The Code Breaker Page 2
That year she finally made a close friend, one she kept throughout her life. Lisa Hinkley (now Lisa Twigg-Smith) was from a classic mixed-race Hawaiian family: part Scottish, Danish, Chinese, and Polynesian. She knew how to handle the bullies. “When someone would call me a f—king haole, I would cringe,” Doudna recalled. “But when a bully called Lisa names, she would turn and look right at him and give it right back to him. I decided I wanted to be that way.” One day in class the students were asked what they wanted to be when they grew up. Lisa proclaimed that she wanted to be a skydiver. “I thought, ‘That is so cool.’ I couldn’t imagine answering that. She was very bold in a way that I wasn’t, and I decided to try to be bold as well.”
Doudna and Hinkley spent their afternoons riding bikes and hiking through sugarcane fields. The biology was lush and diverse: moss and mushrooms, peach and arenga palms. They found meadows filled with lava rocks covered in ferns. In the lava-flow caves there lived a species of spider with no eyes. How, Doudna wondered, did it come to be? She was also intrigued by a thorny vine called hilahila or “sleeping grass” because its fernlike leaves curl up when touched. “I asked myself,” she recalls, “ ‘What causes the leaves to close when you touch them?’ ”3
We all see nature’s wonders every day, whether it be a plant that moves or a sunset that reaches with pink fingers into a sky of deep blue. The key to true curiosity is pausing to ponder the causes. What makes a sky blue or a sunset pink or a leaf of sleeping grass curl?
Doudna soon found someone who could help answer such questions. Her parents were friends with a biology professor named Don Hemmes, and they would all go on nature walks together. “We took excursions to Waipio Valley and other sites on the Big Island to look for mushrooms, which was my scientific interest,” Hemmes recalls. After photographing the fungi, he would pull out his reference books and show Doudna how to identify them. He also collected microscopic shells from the beach, and he would work with her to categorize them so they could try to figure out how they evolved.
Her father bought her a horse, a chestnut gelding named Mokihana, after a Hawaiian tree with a fragrant fruit. She joined the soccer team, playing halfback, a position that was hard to fill on her team because it required a runner with long legs and lots of stamina. “That’s a good analogy to how I’ve approached my work,” she said. “I’ve looked for opportunities where I can fill a niche where there aren’t too many other people with the same skill sets.”
Math was her favorite class because working through proofs reminded her of detective work. She also had a happy and passionate high school biology teacher, Marlene Hapai, who was wonderful at communicating the joy of discovery. “She taught us that science was about a process of figuring things out,” Doudna says.
Although she began doing well academically, she did not feel that there were high expectations in her small school. “I didn’t get the sense that the teachers really expected very much of me,” she said. She had an interesting immune response: the lack of challenges made her feel free to take more chances. “I decided you just have to go for it, because what the hell,” she recalled. “It made me more willing to take on risks, which is something I later did in science when I chose projects to pursue.”
Her father was the one person who pushed her. He saw his oldest daughter as his kindred spirit in the family, the intellectual who was bound for college and an academic career. “I always felt like I was the son that he wanted to have,” she says. “I was treated a bit differently than my sisters.”
James Watson’s The Double Helix
Doudna’s father was a voracious reader who would check out a stack of books from the local library each Saturday and finish them by the following weekend. His favorite writers were Emerson and Thoreau, but as Jennifer was growing up he became more aware that the books he assigned to his class were mostly by men. So he added Doris Lessing, Anne Tyler, and Joan Didion to his syllabus.
Often he would bring home a book, either from the library or the local secondhand bookstore, for her to read. And that is how a used paperback copy of James Watson’s The Double Helix ended up on her bed one day when she was in sixth grade, waiting for her when she got home from school.
She put the book aside, thinking it was a detective tale. When she finally got around to reading it on a rainy Saturday afternoon, she discovered that she was right, in a sense. As she sped through the pages, she became enthralled with what was an intensely personal detective drama, filled with vividly portrayed characters, about ambition and competition in the pursuit of nature’s inner truths. “When I finished, my father discussed it with me,” she recalls. “He liked the story and especially the very personal side of it—the human side of doing that kind of research.”
In the book, Watson dramatized (and overdramatized) how as a twenty-four-year-old bumptious biology student from the American Midwest he ended up at Cambridge University in England, bonded with the biochemist Francis Crick, and together won the race to discover the structure of DNA in 1953. Written in the sparky narrative style of a brash American who has mastered the English after-dinner art of being self-deprecating and boastful at the same time, the book manages to smuggle a large dollop of science into a gossipy narrative about the foibles of famous professors, along with the pleasures of flirting, tennis, lab experiments, and afternoon tea.
In addition to the role of lucky naïf that he concocted as his own persona in the book, Watson’s other most interesting character is Rosalind Franklin, a structural biologist and crystallographer whose data he used without her permission. Displaying the casual sexism of the 1950s, Watson refers to her condescendingly as “Rosy,” a name she never used, and pokes fun at her severe appearance and chilly personality. Yet he also is generous in his respect for her mastery of the complex science and beautiful art of using X-ray diffraction to discover the structure of molecules.
“I guess I noticed she was treated a bit condescendingly, but what mainly struck me was that a woman could be a great scientist,” Doudna says. “It may sound a bit crazy. I guess I must have heard about Marie Curie. But reading the book was the first time I really thought about it, and it was an eye-opener. Women could be scientists.”4
The book also led Doudna to realize something about nature that was at once both logical and awe-inspiring. There were biological mechanisms that governed living things, including the wondrous phenomena that caught her eye when she hiked through the rainforests. “Growing up in Hawaii, I had always liked hunting with my dad for interesting things in nature, like the ‘sleeping grass’ that curls up when you touch it,” she recalls. “The book made me realize you could also hunt for the reasons why nature worked the way it did.”
Doudna’s career would be shaped by the insight that is at the core of The Double Helix: the shape and structure of a chemical molecule determine what biological role it can play. It is an amazing revelation for those who are interested in uncovering the fundamental secrets of life. It is the way that chemistry—the study of how atoms bond to create molecules—becomes biology.
In a larger sense, her career would also be shaped by the realization that she was right when she first saw The Double Helix on her bed and thought that it was one of those detective mysteries that she loved. “I have always loved mystery stories,” she noted years later. “Maybe that explains my fascination with science, which is humanity’s attempt to understand the longest-running mystery we know: the origin and function of the natural world and our place in it.”5
Even though her school didn’t encourage girls to become scientists, she decided that is what she wanted to do. Driven by a passion to understand how nature works and by a competitive desire to turn discoveries into inventions, she would help make what Watson, with his typical grandiosity cloaked in the pretense of humility, would later tell her was the most important biological advance since the double helix.
Darwin
Mendel
CHAPTER 2 The Gene
Darwin
r /> The paths that led Watson and Crick to the discovery of DNA’s structure were pioneered a century earlier, in the 1850s, when the English naturalist Charles Darwin published On the Origin of Species and Gregor Mendel, an underemployed priest in Brno (now part of the Czech Republic), began breeding peas in the garden of his abbey. The beaks of Darwin’s finches and the traits of Mendel’s peas gave birth to the idea of the gene, an entity inside of living organisms that carries the code of heredity.1
Darwin had originally planned to follow the career path of his father and grandfather, who were distinguished doctors. But he found himself horrified by the sight of blood and the screams of a strapped-down child undergoing surgery. So he quit medical school and began studying to become an Anglican parson, another calling for which he was uniquely unsuited. His true passion, ever since he began collecting specimens at age eight, was to be a naturalist. He got his opportunity in 1831 when, at age twenty-two, he was offered the chance to ride as the gentleman collector on a round-the-world voyage of the privately funded brig-sloop HMS Beagle.2
In 1835, four years into the five-year journey, the Beagle explored a dozen or so tiny islands of the Galápagos, off the Pacific coast of South America. There Darwin collected carcasses of what he recorded as finches, blackbirds, grosbeaks, mockingbirds, and wrens. But two years later, after he returned to England, he was informed by the ornithologist John Gould that the birds were, in fact, different species of finches. Darwin began to formulate the theory that they had all evolved from a common ancestor.
He knew that horses and cows near his childhood home in rural England were occasionally born with slight variations, and over the years breeders would select the best to produce herds with more desirable traits. Perhaps nature did the same thing. He called it “natural selection.” In certain isolated locales, such as the islands of the Galápagos, he theorized, a few mutations (he used the playful term “sports”) would occur in each generation, and a change in conditions might make them more likely to win the competition for scarce food and thus be more likely to reproduce. Suppose a species of finch had a beak suited for eating fruit, but then a drought destroyed the fruit trees; a few random variants with beaks better suited for cracking nuts would thrive. “Under these circumstances, favorable variations would tend to be preserved, and unfavorable ones to be destroyed,” he wrote. “The results of this would be the formation of a new species.”
Darwin was hesitant to publish his theory because it was so heretical, but competition acted as a spur, as often happens in the history of science. In 1858, Alfred Russel Wallace, a younger naturalist, sent Darwin a draft of a paper that proposed a similar theory. Darwin rushed to get a paper of his own ready for publication, and they agreed that they would present their work on the same day at an upcoming meeting of a prominent scientific society.
Darwin and Wallace had a key trait that is a catalyst for creativity: they had wide-ranging interests and were able to make connections between different disciplines. Both had traveled to exotic places where they observed the variation of species, and both had read “An Essay on the Principle of Population” by Thomas Malthus, an English economist. Malthus argued that the human population was likely to grow faster than the food supply. The resulting overpopulation would lead to famine that would weed out the weaker and poorer people. Darwin and Wallace realized this could be applied to all species and thus lead to a theory of evolution driven by the survival of the fittest. “I happened to read for amusement Malthus on population, and… it at once struck me that under these circumstances favorable variations would tend to be preserved and unfavorable ones to be destroyed,” Darwin recalled. As the science fiction writer and biochemistry professor Isaac Asimov later noted concerning the genesis of evolutionary theory, “What you needed was someone who studied species, read Malthus, and had the ability to make a cross-connection.”3
The realization that species evolve through mutations and natural selection left a big question to be answered: What was the mechanism? How could a beneficial variation in the beak of a finch or the neck of a giraffe occur, and then how could it get passed along to future generations? Darwin thought that organisms might have tiny particles that contained hereditary information, and he speculated that the information from a male and female blended together in an embryo. But he soon realized, as did others, that this would mean that any new beneficial trait would be diluted over generations rather than be passed along intact.
Darwin had in his personal library a copy of an obscure scientific journal that contained an article, written in 1866, with the answer. But he never got around to reading it, nor did almost any other scientist at the time.
Mendel
The author was Gregor Mendel, a short, plump monk born in 1822 whose parents were German-speaking farmers in Moravia, then part of the Austrian Empire. He was better at puttering around the garden of the abbey in Brno than being a parish priest; he spoke little Czech and was too shy to be a good pastor. So he decided to become a math and science teacher. Unfortunately, he repeatedly failed his qualifying exams, even after studying at the University of Vienna. His performance on one biology exam was especially dreadful.4
With little else to do after his final failure at passing the exams, Mendel retreated to the abbey garden to pursue what had become his obsessive interest in breeding peas. In previous years, he had concentrated on creating purebreds. His plants had seven traits that came in two variations: yellow or green seeds, white or violet flowers, smooth or wrinkled seeds, and so on. By careful selection, he produced purebred vines that had, for example, only violet flowers or only wrinkled seeds.
The following year he experimented with something new: breeding together plants with differing traits, such as those that had white flowers with those that had violet ones. It was a painstaking task that involved snipping off each of the plant’s receptors with forceps and using a tiny brush to transfer pollen.
What his experiments showed was momentous, given what Darwin was writing at the time. There was no blending of traits. Tall plants cross-bred with short ones did not produce medium-size offspring, nor did purple-flowered plants cross-bred with white-flowered ones produce some pale mauve hue. Instead, all the offspring of a tall and a short plant were tall. The offspring from purple flowers crossbred with white flowers produced only purple flowers. Mendel called these the dominant traits; the ones that did not prevail he called recessive.
An even bigger discovery came the following summer, when he produced offspring from his hybrids. Although the first generation of hybrids had displayed only the dominant traits (such as all purple flowers or tall stems), the recessive trait reappeared in the next generation. And his records revealed a pattern: in this second generation, the dominant trait was displayed in three out of four cases, with the recessive trait appearing once. When a plant inherited two dominant versions of the gene or a dominant and a recessive version, it would display the dominant trait. But if it happened to get two recessive versions of the gene, it would display that less common trait.
Science advances are propelled by publicity. The quiet friar Mendel, however, seemed to have been born under a vanishing cap. He presented his paper in 1865, in two monthly installments, to forty farmers and plant-breeders of the Natural Science Society in Brno, which later published it in its annual journal. It was rarely cited between then and 1900, at which point it was rediscovered by scientists performing similar experiments.5
The findings of Mendel and these subsequent scientists led to the concept of a unit of heredity, what a Danish botanist named Wilhelm Johannsen in 1905 dubbed a “gene.” There was, apparently, some molecule that encoded bits of hereditary information. Painstakingly, over many decades, scientists studied living cells to try to determine what molecule that might be.
Watson and Crick with their DNA model, 1953
CHAPTER 3 DNA
Scientists initially assumed that genes are carried by proteins. After all, proteins do most of the important task
s in organisms. They eventually figured out, however, that it is another common substance in living cells, nucleic acids, that are the workhorses of heredity. These molecules are composed of a sugar, phosphates, and four substances called bases that are strung together in chains. They come in two varieties: ribonucleic acid (RNA) and a similar molecule that lacks one oxygen atom and thus is called deoxyribonucleic acid (DNA). From an evolutionary perspective, both the simplest coronavirus and the most complex human are essentially protein-wrapped packages that contain and seek to replicate the genetic material encoded by their nucleic acids.
The primary discovery that fingered DNA as the repository of genetic information was made in 1944 by the biochemist Oswald Avery and his colleagues at Rockefeller University in New York. They extracted DNA from a strain of bacteria, mixed it with another strain, and showed that the DNA transmitted inheritable transformations.
The next step in solving the mystery of life was figuring out how DNA did it. That required deciphering the clue that is fundamental to all of nature’s mysteries. Determining the exact structure of DNA—how all the atoms fit together and what shape resulted—could explain how it worked. It was a task that required mixing three disciplines that had emerged in the twentieth century: genetics, biochemistry, and structural biology.