The Code Breaker Read online

  Watson returned to the machine shop to prod them to speed up production of the four types of bases for the model. By this point the machinists were infused with his excitement, and they finished soldering the shiny metal plates in a couple of hours. With all the parts now on hand, it took Watson only an hour to arrange them so that the atoms comported with the X-ray data and the laws of chemical bonds.

  In Watson’s memorable and only slightly hyperbolic phrase in The Double Helix, “Francis winged into the Eagle to tell everyone within hearing distance that we had found the secret of life.” The solution was too beautiful not to be true. The structure was perfect for the molecule’s function. It could carry a code that it could replicate.

  * * *

  Watson and Crick finished their paper on the last weekend of March 1953. It was a mere 975 words, typed by Watson’s sister, who was persuaded to do so by his argument that “she was participating in perhaps the most famous event in biology since Darwin’s book.” Crick wanted to include an expanded section on the implications for heredity, but Watson convinced him that a shorter ending would actually carry more punch. Thus was produced one of the most significant sentences in science: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

  The Nobel Prize was awarded in 1962 to Watson, Crick, and Wilkins. Franklin was not eligible because she had died in 1958, at age thirty-seven, of ovarian cancer, likely caused by her exposure to radiation. If she had survived, the Nobel committee would have faced an awkward situation: each prize can be awarded to only three winners.

  * * *

  Two revolutions coincided in the 1950s. Mathematicians, including Claude Shannon and Alan Turing, showed that all information could be encoded by binary digits, known as bits. This led to a digital revolution powered by circuits with on-off switches that processed information. Simultaneously, Watson and Crick discovered how instructions for building every cell in every form of life were encoded by the four-letter sequences of DNA. Thus was born an information age based on digital coding (0100110111001…) and genetic coding (ACTGGTAGATTACA…). The flow of history is accelerated when two rivers converge.

  CHAPTER 4 The Education of a Biochemist

  Girls do science

  Jennifer Doudna would later meet James Watson, work with him on occasion, and be exposed to all of his personal complexity. In some ways he would be like an intellectual godfather, at least until he began saying things that seemed to emanate from the dark side of the Force. (As Chancellor Palpatine said to Anakin Skywalker, “The dark side of the Force is a pathway to many abilities that some consider to be unnatural.”)

  But her reactions when she first read his book as a sixth-grader were far simpler. It sparked the realization that it was possible to peel back the layers of nature’s beauty and discover, as she says, “how and why things worked at the most fundamental and inner level.” Life was made up of molecules. The chemical components and structure of these molecules governed what they would do.

  In the lab at Pomona College

  The book also sparked the feeling that science could be fun. All of the previous science books she read had “pictures of emotionless men wearing lab coats and glasses.” But The Double Helix painted a more vibrant picture. “It made me realize that science can be very exciting, like being on a trail of a cool mystery and you’re getting a clue here and a clue there. And then you put the pieces together.” The tale of Watson and Crick and Franklin was one of competition and collaboration, of letting data dance with theory, and of being in a race with rival labs. All of that resonated with her as a kid, and it would continue to do so throughout her career.1

  * * *

  In high school Doudna got a chance to do the standard biology experiments involving DNA, including one that involved breaking apart salmon sperm cells and stirring their gooey contents with a glass rod. She was inspired by an energetic chemistry teacher and by a woman who gave a lecture on the biochemical reasons that cells become cancerous. “It reinforced my realization that women could be scientists.”

  There was a thread that wove together her childhood curiosity about the eyeless spiders in the lava tubes, the sleeping grass that curled when you touched it, and the human cells that became cancerous: they were all connected to the detective story of the double helix.

  She decided that she wanted to study chemistry at college, but like many female scientists of the time, she met resistance. When she explained her college goals to her school’s guidance counselor, an older Japanese American man with traditional attitudes, he began to grunt, “No, no, no.” She paused and looked at him. “Girls don’t do science,” he asserted. He discouraged her from even taking the College Board chemistry test. “Do you really know what that is, what that test is for?” he asked her.

  “It hurt me,” Doudna recalled, but it also stiffened her resolve. “Yes I will do it,” she remembers telling herself. “I will show you. If I want to do science, I am going to do it.” She applied to Pomona College in California, which had a good program in chemistry and biochemistry, was admitted, and enrolled in the fall of 1981.

  Pomona

  At first she was unhappy. Having skipped a grade in school, she was now only seventeen. “I was suddenly a small fish in a very big pond,” she recalled, “and I doubted I had what it took.” She was homesick and, once again, felt out of place. Many of her classmates came from wealthy Southern California families and had their own cars, while she was on a scholarship and worked part time to pay her living expenses. In those days, it was expensive to phone home. “My parents didn’t have a lot of money so they told me to call collect, but only once a month.”

  Having willed herself to major in chemistry, she began to doubt she could handle it. Perhaps her high school counselor had been right. Her general chemistry class had two hundred students, most of whom had gotten a 5 on the AP chemistry test. “It made me question whether I’d set my sights on something that was just not achievable by me,” she said. Because of her competitive streak, the field had little appeal if she was going to be just a mediocre student. “I thought, ‘I don’t want to become a chemist if I’m not going to have a shot at being at the top.’ ”

  She thought about changing her major to French. “I went to talk to my French teacher about that, and she asked what I was majoring in.” When Doudna replied that it was chemistry, the teacher told her to stick with it. “She was really insistent. She said ‘If you major in chemistry you’ll be able to do all sorts of things. If you major in French you will be able to be a French teacher.’ ”2

  * * *

  Her outlook brightened the summer after her freshman year when she got a job working in the lab of her family’s friend Don Hemmes, the University of Hawaii biology professor who had taken her on nature walks. He was using electron microscopy to investigate the movement of chemicals inside cells. “Jennifer was fascinated by the ability to look inside cells and study what all the small particles were doing,” he recalled.3

  Hemmes was also studying the evolution of tiny shells. An active scuba diver, he would scoop up samples of the smallest ones, almost microscopic in size, and his students would help him embed them in resin and slice thin sections for analysis under an electron microscope. “He taught us how to use various kinds of chemicals to stain the samples differently, so we could look at shell development,” explained Doudna. She kept a lab notebook for the first time.4

  In chemistry class at college, most of the experiments were conducted by following a recipe. There was a rigid protocol and a right answer. “The work in Don’s lab wasn’t like that,” she said. “Unlike in class, we didn’t know the answer we were supposed to get.” It gave her a taste of the thrill of discovery. It also helped her see what it would be like to be part of the community of scientists, making advances and piecing them together to discover the ways that nature worked.

  * * *

  When she returned to Pomona in the fall, she made friends, fit in better, and became more confident in her ability to do chemistry. As part of her work-study program, she had a series of jobs in the college chemistry labs. Most did not engage her because they did not explore how chemistry intersected with biology. But that changed after her junior year, when she got a summer position in the lab of her advisor Sharon Panasenko, a biochemistry professor. “It was more challenging for women biochemists at universities back then, and I admired her not only for being a good scientist but also for being a role model.”5

  Panasenko was studying a topic that aligned with Doudna’s interest in the mechanisms of living cells: how some bacteria found in soil are able to communicate so that they can join together when they are starved for nutrients. They form a commune called a “fruiting body.” Millions of the bacteria figure out how to aggregate by sending out chemical signals. Panasenko enlisted Doudna to help figure out how those chemical signals worked.

  “I have to warn you,” Panasenko told her, “that a technician in my lab has been working on growing these bacteria for six months, and he hasn’t been able to make it work.” Doudna began trying to grow the bacteria in large baking pans rather than the usual Petri dishes. One night she put her preparations in the incubator. “I came in the next day, and when I peeled back the foil on the baking dish that lacked nutrients, I was stunned to see these beautiful structures!” They looked like little footballs. She had succeeded where the other technician had failed. “It was an incredible moment, and it made me think I could do science.”

  The experiments yielded strong enough results that Panasenko was able to publish a research paper in the Journal of Bacteriology, in which she acknowledged Doudna as one of four lab assistants “whose preliminary observations ma
de significant contributions to this project.” It was the first time Doudna’s name appeared in a scientific journal.6

  Harvard

  When it came time to go to graduate school, she did not initially consider Harvard, despite being the top student in her physical chemistry class. But her father pushed her to apply. “Come on, Dad,” she pleaded, “I will never get in.” To which he replied, “You certainly won’t get in if you don’t apply.” She did get in, and Harvard even offered her a generous stipend.

  She spent part of the summer traveling in Europe on the money she had saved from her work-study program at Pomona. When her trip ended in July 1985, she went right to Harvard so that she could begin working before classes started. Like other universities, Harvard required graduate chemistry students to work each semester in the lab of a different professor. The goal of these rotations was to allow students to learn different techniques and then select a lab for their dissertation research.

  Doudna called Roberto Kolter, who was head of the graduate studies program, to ask if she could begin her rotations in his lab. A young Spanish specialist in bacteria, he had a big smile, an elegant sweep of hair, wireless glasses, and a bouncy style of talking. His lab was international, with many of the researchers from Spain or Latin America, and Doudna was struck by how young and politically active they were. “I had been highly influenced by the media’s presentation of scientists as old white men, and I thought that’s who I would be interacting with at Harvard. That wasn’t my experience at all at the Kolter Lab.” Her ensuing career, from CRISPR to coronavirus, would reflect the global nature of modern science.

  Kolter assigned Doudna to study how bacteria make molecules that are toxic to other bacteria. She was responsible for cloning (making an exact DNA copy of) genes from the bacteria and testing their functions. She thought of a novel way to set up the process, but Kolter declared it wouldn’t work. Doudna was stubborn and went ahead with her idea. “I did it my way and got the clone,” she told him. He was surprised but supportive. It was a step in overcoming the insecurity that lurked inside her.

  * * *

  Doudna eventually decided to do her dissertation work in the lab of Jack Szostak, an intellectually versatile Harvard biologist who was studying DNA in yeast. A Canadian American of Polish descent, Szostak was one of the young geniuses then in Harvard’s Department of Molecular Biology. Even though he was managing a lab, Szostak was still working as a bench scientist, so Doudna got to watch him perform experiments, hear his thought process, and admire the way he took risks. The key aspect of his intellect, she realized, was his ability to make unexpected connections between different fields.

  Her experiments gave her a glimpse of how basic science can be turned into applied science. Yeast cells are very efficient at taking up pieces of DNA and integrating them into their genetic makeup. So she worked on a way to make use of this fact. She engineered strands of DNA that ended with a sequence that matched a sequence in the yeast. With a little electric shock, she opened up tiny passageways in the cell wall of the yeast, allowing the DNA that she made to wriggle inside. It then recombined into the yeast’s DNA. She had made a tool that could edit the genes of yeast.

  Craig Venter and Francis Collins

  CHAPTER 5 The Human Genome

  James and Rufus Watson

  In 1986, when Doudna was working in Jack Szostak’s lab, a massive international science collaboration was being hatched.1 It was called the Human Genome Project, and its goal was to figure out the sequence of the three billion base pairs in our DNA and map the more than twenty thousand genes that these base pairs encode.

  One of the many roots of the Human Genome Project involved Doudna’s childhood hero James Watson and his son Rufus. The provocative author of The Double Helix was the director of Cold Spring Harbor Laboratory, a haven for biomedical research and seminars on a 110-acre wooded campus on the north shore of Long Island. Founded in 1890, it has a history of important research. It was there in the 1940s that Salvador Luria and Max Delbrück led a study group on phages that included the young Watson. But it is also haunted by more controversial ghosts. From 1904 until 1939, under director Charles Davenport, it served as a center for eugenics, producing studies asserting that different races and ethnic groups had genetic differences in such traits as intelligence and criminality.2 By the end of Watson’s tenure as director there from 1968 to 2007, his own pronouncements on race and genetics would revive these ghosts.

  In addition to being a research center, Cold Spring Harbor hosts around thirty meetings a year on selected topics. In 1986, Watson decided to launch an annual series titled “The Biology of Genomes.” The agenda for the first year’s meeting was to plan the Human Genome Project.

  On the day the meeting began, Watson made a shocking announcement to the gathered scientists. His son Rufus had broken out of a psychiatric hospital, where he had been committed after trying to break a window and jump to his death from the World Trade Center. He was now missing, and Watson was leaving to help find him.

  * * *

  Born in 1970, Rufus had the lean face, tousled hair, and lopsided grin of his father. He was also very bright. “I was very pleased,” Watson says, “because for a while he would go bird-watching with me, and we had some relationship.” Bird-watching was something that Watson had done with his own father as a smart, skinny kid in Chicago. But when Rufus was young, he began to show signs of not being able to interact well with people, and in tenth grade at his boarding school, Exeter, he had a psychotic incident and was sent home. A few days later, he went to the top of the World Trade Center with the plan of ending his life. Doctors diagnosed him as schizophrenic. The elder Watson cried. “I had never seen Jim weep before—or ever since in his life,” his wife, Elizabeth, says.3

  Watson missed most of the Cold Spring Harbor genome meeting, while he and Elizabeth joined the hunt for their son. He was finally found wandering in the woods. Watson’s science had intersected with real life. The massive international project to map the human genome would no longer be for him an abstract, academic pursuit. It was personal, and it would ingrain in him a belief, bordering on obsession, in the power of genetics to explain human life. Nature, not nurture, made Rufus the way he was, and it also made different groups of people the way they were.

  Or so it appeared to Watson, who saw things through glasses filtered by his DNA discovery and his son’s condition. “Rufus is as smart as can be, very perceptive, and can be caring but also intense in his anger,” Watson says. “My wife and I hoped when he was young we could set up the right environment for him to succeed. But I soon realized that his troubles lay in his genes. That drove me to lead the Human Genome Project. The only way I could understand our son and help him live at a normal level was to decipher the genome.”4

  The race to sequence

  When the Human Genome Project was formally launched in 1990, Watson was anointed its first director. All the major players were men. Watson was eventually succeeded by Francis Collins, who in 2009 became the director of the U.S. National Institutes of Health. Among the whiz kids was the charismatic and driven Eric Lander, a breathtakingly brilliant Brooklyn-bred high school math team captain who did a doctoral dissertation on coding theory as a Rhodes Scholar at Oxford and then decided to become a geneticist at MIT. The most controversial player was the wild and abrasive Craig Venter, who had worked in a U.S. Navy field hospital as a draftee during the Tet Offensive of the Vietnam War, had attempted suicide by swimming out to sea, and then became a biochemist and biotech entrepreneur.

  The project began as a collaboration, but as with many tales of discovery and innovation it also became a competition. When Venter found different ways to do the sequencing cheaper and faster than everyone else, he broke away to form a private company, Celera, which sought to profit from patenting its discoveries. Watson enlisted Lander to help reorganize the public effort and speed up its work. Lander bruised some egos, but he was able assure that it could keep pace with Venter’s private effort.5