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

by Walter Isaacson

The gene-editing tool that Doudna and others developed in 2012 is based on a virus-fighting trick used by bacteria, which have been battling viruses for more than a billion years. In their DNA, bacteria develop clustered repeated sequences, known as CRISPRs, that can remember and then destroy viruses that attack them.

Many creative people—including most of those I have chronicled, such as Leonardo da Vinci, Albert Einstein, Henry Kissinger, and Steve Jobs—grew up feeling alienated from their surroundings. That was the case for Doudna as a young blond girl among the Polynesians in Hilo.

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

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.

In June 2020, Gray got some even more exciting news: the treatment seemed to be lasting. After nine months, she still had not suffered any sickle-cell pain attacks, nor did she need any further blood transfusions. Tests showed that 81 percent of her bone marrow cells were producing the good fetal hemoglobin, meaning that the gene edits were sustained.2 “High school graduations, college graduations, weddings, grandkids—I thought I wouldn’t see none of that,” she said after getting the news. “Now I’ll be there to help my daughters pick out their wedding dresses.”3 It was an amazing milestone: CRISPR had apparently cured a genetic disease in humans.

In addition to treating blood disorders, such as sickle-cell anemia, CRISPR has been used to fight cancer. China has been the pioneer in this field, and it is two or three years ahead of the United States in devising treatments and getting them into clinical trials.

Mammoth Biosciences, a company that Doudna founded with two of her graduate students, is designing diagnostic tools based on CRISPR that can be used on tumors to identify quickly and easily the DNA sequences associated with different types of cancers. Then precision treatments can be tailored for each patient.

The conference had two goals: guarding against the hazards that could come from creating new forms of genes and guarding against the threat that politicians would ban genetic engineering altogether. On both fronts, the Asilomar process was successful. They were able to chart “a prudent path forward,” an approach that Baltimore and Doudna would later replicate in the debates over CRISPR gene editing. The restrictions agreed to at Asilomar were accepted by universities and funding agencies worldwide.

If the participants wanted to prevent a popular backlash against gene editing, he said, they would have to convince people to trust not only white-coated scientists but also commercially driven corporations. That could be a tough sell.

In the end, they decided to call for a temporary halt on germline editing in humans, at least until the safety and social issues could be further understood. “We wanted the scientific community to hit the Pause button until the societal, ethical, and philosophical implications of germline editing could be properly and thoroughly discussed—ideally at a global level,” Doudna says.

The New York Times ran a story on page 1 by Nicholas Wade, with a picture of Doudna at her Berkeley desk and the headline “Scientists Seek Ban on Method of Editing the Human Genome.”7 But the headline was misleading.

In Russia, there were no laws to prevent the use of gene editing in humans, and President Vladimir Putin in 2017 touted the potential of CRISPR. At a youth festival that year, he spoke of the benefits and dangers of creating genetically engineered humans, such as super-soldiers. “Man has the opportunity to get into the genetic code created by either nature, or as religious people would say, by God,” he said. “One may imagine that scientists could create a person with desired features. This may be a mathematical genius, an outstanding musician, but this can also be a soldier, a person who can fight without fear or compassion, mercy or pain.”

Hurlbut viewed Jiankui as “a well-meaning person who wants his efforts to count for good” but who was spurred by a scientific culture “that puts a premium on provocative research, celebrity, national scientific competitiveness, and firsts.”

“The first attempt to hack the code of life and, ostensibly, improve the health of human babies had in fact been a hack job.”

In the upcoming decades, as we gain more power to hack our own evolution, we will have to wrestle with deep moral and spiritual questions: Is there an inherent goodness to nature? Is there a virtue that arises from accepting what is gifted to us? Does empathy depend on believing that but for the grace of God, or the randomness of the natural lottery, we could have been born with a different set of endowments? Will an emphasis on personal liberty turn the most fundamental aspects of human nature into consumer choices made at a genetic supermarket? Should the rich be able to buy the best genes? Should we leave such decisions to individual choice, or should society come to some consensus about what it will allow?

“Maybe one day with CRISPR,” Porteus told him, “they could go in and change the gene in the embryo so that the kid, when it’s born, doesn’t have sickle cell.” Sanchez’s eyes lit up. “I guess that’s kind of cool,” he said. Then he paused. “But I think that should be up to the kid later.” Asked why, he reflected for a moment and then continued slowly. “There’s a lot of things that I learned having sickle cell. Because I had it, I learned patience with everyone. I learned how just to be positive.” But would he like to have been born without sickle cell? Again, he pauses. “No, I don’t wish that I’d never had it,” he says. “I don’t think that I would be me if I didn’t have sickle cell.” Then he bursts into a big and lovely smile. He was born to be in such a documentary.

Challenges and so-called disabilities often build character, teach acceptance, and instill resilience. They may even be correlated to creativity. Take Miles Davis. The pain of sickle cell drove him to drugs and drink. It may have even driven him to his death. It also, however, may have driven him to be the creative artist who could produce Kind of Blue and Bitches Brew. Would Miles Davis have been Miles Davis without sickle cell?

Very interesting argument. Though I'm not sure this would eliminate all challenges in life, so I'd net that it's worth doing.

Among those interested in these types of gene edits, other than cattle breeders, are athletic directors. Pushy parents who want champion children are sure to follow. Especially by using germline editing, they might produce a whole new breed of athletes with bigger bones and stronger muscles. Add to this mix a rare gene mutation that was discovered in the Olympic champion skier Eero Mäntyranta. Initially accused of doping, he was found to have a gene that increased his number of red blood cells by more than 25 percent, which naturally improved his stamina and ability to use oxygen.

But even if we agree that we want to rid humanity of schizophrenia and similar disorders, we should consider whether there might be some cost to society, even to civilization. Vincent van Gogh had either schizophrenia or bipolar disorder. So did the mathematician John Nash. (And also Charles Manson and John Hinckley.) People with bipolar disorder include Ernest Hemingway, Mariah Carey, Francis Ford Coppola, Carrie Fisher, Graham Greene, Julian Huxley (the eugenicist), Gustav Mahler, Lou Reed, Franz Schubert, Sylvia Plath, Edgar Allan Poe, Jane Pauley, and hundreds of other artists and creators. The number of creative artists with major depressive disorder is in the thousands. A study by schizophrenia-research pioneer Nancy Andreasen of thirty prominent contemporary authors showed that twenty-four had experienced at least one episode of major depression or mood disorder, and twelve were diagnosed with bipolar disorder.

These design flaws are not mere exceptions. They are the natural consequence of the way evolution progresses. It stumbles upon and then cobbles together new features, sort of like what happened during the worst eras of Microsoft Office, rather than proceed with a master plan and end product in mind.

Amazing analogy - to MS Office?!

His troubles began in 2003, when he marked the fiftieth anniversary of his co-discovery of DNA’s structure by giving an interview for a documentary on PBS and the BBC. Genetic engineering should someday be used to “cure” people who have low intelligence, he said. “If you really are stupid, I would call that a disease.” It reflected his deep belief, perhaps fostered by pride in his seminal scientific discovery as well as the daily angst of living with his schizophrenic son, Rufus, in the power of DNA to explain human nature.

Watson added that gene-editing could also be used to enhance people’s looks. “People say it would be terrible if we made all girls pretty. I think it would be great.”

The toast prompted a backlash, especially on Twitter. Lander, already burned by blasts for minimizing the roles of Doudna and Charpentier in his “Heroes of CRISPR” article, apologized. “I was wrong to toast, and I’m sorry,” he wrote in a note to his Broad colleagues that he made public. “I reject his views as despicable. They have no place in science, which must welcome everyone.”

Cancelled

that there be new knowledge that says that your nurture is much more important than nature,” he said as the cameras rolled. “But I haven’t seen any knowledge. And there’s a difference on the average between blacks and whites on I.Q. tests. I would say the difference is, it’s genetic.”

“That’s when I thought, ‘Huh, maybe the FDA and the CDC haven’t talked about this at all,’ ”

With the failure of the Trump administration to carry out widespread testing, university research labs began taking on a role that has normally been performed by the government.

Mammoth Biosciences launched officially in April 2018 with Doudna as chair of its scientific advisory board.

Developers and entrepreneurs may someday be able to use CRISPR-based home testing kits as platforms on which to build a variety of biomedical apps: virus detection, disease diagnosis, cancer screening, nutritional analyses, microbiome assessments, and genetic tests. “We can get people in their homes to check if they have the flu or just a cold,” says Zhang. “If their kids have a sore throat, they can determine if it’s strep throat.”

David Ishee is a ponytailed rural Mississippi dog breeder who uses CRISPR to edit the genes of Dalmatians and mastiffs to try to make them healthier, stronger, and in one offbeat experiment glow in the dark.

Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. The first known one was the Babylon flu epidemic around 1200 BC. The plague of Athens in 429 BC killed close to 100,000 people, the Antonine plague in the second century killed ten million, the plague of Justinian in the sixth century killed fifty million, and the Black Death of the fourteenth century took almost 200 million lives, close to half of Europe’s population.

The long-range solution to our fight against viruses is the same as the one bacteria found: using CRISPR to guide a scissors-like enzyme to chop up the genetic material of a virus, without having to enlist the patient’s immune system.

When at-home testing kits become low-cost and easy to use, Zhang replied, they will democratize and decentralize medicine. The most important next steps will be innovations in “microfluidics,” which involves channeling tiny amounts of liquid in a device, and then connecting the information to our cell phones. That will allow us all, in the privacy of our homes, to test our saliva and blood for hundreds of medical indicators, monitor our health conditions on our phones, and share the data with doctors and researchers.

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.

Cold Spring Harbor Laboratory was founded in 1890 based on a belief in the magic of in-person meetings. The formula is to attract interesting people to an idyllic locale and provide them with opportunities to interact, including at a nice bar. The beauty of nature and the joy that comes from unstructured human engagement is a powerful combination. Even when they don’t interact—such as when an awed young Jennifer Doudna passes the aging icon Barbara McClintock on a path through the Cold Spring Harbor campus—people benefit from an atmosphere that is charged in a way that sparks creativity.

Until 2020, only five women, beginning with Marie Curie in 1911, had won a Nobel for chemistry, out of 184 honorees.

For many women there’s a feeling that, 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.”

Curiosity is the key trait of the people who have fascinated me, from Benjamin Franklin and Albert Einstein to Steve Jobs and Leonardo da Vinci. Curiosity drove James Watson and the Phage Group, who wanted to understand the viruses that attack bacteria, and the Spanish graduate student Francisco Mojica, who was intrigued by clustered repeated sequences of DNA, and Jennifer Doudna, who wanted to understand what made the sleeping grass curl up when you touched it. And maybe that instinct—curiosity, pure curiosity—is what will save us.