang understood its fundamental natural purpose. Sketching on a piece of paper as he sipped tea, he explained why a jellyfish might need that fluorescent protein as it moved up and down layers of the ocean during different phases of its life cycle. “He drew it in a way that you could just picture the jellyfish and the ocean and nature’s wonders.”
Levy “held my hand,” Zhang recalls, “as I did my first experiment.” It involved putting the gene for green fluorescent protein into human melanoma (skin cancer) cells. It was a simple but exciting example of genetic engineering: he had inserted a gene from one organism (a jellyfish) into the cells of another (a human), and he could see the proof of his success when the bluish-green glow emanated from the manipulated cells. “I was so excited that I began to shout, ‘It’s glowing!’ ” He had reengineered a human gene.
Zhang spent the next few months studying whether the green fluorescent protein, which absorbs ultraviolet light when it glows, could protect the human cell’s DNA from the damage that can be caused by exposure. It worked. “I was using the jellyfish’s GFP as a sunscreen to protect human DNA from ultraviolet light damage,” he says.
The second science project he did with Levy was to deconstruct HIV, the virus that causes AIDS, and examine how each of the components worked. Part of the goal of the Des Moines enrichment programs was to help students do projects to compete in the Intel Science Search, a national competition. Zhang’s virus experiment won him third place, which carried a hefty $50,000 prize. He used it to help pay his tuition when he got into Harvard in 2000.
Harvard and Stanford
Zhang was at Harvard at the same time as Mark Zuckerberg, and it’s interesting to speculate on which of them will end up having the most impact on the world. It’s a proxy for the larger question, which future historians will answer, of whether the digital revolution or the life-science revolution will end up being the more important.
Majoring in both chemistry and physics, Zhang initially did research with Don Wiley, a crystallographer who was a master at determining the structure of complex molecules. “I don’t understand anything in biology unless I know what it looks like,” he liked to say, a credo worthy of all structural biologists, from Watson and Crick to Doudna. But in November of Zhang’s sophomore year, Wiley mysteriously disappeared one night while attending a conference at St. Jude’s Children’s Hospital in Memphis, leaving his rental car on a bridge. His body was later found in the river.
That year Zhang also had to help a close friend in his class who was spiraling into major depression. The friend would be sitting in their room studying, and then suddenly he would get hit by an anxiety or depressive attack and not be able to get up or move. “I had heard of depression, but I thought it was like having a bad day and you had to barrel through,” Zhang says. “Growing up in my family, I mistakenly thought that psychiatric disease was when someone just wasn’t being strong enough.” Zhang would sit with his friend to help him avoid suicide. (The student took time off and recovered.) The experience caused Zhang to turn his attention to researching treatments for mental illness.
So when he went to Stanford for graduate school, he asked to join the lab of Karl Deisseroth, a psychiatrist and neuroscientist who was developing ways to make the workings of the brain and its nerve cells, known as neurons, more visible. Along with another graduate student, they pioneered the field of optogenetics, which uses light to stimulate neurons in the brain. That allowed them to map different circuits in the brain and gain insights about how they functioned or malfunctioned.
Zhang focused on inserting light-sensitive proteins into the neurons—an echo of his high school work inserting green fluorescent protein into skin cells. His method was to use viruses as a delivery mechanism. For one demonstration, he inserted these proteins, which become activated when light hits them, into the part of a mouse brain that controls its movement. By using light pulses, the researchers could trigger the neurons and cause the mice to walk in circles.3
Zhang faced a challenge. It was difficult to insert the gene for the light-sensitive proteins into the exact right location of the DNA of the brain cell. Indeed, the entire field of genetic engineering was hampered by the lack of simple molecular tools for cutting and pasting desired genes into strands of DNA inside a cell. So after he got his doctorate in 2009, Zhang took a postdoc position at Harvard and began researching the gene-editing tools that were available at the time, such as TALENs.
At Harvard, Zhang focused on ways to make TALENs more versatile so that they could be programmed to target different gene sequences.4 It was difficult; TALENs are hard to engineer and reengineer. Fortunately, he was working in the most exciting lab at Harvard Medical School, which was run by a professor who was beloved for embracing new ideas, sometimes wildly, and who fostered a jovial atmosphere that encouraged exploration: Doudna’s longtime friend, the avuncular and bushy-bearded George Church, one of the contemporary legends of biology and a scientific celebrity. He became for Zhang, as he did for almost all of his students, a loving and beloved mentor—until the day Church believed that Zhang had betrayed him.
CHAPTER 23 George Church
Tall and gangly, George Church looks like, and actually is, both a gentle giant and a mad scientist. He is one of those iconic characters who is equally charismatic on Stephen Colbert’s TV show and in his bustling Boston lab amid a gaggle of adoring researchers. Always calm and genial, he has the amused demeanor of a time traveler who is eager to get back to the future. With his wild-man beard and halo of hair, he looks like a cross between Charles Darwin and a woolly mammoth, an extinct species that he wants, perhaps out of a vague sense of kinship, to resurrect using CRISPR.1
Although he is personable and charming, Church has the literalness often found in successful scientists and geeks. At one point we were discussing some decision that Doudna had made, and I asked him whether he thought it had been necessary. “Necessary?” he replied. “Nothing is necessary. Even breathing is not necessary. You can even stop breathing if you really want to.” When I joked that he had taken me too literally, he remarked that one reason he is a good scientist, and also thought of as a bit of a madman, is that he questions the necessity of any premise. He then wandered off into a discourse on free will (which he doesn’t believe humans have) until I was able to get him back on track talking about his career.
Born in 1954, he grew up in the marshy exurbs of Clearwater, on Florida’s Gulf Coast near Tampa, where his mother went through three husbands. As a result, George had many last names and different schools, which made him feel, he says, “like a real outsider.” His birth father had been a pilot at nearby MacDill Air Force Base and a barefoot water-ski champion who was in the Water Ski Hall of Fame. “But he couldn’t hold a job, and my mother moved on,” Church explains.
The young Church was fascinated by science. In those days when parents were less overprotective, his mother let him roam alone in the marshes and mudflats near Tampa Bay, hunting for snakes and insects. He would crawl through the high swamp grass collecting specimens. One day he found an odd caterpillar that looked like a “submarine with legs” and put it in his jar. The next day he discovered, to his astonishment, that it had transformed into a dragonfly, a metamorphosis that is truly one of nature’s thrilling everyday miracles. “That helped set me on my path to be a biologist,” he says.
When he came home in the evening, mud on his boots, he would dive into the books his mother provided, including a set of Collier’s Encyclopedia and a twenty-five-volume series of vibrantly illustrated nature books from Time-Life. Because he was mildly dyslexic, he had trouble reading but could absorb information from pictures. “It made me a more visual person. I could imagine 3-D objects, and by visualizing the structure I could understand how things worked.”
When George was nine, his mother married a physician named Gaylord Church, who adopted George and gave him a permanent surname. His new stepfather had a bulging medical bag that George loved to rummage through. He was particularly fascinated by the hypodermic needle, which his stepfather used liberally to administer painkillers and feel-good hormones to his patients and to himself. He taught George how to use the instruments and would sometimes take him on house calls. At a Harvard Square pub over a soybean burger, Church chuckles as he recalls this odd childhood. “My father would let me give his women patients hormone shots, and they loved him for it,” he says, “and he let me give him shots of Demerol. I later realized he was addicted to painkillers.”
Using the ingredients in his stepfather’s medicine bag, Church began to perform experiments. One involved thyroid hormones that his stepfather supplied to grateful patients who complained of fatigue or depression. At age thirteen, Church put some hormones in the water of a group of tadpoles, leaving another group in untreated water. The first group grew faster. “It was my first true biology experiment, with a control set and all,” he recalls.
When his mother drove him in her Buick up to the 1964 World’s Fair in New York, he became tantalized by the future. It made him feel impatient about being stranded in the present. “I wanted to get to the future, I felt that’s where I belonged, and that’s when I realized that it was something I had to help create,” he says. As the science writer Ben Mezrich noted of Church, “Later in life, he would return to this moment as the instant when he first started to think of himself as a sort of time traveler. Deep down, he started to believe that he was from the far future, and had somehow been left in the past. It was his task in life to try to get back, to try to shift the world to where he had once been.”2
Bored in his backwater high school, Church soon became a handful, especially to his stepfather, who had initially indulged him. “He decided he wanted me to go away,” Church says, “and my mother realized it was a great opportunity, because he would pay for boarding school.” So he was packed off to Phillips Academy in Andover, Massachusetts, America’s oldest prep school. The idyllic quads with their Georgian buildings were almost as wondrous as the marshlands of his childhood. He taught himself computer coding, maxed out on all the chemistry courses, and then was given a key to the chemistry lab so he could explore on his own. Among his many triumphs: making flytrap plants grow huge by spiking their water with hormones.
He went on to Duke, where he earned two undergraduate degrees in two years and then skipped ahead into a PhD program. There he stumbled. He became so involved in the lab research of his advisor, which included using crystallography to figure out the three-dimensional structure of different RNA molecules, that he stopped going to classes. After failing two of them, he got a letter from the dean coldly informing him, “You are no longer a candidate for the Doctor of Philosophy degree in the department of Biochemistry at Duke University.” He kept the letter as a source of pride, the way others keep their framed diplomas.
He had already been a coauthor of five important papers and was able to talk his way into Harvard Medical School. “It’s a mystery why Harvard would accept me after flunking out of Duke,” he said in an oral history. “Usually, it’s the other way around.”3 There he worked with Nobel laureate Walter Gilbert to develop methods for sequencing DNA, and he was at the initial 1984 retreat sponsored by the Department of Energy that led to the launch of the Human Genome Project. But in a preview of their later disputes, he clashed with Eric Lander, who rejected Church’s method for streamlining the sequencing tasks by clonally amplifying the DNA.
Church became a quirky popular celebrity in 2008, when the New York Times science writer Nicholas Wade interviewed him about the possibility of using his genetic engineering tools to regenerate the extinct woolly mammoth from frozen hairs found in the Arctic. Not surprisingly, the idea had a playful appeal to Church, born of his days juicing up tadpoles with hormones. He became a public face of the effort, still underway, to take the skin cell from a modern elephant, convert it to its embryonic state, and then modify the genes until they match those sequenced from the woolly mammoth.4
* * *
When Jennifer Doudna was a PhD student at Harvard in the late 1980s, she admired Church’s unconventional style and thinking. “He was a new professor, tall and gangly and already had his big beard, and he was quite the maverick,” she says. “He was not afraid of being different, and I liked that.” Church recalls being impressed by Doudna’s demeanor. “She did stellar work, especially on the structure of RNA,” he says. “We shared that esoteric interest.”
During the 1980s, Church worked to create new gene-sequencing methods. He became prolific not only as a researcher but as a founder of companies to commercialize the work coming out of his lab. Later he focused on finding new tools for gene editing. So when Doudna and Charpentier’s Science article describing CRISPR-Cas9 went online in June 2012, Church decided to try to get it to work in humans.
He did the polite thing and sent both of them an email. “I was collegial and tried to find out who was working in the field to see if they would mind if I did so,” he recalls. An early riser, he dispatched it just after 4 a.m. one day:
Jennifer and Emmanuelle,
Just a quick note to say how inspiring and helpful is your CRISPR paper in Science.
My group is trying to apply some of the lessons from your study to genome engineering in human stem cells. I’m sure that you have received similar appreciative comments from other labs.
I look forward to staying in contact as things progress.
Best wishes, George
Later that day, Doudna wrote back:
Hi George,
Thanks for your message. We will be very interested to hear how your experiments progress. And yes, there is a lot of interest in Cas9 at the moment—we are hopeful that it will turn out to be useful for genome editing and regulation in various cell types.
All the best, Jennifer
They followed up with some phone conversations, and Doudna told him that she was likewise working on trying to get CRISPR to work in human cells. It was characteristic of the way Church did science: collegially, with a greater inclination toward cooperation and openness than competition and secrecy. “It was very typical of George,” Doudna says. “He is incapable of being devious.” The best way to get a person to trust you is for you to trust them. Doudna is a guarded person, but she was always open with Church.
There was one person Church did not think of contacting: Feng Zhang. The reason was, he says, that he had no idea that his former doctoral student was working on CRISPR. “If I had known Feng was working on it, I would have asked him about it,” Church says. “But he was very secretive when he suddenly hopped on CRISPR.”5
CHAPTER 24 Zhang Tackles CRISPR
Stealth mode
After completing his postdoctoral work in Church’s Harvard Medical School lab in Boston, Zhang had moved across the Charles River to the Broad Institute in Cambridge. Ensconced in state-of-the-art lab buildings on the edge of MIT’s campus, the Broad was founded in 2004 by the irrepressible Eric Lander with funding (eventually $800 million) from Eli and Edythe Broad. Its mission was to advance the treatment of diseases using the knowledge spawned by the Human Genome Project, on which Lander had been the most prolific gene-sequencer.
A mathematician turned biologist, Lander envisioned the Broad as a place where different disciplines would work together. This required a new type of institution, one that fully integrated biology, chemistry, mathematics, computer science, engineering, and medicine. Lander also forged something even more difficult: a collaboration between MIT and Harvard. By 2020, the Broad community included more than three thousand scientists and engineers. It thrived because Lander is a joyful and intensely committed mentor, cheerleader, and fundraiser for wave after wave of young scientists who gravitated to the Broad. He also is able to connect science to public policy and social good; for example, he is spearheading a movement called “Count Me In” that encourages cancer patients to anonymously share their medical information and DNA sequences in a public database that any researcher can access.
