The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

by Walter Isaacson

The invention of CRISPR and the plague of COVID will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery, beginning just over a century ago, of the three fundamental kernels of our existence: the atom, the bit, and the gene. The first half of the twentieth century, beginning with Albert Einstein’s 1905 papers on relativity and quantum theory, featured a revolution driven by physics. In the five decades following his miracle year, his theories led to atom bombs and nuclear power, transistors and spaceships, lasers and radar. The second half of the twentieth century was an information-technology era, based on the idea that all information could be encoded by binary digits—known as bits—and all logical processes could be performed by circuits with on-off switches. In the 1950s, this led to the development of the microchip, the computer, and the internet. When these three innovations were combined, the digital revolution was born. Now we have entered a third and even more momentous era, a life-science revolution. Children who study digital coding will be joined by those who study genetic code.

She had succeeded where the other technician had failed. “It was an incredible moment, and it made me think I could do 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.

in addition to taking risks by moving into new fields: Ask big questions. Even though Szostak liked diving into the details of experiments, he was a grand thinker, someone who was constantly pursuing truly profound inquiries. “Why else would you do science?” he asked Doudna. It was an injunction that became one of her own guiding principles.5

“I felt like I was in the presence of a goddess,” she says, still in awe. “Here’s this woman who’s so famous and so incredibly influential in science acting so unassuming and walking toward her lab thinking about her next experiment. She was what I wanted to be.”

By 2008, scientists had discovered a handful of enzymes produced by genes that are adjacent to the CRISPR sequences in a bacteria’s DNA. These CRISPR-associated (Cas) enzymes enable the system to cut and paste new memories of viruses that attack the bacteria. They also create short segments of RNA, known as CRISPR RNA (crRNA), that can guide a scissors-like enzyme to a dangerous virus and cut up its genetic material. Presto! That’s how the wily bacteria create an adaptive immune system! The notation system for these enzymes was still in flux in 2009, largely because they were being discovered in different labs. Eventually they were standardized into names such as Cas1, Cas9, Cas12, and Cas13.

Genentech, Inc. Genentech was spawned in 1972, when Stanford medical professor Stanley Cohen and biochemist Herbert Boyer of the University of California, San Francisco, attended a conference in Honolulu that dealt with recombinant DNA technology, which was Stanford biochemist Paul Berg’s discovery of how to splice pieces of DNA from different organisms to create hybrids. At the conference, Boyer gave a talk about his own discovery of an enzyme that could create these hybrids very efficiently. Cohen then spoke about how to clone thousands of identical copies of a piece of DNA by introducing it into E. coli bacteria.

Bored and still a bit hungry after their conference dinner one night, they walked to a New York–style deli, with a neon sign reading “Shalom” rather than the usual “Aloha,” in a strip mall near Waikiki Beach. Over pastrami sandwiches, they brainstormed how to combine their discoveries to create a method for engineering and manufacturing new genes. They agreed to work together on the idea, and within four months they had spliced together DNA fragments from different organisms and cloned millions of them, giving birth to the field of biotechnology and launching the genetic engineering revolution.2 One of Stanford’s

Most mornings when she is in her lab, Doudna schedules a steady stream of her researchers to come present their most recent results. Her questions tend to be Socratic: Have you thought about adding RNA? Can we image that in living cells? “She has a knack for asking the right critical big questions when you’re developing your project,” says Jinek. They were designed to get her researchers to look up from the details and see the big picture. Why are you doing this? she will ask. What’s the point?

Like the organisms she studied, her need to adapt to new environments kept her innovative. “My instinct to keep moving can be destabilizing, but that can be good,” she says. “It assures that you never get stuck.” Going from one place to another was her way of repeatedly reconsidering her research and forcing herself to start fresh. “The more one moves, the more one learns to analyze as a new situation and see things that others who have been in the system a long time have not identified.” Moving also made her feel like a bit of a foreigner most of the time, the way the young Jennifer Doudna felt as a child in Hawaii. “It’s important to know how to be an outsider,” Charpentier says. “You’re never completely at home, and that can drive you. It can challenge you not to seek being comfortable.” As with so many other observant and creative people, she found that a sense of detachment or slight alienation made her better at figuring out the forces

That helped her honor the maxim often preached by Louis Pasteur himself: Be prepared for the unexpected.

One evening, right after a key experiment had produced positive results, Doudna was at home cooking spaghetti. The swirls in the boiling water reminded her of the salmon sperm she had studied under a microscope back in high school when learning about DNA, and she started to laugh. Her son, Andy, who was nine, asked her why. “We found this protein, an enzyme called Cas9,” she explained. “It can be programmed to find viruses and cut them up. It’s so incredible.” Andy kept asking how it worked. Over billions of years, she explained, bacteria evolved this totally weird and astonishing way to protect themselves against viruses. And it was adaptable; every time a new virus emerged, it learned how to recognize it and beat it back. He was fascinated. “It was a double joy,” she recalled, “a moment of fundamental discovery of something that is so cool, and being able to share it with my son and explaining it in a manner where he can get it.” Curiosity can be beautiful that way.3

In the history of science, there are few real eureka moments, but this came pretty close. “It wasn’t just some gradual process where it slowly dawned on us,” Doudna says. “It was an oh-my-God moment.” When Jinek showed Doudna his data demonstrating that you could program Cas9 with different guide RNAs to cut DNA wherever you desired, they actually paused and looked at each other. “Oh my God, this could be a powerful tool for gene editing,” she declared. In short, they realized that they had developed a means to rewrite the code of life.4

The 3,500-word paper went into great detail on how the crRNA and the tracrRNA worked to bind the Cas9 protein onto the target DNA. It also showed how the structure of two Cas9 domains determined how each cut one of the DNA strands at a specific location. Finally, it described how they were able to fuse the crRNA and tracrRNA to engineer a single-guide RNA. This system, the authors noted, could be used to edit genes.

And finally there was Doudna, who was not only competitive but also comfortable with her competitiveness. It was one of the reasons a certain coolness developed between her and Charpentier, who expressed some amusement and a bit of disdain for Doudna’s drive for credit. “She is sometimes stressed about credit, which made her seem insecure or not fully grateful for her success,” Charpentier says. “I am French and not as worked up, so I was always telling her, ‘Surf on the good wave.’ ” But when pressed, Charpentier admits that the competitiveness that Doudna exhibits is the force that drives most scientific pioneers, and thus science itself. “If it were not for competitive people like Jennifer, our world would not be as good,” she says. “Because what drives people to do good things is recognition.”3

The main theme of Lander’s essay was important and correct. “Scientific breakthroughs are rarely eureka moments,” he concluded. “They are typically ensemble acts, played out over a decade or more, in which the cast becomes part of something greater than what any one of them could do alone.” Yet the article clearly had another thrust, one that was done with a velvet glove but was nonetheless an unmistakable diminishment of Doudna. Oddly for an academic journal, Cell did not disclose that Lander’s Broad Institute was competing for patents with Doudna and her colleagues.

The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes encoded by DNA are transcribed into snippets of RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to chop up dangerous viruses. Great inventions come from understanding basic science. Nature is beautiful that way.

Because of its small size and highly specific targeting capability, the Cas13d that Hsu discovered was chosen by Qi as the best enzyme to target the coronavirus in human lung cells. In the competition to come up with good acronyms, Qi scored high. He dubbed his system PAC-MAN, which he had extracted from “prophylactic antiviral CRISPR in human cells.” The name was that of the chomping character in the once popular video game. “I like video games,” Qi told Wired’s Steven Levy. “The Pac-Man tries to eat cookies, and it is chased by a ghost. But when it encounters a specific kind of cookie called the power cookie—in our case a CRISPR-Cas13 design—suddenly it turns itself to be so powerful. It can start eating the ghost and start cleaning up the whole battlefield.”15

One way this could work, Qi says, is by delivering PAC-MAN treatments through a nasal spray or some other form of nebulizer. “My son has asthma,” he says, “so as a little kid playing football he used a nebulizer as a preventive measure. People use these regularly to prepare the lung to be less allergic if they are exposed to something.” The same could be done during a coronavirus pandemic; people could use a nasal spray so that PAC-MAN or another CRISPR-Cas13 prophylactic treatment will protect them.

Fyodor Urnov, who directed the COVID testing lab that Doudna created at Berkeley, gave the opening tribute to Franklin. I expected him to deliver it with his usual dramatic flair, but instead he made it, properly, a serious look at her scientific work, including her research into the location of RNA in tobacco mosaic viruses. The only flourish came at the end when he showed a picture of Franklin’s empty lab bench after her death. “The best way to honor her is to remember that the structural sexism she faced remains with us today,” he said, his voice choking up a bit. “Rosalind is the godmother of gene editing.”

Doudna added that the pandemic had accelerated the convergence of science with other fields. “The engagement of non-scientists in our work will help achieve an incredibly interesting biotechnology revolution,” she predicted. This was molecular biology’s moment.

The diversity issue, it struck me, involves far more than just clinical trials. Judging from the list of attendees at the meeting, women are becoming well represented in the field of biological research. But there were very few African Americans, either at the conference or on the benches in the various labs I had visited. In that regard, the new life-sciences revolution resembles, unfortunately, the digital revolution. If there are not efforts at outreach and mentorship, biotechnology will be yet another revolution that leaves most Blacks behind.

whatever they do, their work may not be as recognized as it might be if they were a man. I would like to see that change, and this is a step in the right direction.” Later, she reflected on her days as a schoolgirl. “I was told more than a few times that girls don’t do chemistry or girls don’t do science. Fortunately, I ignored that.” As she spoke, Charpentier was holding her own press conference in Berlin, where it was midafternoon.

“I had been told that this might someday come,” she told me, “but when I received the call I became very moved, very emotional.” It took her back, she said, to her early childhood and deciding, while walking past the Pasteur Institute in her native Paris, that she someday would be a scientist. But by the time of her press conference, her emotions were well hidden behind her Mona Lisa smile. Carrying a glass of white wine, she came into the lobby of her institute, posed next to a bust of its namesake, Max Planck, and then answered questions in a way that managed to be both lighthearted and earnest. As happened in Berkeley, most of the focus was on what the award meant for women. “The fact that Jennifer and I were awarded this prize today can provide a very strong message for young girls,” she said. “It can show them that women can also be awarded prizes.”

The nicest toast came from Jack Szostak, the Harvard professor who had turned her on to the wonders of RNA back when she was a graduate student. Szostak, who had won a Nobel in medicine in 2009 (jointly with two women), raised a glass of champagne while sitting in the backyard of his stately brick Boston townhouse. “The only thing better than winning a Nobel Prize,” he said, “is having one of your students win one.”

the world.5 George Church says he had long wondered whether there would ever be a biological event that was catalytic enough to bring science into our daily lives. “COVID is it,” he says. “Every now and then a meteor hits, and suddenly the mammals are in charge.”6 Most

One fundamental aspect of science will remain the same. It has always been a collaboration across generations, from Darwin and Mendel to Watson and Crick to Doudna and Charpentier. “At the end of the day, the discoveries are what endure,” Charpentier says. “We are just passing on this planet for a short time. We do our job, and then we leave and others pick up the work.”7 All of the scientists I write about in this book say that their main motivation is not money, or even glory, but the chance to unlock the mysteries of nature and use those discoveries to make the world a better place. I believe them. And I think that may be one of the most important legacies of the pandemic: reminding scientists of the nobility of their mission.

All creatures large and small use whatever tricks they can to survive, and so should we. It’s natural. Bacteria came up with a pretty clever virus-fighting technique, but it took them trillions of life cycles to do so. We can’t wait that long. We will have to combine our curiosity with our inventiveness to speed up the process.