The Double Helix remains an astonishing story of naked scientific ambition and fierce rivalries. Watson was widely criticized for the sexist manner in which he portrayed Rosalind Franklin. It was Franklin’s unpublished X-ray image of DNA fibers—photograph 51—that inspired Crick and Watson to construct their classic model. Watson literally pieced together the final pieces of the three-dimensional puzzle, showing how the four DNA bases fit together, adenine (A) always pairs with thymine (T), while cytosine (C) partners with guanine (G). The report was published in Nature, eight hundred words of pure gold, “tight as a sonnet” in the words of Colin Tudge.2 Franklin died in 1958 and thus was denied a share of the Nobel Prize, which was awarded to Crick, Watson, and her former colleague, Maurice Wilkins, in 1962.
The Double Helix captured Doudna’s imagination, as it has countless young scientists, revealing how biologists could solve the secrets of life by probing the atomic structure of biomolecules such as DNA. Outside the classroom, Doudna experienced isolation and ostracization; she was a minority, referred to by the locals as a haole (a disparaging term for non-native). She found refuge in the library and the lab, delightedly spooling translucent DNA fibers around a glass rod. A family friend, Don Hemmes, let Doudna spend a summer working in his UH lab, playing with an electron microscope while studying worms and mushrooms. When her high school counselor told her “girls don’t do science,” Doudna’s determination only intensified.
Doudna graduated in chemistry from Pomona College in California after briefly flirting with the idea of switching to French, supported by her mentor and undergraduate advisor, Sharon Panasenko.3 She moved to Boston in 1985 for her PhD at Harvard Medical School, working with Jack Szostak, a brilliant RNA biochemist who went on to win the Nobel Prize. She published a major paper with him in 1989 revealing a surprising enzymatic function for certain RNA molecules. Doudna became smitten with RNA, not to be fashionable but to learn more about the versatility and functionality of ribonucleic acid.
In the central dogma of molecular biology first articulated by Francis Crick—DNA >>> RNA >>> protein—RNA was sometimes overlooked. It was considered by some a disposable copy of the genome, lacking the majestic symmetry of the double helix or the exquisite three-dimensional complexity and diversity of proteins, which carry out the essential functions in life. In 1960, Crick and Sydney Brenner postulated the existence of messenger RNA (mRNA), a facsimile of DNA relaying the freshly copied instructions in the book of life beyond the cell nucleus to the protein-manufacturing factories, the ribosomes.
While Doudna was focusing on RNA, she was acutely aware of colleagues who were breaking new ground in other branches of genetics. One was Jim Gusella, who wanted to help patients with the incurable Huntington’s disease. Like a darts player throwing a lucky bullseye, Gusella had fortuitously pinpointed the location of the Huntington’s gene on chromosome 4 in one of his first experiments in 1983. Fatefully, it would take a decade of toil before his team identified the gene itself.
Doudna’s next move was to join another Nobel laureate, spending three years in Colorado working on RNA enzymes with Tom Cech, who won the Nobel Prize in 1989. “I think Jennifer had something to do with both of those [Nobel Prizes],” says her colleague Barbara Meyer, although that would require Doudna mastering in time travel. She opened her own lab at Yale University, and immediately made an impression. Vic Myer, a leading gene editor, recalls, “she was bright, energetic, insightful, and asked very good questions. Fundamentally she is driven by the science, excited by the science, and a great person.”4
In 2002, Doudna moved her lab across the country from Yale to Berkeley, California, to be closer to home, family, and a major synchrotron source for her structural biology studies. Her husband, Jamie Cate, whom she met in the Cech lab, set up his own lab next door. The big question scientifically at the time centered on the RNA World hypothesis, the idea that life began on earth in the form of RNA molecules.
Jill Banfield, a microbiologist at Berkeley, characterizes new species of bacteria and Archaea, expanding our understanding of the evolutionary tree of life. Like an archeologist searching for rare living microbes, her research takes her around the world to a range of environments, some more exotic than others: salt lakes in her native Australia, mine shafts in Colorado, geysers in Yellowstone National Park, as well as simple groundwater wells. Banfield’s team has characterized literally hundreds of new microbial species from these extreme locales, the winners in a billion-year-old game of Survivor.
In 2006, Banfield was stumped. Samples of the same species collected from the same location should have identical sequences, she reasoned, but to her surprise no two DNA traces had the same sequence. “It was shocking,” she recalls. She had stumbled on the fast-evolving CRISPR region. The latest news on that front had come in a paper from Kira Makarova and Eugene Koonin at the NIH that included a rare sighting in science: a confession. The duo had previously suggested that the function of the CRISPR-associated genes was in DNA repair. They were wrong. Abandoning that hypothesis, they now proposed that CRISPR was a genetic defense system that targeted viruses via a mechanism called RNA interference (RNAi), which would earn its discoverers, Stanford’s Andy Fire and Craig Mello at the University of Massachusetts, a Nobel Prize.5
Banfield typed in “RNAi” and “UC Berkeley” into her search engine. The first name that popped up was Doudna’s. She decided to give her colleague a call. “You’re doing the type of research that I think could be very interesting for something that I’ve stumbled across in my own work,” she said.6 And she introduced Doudna to a new piece of scientific jargon: CRISPR. Now it was Doudna’s turn to google Banfield. A few days later, the geomicrobiologist and the RNA biochemist met at the Free Speech Movement Café, a popular central meeting spot in the heart of the Berkeley campus. Seated at an outdoor table, Banfield excitedly told Doudna about her work sequencing bacterial genomes and the clusters of strange palindromic repeat sequences contained in some of her newly discovered organisms.
Banfield took her notepad and sketched a circular bacterial genome and then, magnifying a section of the DNA, drew a series of symbols:
Array of Light: In her first meeting with Doudna, Jill Banfield sketched the CRISPR array showing the alternating pattern of repeats (diamonds) and spacers (squares) derived from viral DNA.
This was the CRISPR array, a series of identical motifs about thirty bases in length interspersed with other sequences—Banfield drew squares, giving each a number—that apparently had nothing in common with each other. Banfield knew the spacers were derived from viruses and that they evolved at a faster clip than other parts of the bacterial genome. And now there was the suggestion that CRISPR was the blueprint for an antiviral defense system involving RNAi. In Doudna, one of the world’s experts on RNA structure and function, she’d found the perfect ally.