By Walter Isaacson, Simon & Schuster, March 9, 2021, 1982115866
Walter Isaacson is brilliant writer. The Code Breaker is filled with an amazing amount of detail, and weighs in at 500 pages, but I finished it in five days. Normally, it would take me a month. I just couldn’t put the book down at times.
Jennifer Doudna is the star of the book, but she’s a (competitive) team player. If you’re on her team, awesome. If not, well, things might get ugly. I’m not personally like that, but I appreciate her drive to win. And that she did.
The book taught me a great deal about CRISPR. It’s not a textbook, but it’s close. It piqued my (on-and-off-again) interest in biochemistry. If you don’t know anything about biochemistry, you should read this book. It’ll teach you why it’s important, and how it works, to some degree.
The part that most amazes me about Isaacson is that he is able to synthesize a thesis about the need for us to understand biochemstry and why. His philosophical analysis is spot on imho. He ends the book with very astute thoughts that you might be able to read standalone, but really should be read in the context of understanding gene editing.
The book is topical: COVID-19 is featured. RNA is the protagonist, in a way. It’s necessary to understand why RNA is so important in order to understand how the vaccines and cures have been rapidly achieved. CRISPR, too, is key, because it wasn’t invented but discovered. Evolution honed during the last billion years on earth. We’re just repurposing it to chop up bad genes (virii) or replace them in the human genome to fix problems, such as sickle cell anemia, with somatic cell edits, or someday, permanently with germline (inheritable) edits.
[k691] Szostak had a guiding principle: Never do something that a thousand other people are doing. That appealed to Doudna.
[k719] As a young PhD student, Doudna mastered the special combination of skills that distinguished Szostak and other great scientists: she was good at doing hands-on experiments and also at asking the big questions. She knew that God was in the details but also in the big picture. “Jennifer was fantastically good at the bench, because she was fast and sharp and could seemingly get anything to work,” Szostak says. “But we talked quite a bit about why the really big questions are the important questions.”
[k752] Doudna would stay in touch with Watson, attending many of the Cold Spring Harbor meetings he organized. Over the years, he would evolve into an increasingly controversial character because of his unmoored blurtings about racial genetic differences. Doudna generally refrained from letting his behavior diminish her respect for his scientific achievements. “When I saw him, he often would say things he thought were provocative,” she says with a slightly defensive laugh. “That was his way. You know how it is.” Despite his frequent public comments about women’s looks, beginning with Rosalind Franklin in The Double Helix, he was a good mentor to women. “He was very supportive to a close woman friend of mine who was a postdoc,” Doudna says. “That influenced my opinion of him.”
[k759] Ever since she puzzled over the touch-sensitive leaves of the sleeping grass that she found on her walks as a child in Hawaii, Doudna had been passionately curious about the underlying mechanisms of nature.
[k765] Wielding imaging techniques such as X-ray crystallography, which is what Rosalind Franklin used to find evidence of the structure of DNA, structural biologists try to discover the three-dimensional shape of molecules.
[k811] Doudna’s mission when she arrived at the University of Colorado as a postdoc was to map the intron that Cech had discovered could be a self-splicing piece of RNA, showing all of its atoms, bonds, and shapes.
[k828] One breakthrough came as a result of the random things that often happen in science: a slight blunder, like the mold that got on Alexander Fleming’s Petri dishes and led to the discovery of penicillin. One day a technician was working with Doudna to try to make crystals, and she put the experiment into an incubator that was not working properly. They thought the experiment was spoiled, but when they looked at the samples through a microscope they could see crystals growing. “The crystals had RNA in them and were beautiful,” Doudna recalled, “and that was the first breakthrough showing us that to get these crystals we had to elevate the temperature.”
[k969] Throughout the history of life on our planet, some organisms (though not humans) have evolved ways to use RNA interference to fight off viruses. As Doudna wrote in a scholarly publication back in 2013, researchers hoped to find ways to use RNA interference to protect humans from infections. Two papers published in Science that year gave strong evidence that it might work. The hope then was that drugs based on RNA interference might someday be a good option for treating severe viral infections, including those from new coronaviruses.
[k1015] But he knew that bacteria and archaea have small amounts of genetic material. They cannot afford to waste a lot of it on sequences that have no important function.
[k1043] What he found was intriguing: the spacer segments matched sequences that were in viruses that attacked E. coli. He found the same thing when he looked at other bacteria with CRISPR sequences; their spacer segments matched those of viruses that attacked that bacteria.
[k1058] Mojica found that bacteria with CRISPR spacer sequences seemed to be immune from infection by a virus that had the same sequence. But bacteria without the spacer did get infected. It was a pretty ingenious defense system, but there was something even cooler: it appeared to adapt to new threats. When new viruses came along, the bacteria that survived were able to incorporate some of that virus’s DNA and thus create, in its progeny, an acquired immunity to that new virus.
[k1063] But Mojica had a ridiculously difficult time getting it published.
[k1195] 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!
[k1243] Starter cultures for yogurt and cheese are made from bacteria, and the greatest threats to the $40 billion global market are viruses that can destroy bacteria.
[k1491] “She definitely doesn’t hover over you,” says Wilson, who now runs his own Berkeley lab aligned with Doudna’s, “but when she goes over your experiments and results with you, there are times when she will lower her voice a bit, look you right in the eye, lean in, and say, ‘What if you tried…?’ “ Then she would describe a new approach, a new experiment, or even a big new idea, usually involving some new way of deploying RNA.
One day, for example, Wilson came to her office to show some results about how two molecules that he had crystallized interacted. “If you can disrupt this interaction based on knowing how it works,” she said, “maybe we can make that same disruption inside the cell and see how it changes the behavior of the cell.” It pushed Wilson to move beyond the test tube and delve into the inner workings of a living cell. “I would never have thought of doing that,” he says, “but it worked.”
[k1502] Although she takes a hands-off approach during the early stages of a researcher’s project, as it gets close to fruition she engages intensely. “Once something exciting emerges or a real discovery is in the works, she senses when it’s a big deal and she gets super involved,” says Lucas Harrington, one of her former students.
[k1505] She doesn’t want another lab to beat hers to a discovery.
[k1569] By the time Doudna and Haurwitz started their company in 2011, Berkeley had become savvier about encouraging its researchers to be more entrepreneurial.
[k1581] That led her to join a local professional development group for young CEOs, the Alliance of Chief Executives, which met for a half-day each month to share problems and solutions. It’s hard to imagine Steve Jobs or Mark Zuckerberg joining such a support group, but Haurwitz, like her mentor Doudna, had a self-awareness and humility not usually found among alpha males.
[k1584] Today the mere appearance of the word CRISPR in a prospectus is enough to cause venture capitalists to go into heat. But when Doudna and Haurwitz tried to raise money, they had little luck.
[k1590] Its bootstrap success may, on the surface, make Caribou Biosciences seem like a poster child for pure free-market capitalism.
[k1588] None of the venture capitalists they met with was a woman, and this was in 2012. So instead of continuing to seek venture money, they decided to raise what they could from friends and family. Both Doudna and Haurwitz put in their own money.
Its bootstrap success may, on the surface, make Caribou Biosciences seem like a poster child for pure free-market capitalism.
[k1596] [Vannevar] Bush’s recommendation was that government should not build big research labs of its own, as it had done with the atomic bomb project, but instead should fund research at universities and corporate labs.
[k1603] In addition, Caribou itself was able to get a federal grant from the NIH’s small business innovation program, which provided $159,000 to the company to create kits to analyze RNA-protein complexes. The program was designed to help innovators turn basic research into commercial products. It kept Caribou alive during the early years, when venture funding was not forthcoming.
[k1667] “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.”
[k1682] Researchers had shown that if you deactivated Cas9 in bacteria, the CRISPR system no longer cut up the invading viruses.
[k1690] It turns out that tracrRNA performs two important tasks. First, it facilitates the making of the crRNA, the sequence that carries the memory of a virus that previously attacked the bacteria. Then it serves as a handle to latch on to the invading virus so that the crRNA can target the right spot for the Cas9 enzyme to chop.
[k1799] “Once we figured out the components of the CRISPR-Cas9 assembly, we realized that we could program it on our own,” Doudna says. “In other words, we could add a different crRNA and get it to cut any different DNA sequence we chose.”
[k1822] He also discussed the idea with Chylinski, and they quickly designed a series of experiments. Once they had figured out what parts of the two RNAs could be deleted and how they could be connected, it took only three weeks to make a single-guide RNA that worked.
[k1832] Realizing that it would have implications for a possible patent on gene-editing technology, he told her that she needed to have it written up fully in the lab notebook and witnessed. So Jinek went back to the lab that night and wrote a detailed description of their concept. It was close to 9 p.m., but Sam Sternberg and Rachel Haurwitz were still there. Lab notebooks have witness signature lines at the bottom of each page in order to document important advances, and Jinek asked both of them to sign. Sternberg had never been asked to do that before, so he realized that it was a historic evening.
[k1856] At Doudna’s urging, the editors fast-tracked the review process. She knew that other papers on CRISPR-Cas9, including one from a Lithuanian researcher (more on him in a moment), were already circulating, and she wanted to make sure that her team was the first to publish. The editors at Science had their own competitive motivation: they didn’t want to be scooped by a rival journal. They asked CRISPR pioneer Erik Sontheimer to be one of the reviewers and told him he would have to get his comments back in two days, an unusually fast turnaround. He declined the assignment because he was doing his own work on the topic, but the journal’s editors were able to find others to review the paper quickly.
[k1898] By February 2012, he had produced a paper, with Barrangou and Horvath as secondary authors, that described how, in a CRISPR system, a Cas9 enzyme was guided by a crRNA to cut up an invading virus. He sent it off to the journal Cell, which summarily rejected it. In fact, the journal did not deem the paper interesting enough to send out for peer review. “Even more frustrating, we sent it to Cell Reports, which is kind of a sister journal to Cell,” Siksnys says. “They rejected it too.”
[k1909] The fact that Doudna subsequently hurried to push her own team’s paper into print would cause a small controversy, or at least a few raised eyebrows, among some members of the CRISPR crowd. “You should look at the timing of Jennifer’s patent filing and the submission of her paper to Science,” Barrangou told me. At first glance, it can look suspicious. Doudna got Siksnys’s abstract on May 21, and she and her colleagues filed a patent application on May 25 and submitted their paper to Science on June 8.
[k1978] Barrangou, the Danisco researcher who had been a collaborator on Siksnys’s paper, later said that, as soon as he heard the presentation, he knew that Doudna and Charpentier had taken the field to a whole new level. “Jennifer’s paper was clearly so much better than ours,” he admits. “It wasn’t close. It was the tipping point that moved the CRISPR field from an idiosyncratic interesting microbial-world feature to a technology. So Virginijus and I, we had no hard feelings whatsoever.”
[k2009] The road to engineering human genes began in 1972 when Professor Paul Berg of Stanford discovered a way to take a bit of the DNA of a virus found in monkeys and splice it to the DNA of a totally different virus.
[k2011] Herbert Boyer and Stanley Cohen discovered ways to make these artificial genes more efficiently and then clone millions of copies of them.
[k2012] It took another fifteen years before scientists began to deliver engineered DNA into the cells of humans. The goal was similar to creating a drug. There was no attempt to change the DNA of the patient; it was not gene editing. Instead, gene therapy involved delivering into the patient’s cells some DNA that had been engineered to counteract the faulty gene that caused the disease.
The first trial came in 1990 on a four-year-old girl with a genetic mutation that crippled her immune system and left her at risk for infection. Doctors found a way to get functioning copies of the missing gene into the T cells of her blood system. The T cells were removed from her body, given the missing gene, and then reintroduced into her body. This led to a dramatic improvement of her immune system and allowed her to live a healthy life.
[k2032] The invention of gene editing required two steps. First, researchers had to find the right enzyme that could cut a double-strand break in DNA. Then they had to find a guide that would navigate the enzyme to the precise target in the cell’s DNA where they wanted to make the cut.
[k2044] With ZFNs and TALENs, you had to construct a new protein guide every time you wanted to target a different genetic sequence to cut; it was difficult and time consuming. But with CRISPR you merely had to fiddle with the genetic sequence of the RNA guide.
[k2052] This rather quick success could be taken as evidence, as Doudna and her colleagues would later argue, that making CRISPR-Cas9 work in human cells was an easy and obvious step that was not a separate invention. Or it could be used to argue, as Doudna’s competitors have, that it was a major inventive step that came after a fiercely competitive race.
[k2063] Like any human (is it an evolutionary trait?), they want credit for their accomplishments, payoff for their labor, acclaim from the public, and prize ribbons placed around their necks. That’s why they work late into the night, hire publicists and patent attorneys, and even invite writers (like me) into their labs.
[k2111] In 1991, when Zhang was ten, his mother came to the United States as a visiting scholar at the University of Dubuque, a gem nestled in an architecturally rich Iowa city along the Mississippi River.
[k2124] At first Zhang seemed likely to follow the path of so many super-smart kids in the 1990s and become a computer geek. When he got his first computer (a PC, not a Mac) at age twelve, he learned to take it apart and use the components to build other computers. He also became a wizard at using open-source Linux operating system software. So his mother sent him to computer camp and, just to make sure he was wired for success, debate camp as well. It was the type of enhancement that privileged parents can do even without gene editing.
Instead of pursuing computer science, however, Zhang became a forerunner of what will, I think, soon be common among aspiring geeks: his interests shifted from digital tech to biotech. Computer code was something his parents and their generation did. He became more interested in genetic code.
Zhang’s path to biology began with his Des Moines middle school’s Gifted and Talented Program, which included a Saturday enrichment class in molecular biology.
[k2138] “I was excited to discover that animals could be a programmable system,” he says. “That meant human genetic coding could be programmable as well.” It was more exciting than Linux.
[k2146] Zhang’s Saturday teacher helped him get selected to spend his afternoons and free time at the gene therapy lab of Methodist Hospital in Des Moines. As a high school student, he worked under a psychologically intense but very personable molecular biologist named John Levy, who explained over tea each day the work he was doing and assigned Zhang to increasingly more sophisticated experiments.
[k2165] Zhang was at Harvard at the same time as Mark Zuckerberg, and it’s interesting to speculate on which of them will end up having the most impact on the world.
[k2167] Majoring in both chemistry and physics, Zhang initially did research with Don Wiley, a crystallographer who was a master at determining the structure of complex molecules.
[k2170] But in November of Zhang’s sophomore year, Wiley mysteriously disappeared one night while attending a conference at St. Jude’s Children’s Hospital in Memphis, leaving his rental car on a bridge. His body was later found in the river.
That year Zhang also had to help a close friend in his class who was spiraling into major depression.
[k2175] The experience caused Zhang to turn his attention to researching treatments for mental illness.
[k2189] Fortunately, he was working in the most exciting lab at Harvard Medical School, which was run by a professor who was beloved for embracing new ideas, sometimes wildly, and who fostered a jovial atmosphere that encouraged exploration: Doudna’s longtime friend, the avuncular and bushy-bearded George Church, one of the contemporary legends of biology and a scientific celebrity. He became for Zhang, as he did for almost all of his students, a loving and beloved mentor–until the day Church believed that Zhang had betrayed him.
[k2201] Although he is personable and charming, Church has the literalness often found in successful scientists and geeks. At one point we were discussing some decision that Doudna had made, and I asked him whether he thought it had been necessary. “Necessary?” he replied. “Nothing is necessary. Even breathing is not necessary. You can even stop breathing if you really want to.” When I joked that he had taken me too literally, he remarked that one reason he is a good scientist, and also thought of as a bit of a madman, is that he questions the necessity of any premise. He then wandered off into a discourse on free will (which he doesn’t believe humans have) until I was able to get him back on track talking about his career.
[k2237] He went on to Duke, where he earned two undergraduate degrees in two years and then skipped ahead into a PhD program. There he stumbled. He became so involved in the lab research of his advisor, which included using crystallography to figure out the three-dimensional structure of different RNA molecules, that he stopped going to classes. After failing two of them, he got a letter from the dean coldly informing him, “You are no longer a candidate for the Doctor of Philosophy degree in the department of Biochemistry at Duke University.” He kept the letter as a source of pride, the way others keep their framed diplomas.
[k2725] The decision not to pool the CRISPR-Cas9 intellectual property would pave the way for an epic patent battle. It also would end up hampering the easy and widespread licensing of the technology. “I think in retrospect, if I had to do it over again, I would have licensed it differently,” Doudna says. “When you have a platform technology like CRISPR, it’s probably a better idea to license it in a way that offers it as broadly as possible.” She had no expertise with intellectual property, and she was at a university that didn’t have much either. “It was kind of like the blind leading the blind,” she says.
[k3011] The article helped to draw the battle lines in the CRISPR war. Doudna’s admirers at Harvard, led by Church and her PhD advisor, Jack Szostak, were infuriated. “It’s just an awful, awful, piece of writing,” Szostak tells me. “Eric wants the credit for the genetic editing revolution to go to Feng Zhang and him, and not Jennifer. So he just totally belittled her contribution in a way that seems just pure animus.”
[k3195] Would Doudna and Zhang have been better off coming to a deal rather than battling in court? In retrospect, Doudna’s business partner Andy May thinks so. “We would have saved a lot of time and money around all of the legal arguments if we had managed to come together,” he says.
To an unnecessary extent, the prolonged fight was driven by emotions and resentments.
[k3201] Unlike the CRISPR contestants, Noyce and Kilby obeyed an all-important business maxim: Don’t fight over divvying up the proceeds until you finish robbing the stagecoach.
[k3273] Even though the genetic cause of sickle-cell disease has been understood for longer than any similar disorder, new treatments have lagged behind. For example, the fight against cystic fibrosis, which affects primarily white Americans and Europeans, has received eight times more funding from government, charities, and foundations. The great promise of gene editing is that it will transform medicine. The peril is that it will widen the healthcare divide between rich and poor. Doudna’s sickle-cell initiative is designed to find ways to avoid that.
[k3319] At the beginning of 2020, there were two dozen clinical trials for various uses of CRISPR-Cas9 in the pipeline. They included potential treatments for angioedema (a hereditary disease that causes severe swelling), acute myeloid leukemia, super-high cholesterol, and male pattern baldness.
[k3329] Wearing a black T-shirt and tight white jeans, Josiah Zayner stood in front of a roomful of biotechnologists at the Global Synthetic Biology Summit in San Francisco in 2017 and launched into a pitch about a do-it-yourself “frog genetic engineering kit” that he made in his garage.
[k3348] As a teenager, Zayner worked as a programmer for Motorola’s cell phone network, but he got laid off when the tech bubble burst in 2000, so he decided to go to college.
[k3356] Zayner now runs from his garage an online biohacking supply store, The ODIN, which creates and sells “kits and tools that allow anyone to make unique and usable organisms at home or in a lab.” Among its products, in addition to the frog-muscle kit, are a “DIY bacterial gene engineering CRISPR kit” ($169) and a “genetic engineering home lab kit” ($1,999).
Soon after Zayner started his business in 2016, he got an email from Harvard’s George Church. “I like the stuff you’re doing,” Church wrote.
[k3376] “We now all have this ability to program life,” he says. “If millions of people took it up, that would immediately change medicine and agriculture, contributing so much to the world. By demonstrating how easy CRISPR is, I want to inspire people to do that.”
Isn’t it dangerous, I ask, for everyone to have access to this technology? “No, it’s fucking exciting,” he counters. “No great technology has flourished until people had complete access to it.” He has a point. What truly caused the digital age to blossom was when computers became personal.
[k3523] The discussions led Berg to convene a group of biologists in January 1973 at the Asilomar conference center on the California coast near Monterey. Known as “Asilomar I” because it launched a process that would culminate two years later at the same conference site, the meeting focused mainly on lab safety issues.
[k3533] “Their discussions suggest both the vitality of small boys with new chemistry sets and the electricity of back yard gossip,” Michael Rogers of Rolling Stone wrote in a piece aptly titled “The Pandora’s Box Conference.”
One of the primary organizers was a soft-spoken but gently commanding MIT biology professor named David Baltimore, who that year would win the Nobel Prize for his work showing that viruses containing RNA, such as coronaviruses, can insert their genetic material into the DNA of a host cell through a process known as “reverse transcription.” In other words, the RNA can be transcribed into DNA, thus modifying the central dogma of biology, which states that genetic information travels in only one direction, from DNA to RNA. Baltimore would go on to become president of Rockefeller University and then Caltech, and his half-century career as a respected leader of policy councils would become a model for Doudna’s own public involvement.
[k3574] The restrictions agreed to at Asilomar were accepted by universities and funding agencies worldwide. “This unique conference marked the beginning of an exceptional era for science and for the public discussion of science policy,” Berg wrote thirty years later. “We gained the public’s trust, for it was the very scientists who were most involved in the work and had every incentive to be left free to pursue their dream that called attention to the risks inherent in the experiments they were doing. Restrictive national legislation was avoided.”
[k3647] It was absurd, Watson said, to treat the germline as “some great Rubicon and crossing it involved going against natural law.” When he was challenged about the need to respect “the sanctity of the human gene pool,” he erupted. “Evolution can be just damn cruel, and to say that we’ve got a perfect genome and there’s some sanctity to it is utter silliness.” His schizophrenic son, Rufus, was a daily reminder that the genetic lottery could be, as he put it, damn cruel. “The biggest ethical problem we have is not using our knowledge and not having the guts to go ahead and try to help someone,” he insisted.
For the most part, Watson was preaching to the choir. The opinions at the UCLA conference ranged from enthusiasm to unbridled enthusiasm for gene editing.
[k3666] “No state or federal legislation to regulate germline gene therapy should be passed at this time,” organizer Gregory Stock wrote in his summation.
[k3691] Unlike the seventeen other humans in the trial, Gelsinger had a massive immune response caused by the virus transporting the therapeutic gene, which resulted in a high fever followed by the breakdown of his kidneys, lungs, and other organs. In four days he was dead. Work on gene therapy ground to a halt.
[k3716] In 2001, the Kass Commission included many distinguished conservative or neoconservative thinkers, including Robert George, Mary Ann Glendon, Charles Krauthammer, and James Q. Wilson. Two prominent philosophers proved to be especially influential members. The first was Michael Sandel, a Harvard professor who is the contemporary successor to John Rawls in defining the concept of justice. At the time, he was writing an essay titled “The Case Against Perfection: What’s Wrong with Designer Children, Bionic Athletes, and Genetic Engineering,” which he published in The Atlantic in 2004. The other key thinker was Francis Fukuyama, who in 2000 published Our Posthuman Future: Consequences of the Biotechnology Revolution, which was a forceful call for governments to regulate biotechnology.
Not surprisingly, their final 310-page report, Beyond Therapy, was thoughtful, vibrantly written, and filled with qualms about genetic engineering. It warned of the dangers of using technology to go beyond merely treating diseases to using it to enhance human capabilities. “There are reasons to wonder whether life will really be better if we turn to biotechnology to fulfill our deepest human desires,” the report declared.
[k3728] It argued the case, or more accurately it preached the case, that going too far to alter what is “natural” was hubristic and endangered our individual essence.
[k3731] One can almost sense a congregation nodding “Amen” while a few people in the back mutter, “Speak for yourself.”
[k3742] Sitting in front of her, with pen and paper ready to take notes, was Adolf Hitler with the face of a pig. “I want to understand the uses and implications of this amazing technology you’ve developed,” he said. Doudna was jolted awake by the nightmare, she recalls. “As I lay in the dark, my heart racing, I couldn’t escape the awful premonition with which the dream had left me.” She began to have trouble sleeping at night.
[k3829] “We need to create a political safe space by going slow on germline editing so that we can continue working on somatic cell edits,” one participant said.
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.
[k3881] Church’s bio-enthusiasm was given a boost in the popular press by one of his Harvard colleagues, the well-known psychology professor Steven Pinker. “The primary moral goal for today’s bioethics can be summarized in a single sentence,” he wrote in an op-ed for the Boston Globe. “Get out of the way.” He took a brutal swipe at the entire profession of bioethicists. “A truly ethical bioethics should not bog down research in red tape, moratoria, or threats of prosecution based on nebulous but sweeping principles such as ‘dignity,’ ‘sacredness,’ or ‘social justice,’” he argued. “The last thing we need is a lobby of so-called ethicists.”
[k3929] 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.”
[k3954] He Jiankui, the son of struggling rice farmers, was born in the Orwellian year 1984 and grew up in Xinhua, one of the poorest villages in a rural part of Hunan province in east-central China. The average family income there when he was a boy was $100 a year. His parents were so poor that they could not afford to buy him textbooks, so JiankuiI walked to a village bookstore to read them there. “I grew up in a small farming family,” he recalled. “I picked leeches from my legs every day in the summer. I will never forget my roots.”
[k3972] He got his PhD in physics but then decided that the future was in biology. Deem allowed him to go to conferences around the country and provided an introduction to the Stanford bioengineer Stephen Quake, who invited Jiankui to become a postdoc in his lab.
[k3983] Chinese officials had designated genetic engineering as critical to the country’s economic future and its competition with the U.S., and to that end they launched a variety of initiatives to encourage entrepreneurs and lure back researchers who studied overseas. Jiankui benefited from two of them: the Thousand Talents Recruitment Program and the Shenzhen government’s Peacock Initiative.
[k3989] Over the next six years, Jiankui’s company would receive about $5.7 million in funding from government sources. By 2017, its gene sequencer was on the market and the company, of which Jiankui had a one-third stake, was valued at $313 million. “The development of the device is a major technical breakthrough and will significantly improve cost-effectiveness, speed and quality of gene sequencing,” Jiankui said.
[k4006] “I support gene editing for the treatment and prevention of disease,” Jiankui wrote in a post on the social media site WeChat, “but not for enhancement or improving I.Q., which is not beneficial to society.”
[k4031] Jiankui described how he had edited the gene, which produces a protein that can serve as a receptor for the HIV virus, in mice, monkeys, and non-viable human embryos discarded from fertility clinics.
[k4035] “His talk made no impression on me,” Doudna says. “I found him very eager to meet people and be accepted, but he hadn’t published anything important, and he didn’t seem to be doing any important science.”
[k4047] Four months earlier, he had submitted a medical ethics application to Shenzhen’s Harmonicare Women and Children’s Hospital. “We plan to use CRISPR-Cas9 to edit the embryo,” he wrote. “The edited embryos will be transferred to women and pregnancy will follow.” His goal was to allow couples who suffered from AIDS to have babies who would be protected from the HIV virus, as would all of their descendants.
[k4057] There are approximately 1.25 million HIV-positive people in China, a number that is still growing rapidly, and ostracism of victims is widespread.
[k4063] Eleven were implanted into the volunteers unsuccessfully, but by the late spring of 2018 he was able to implant twin embryos into one mother and one embryo into another.
[k4093] As early as 2016, Jiankui told Quake that he wanted to be the first person to create gene-edited babies. Quake told him it was “a terrible idea,” but when Jiankui persisted, Quake suggested that he do it with the proper approvals. “I will take your suggestion that we will get a local ethic approval before we move on to the first genetic edited human baby,” Jiankui told Quake in an email, which was later reported by New York Times health writer Pam Belluck. “Please keep it in confidential.”
[k4132] Instead of following guidelines such as those established by the National Academy of Sciences, Jiankui had crafted a framework that, at least by his thinking, would justify his use of CRISPR to take out the receptor gene for HIV.
[k4144] At the time of Jiankui’s clinical trial, many serious ethical thinkers, and not just gung-ho scientific researchers, had publicly argued, using the CCR5 gene as a specific example, that gene editing to cure or prevent diseases could be permissible and even desirable.
[k4172] “We confirmed Nana’s CCR5 gene was edited successfully with frameshift mutations on both alleles and Lulu’s was heterozygous,” he admitted. In other words, Lulu had different gene versions on her two chromosomes, which meant that her system would still produce some of the CCR5 protein.
In addition, there was evidence that some unwanted off-target edits had been made and also that both embryos had been mosaics, meaning there had been enough cell division before the CRISPR editing was done that some of the resulting cells in the babies were unedited. Despite all of this, Jiankui later said, the parents chose to have both embryos implanted. Kiran Musunuru of the University of Pennsylvania later commented, “The first attempt to hack the code of life and, ostensibly, improve the health of human babies had in fact been a hack job.”
[k4264] One reason Jiankui was defiant was that he had thought he would be hailed as a Chinese hero, perhaps even a global one. Indeed,
[k4358] So they decided, once again, to steer a middle course. There was a need for more specific guidelines on when germline gene editing should be done, but it was also important to avoid rhetoric that would lead to national bans and moratoria. “The sense at the meeting was that the technology had advanced to the stage where we need to have a clear pathway to clinical use of gene editing in embryos,” Doudna says. In other words, instead of trying to stop any further uses of CRISPR to make gene-edited babies, she wanted to pave the way to making it safer to do so. “To put your head in the sand or say we need a moratorium is just not realistic,” she argues. “Instead we should say, ‘If you want to move into the clinic with gene editing, these are the specific steps that need to be taken.’”
[k4377] Josiah Zayner, the biohacker who had injected himself with a CRISPR-edited gene a year earlier, was so excited that he stayed up all night watching a livestream of He Jiankui’s announcement in Hong Kong.
[k4387] “For days I was so excited I couldn’t sleep, because it affirmed to me why I do what I do, which is to try to make sure that people can push humanity forward.”
Push humanity forward? Yes, sometimes it’s the rebels who do so. As Zayner speaks, his flat tones and crazy excitement remind me of a day when Steve Jobs sat in his backyard and recited from memory the lines he had helped craft for Apple’s “Think Different” commercial about the misfits and rebels and troublemakers who are not fond of rules and have no respect for the status quo. “They push the human race forward,” Jobs said. “Because the people who are crazy enough to think they can change the world, are the ones who do.”
One reason it would be hard to prevent future CRISPR babies, Zayner later explained in an essay for Stat, was that the technology would soon be within the reach of accomplished misfits.”
[k4408] As I start to push back, Zayner stops me cold by citing a personal example of the type of genetic disposition he would like to edit. “I suffer from bipolar disorder,” he says. “It’s terrible. It inflicts serious issues on my life. I would love to get rid of it.” Does he worry, I ask, that eliminating the disorder would change who he is? “People try to make up these lies that it helps you be more creative and all this other bullshit, but it’s a disease. It’s an illness that causes suffering, a shitload of suffering. And I think we could probably figure out ways to be creative without this disease.”
[k4421] When Doudna returned home from Hong Kong, she found that her teenage son could not understand why there was so much fuss about Jiankui’s gene editing. “Andy was very cavalier, which makes me wonder whether future generations will see this as such a big deal,” she says. “Maybe they’ll see it like IVF, which was very controversial when it first arose.” Her parents, she recalls, were shocked when the first test-tube baby was born in 1978. She was fourteen, had just read The Double Helix, and remembers discussing with them why they thought creating babies by in vitro fertilization was unnatural and felt wrong.
[k4485] As for Doudna, her opposition to a moratorium became stronger the more that Lander pushed it.
[k4495] Instead of being acclaimed a national hero, as he had fantasized, He Jiankui was put on trial at the end of 2019 in the People’s Court of Shenzhen. The proceedings had many elements of a fair trial: he was permitted to have his own attorneys and to speak in his own defense. But the verdict was not in doubt since he had pleaded guilty to the charge of “illegal medical practice.” He was sentenced to three years in prison, fined $430,000, and banned for life from working in reproductive science. “In order to pursue fame and profit, [he] deliberately violated the relevant national regulations and crossed the bottom lines of scientific and medical ethics,” the court declared.
[k4514] When He Jiankui produced the world’s first CRISPR babies, with the goal of making them and their descendants immune to an attack by a deadly virus, most responsible scientists expressed outrage. His actions were deemed to be at best premature and at worst abhorrent. But in the wake of the 2020 coronavirus pandemic, the idea of editing our genes to make us immune to virus attacks began to seem a bit less appalling and a bit more appealing.
[k4525] 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?
[k4535] There has already been, and rightly so, general acceptance of what is known as somatic editing, the changes that are made in targeted cells of a living patient and do not affect reproductive cells. If something goes wrong in one of these therapies, it can be disastrous for the patient but not for the species.
[k4548] Both of these techniques raise some of the same moral issues as germline gene editing. For example, James Watson, the outspoken co-discoverer of DNA, once opined that a woman should have the right to abort a fetus based on any preference or prejudice, including not wanting a child that would be short or dyslexic or gay or female. This caused a lot of people to recoil, understandably. Nevertheless, preimplantation genetic diagnosis is now considered morally acceptable, and parents are generally free to make their own choices about what criteria to use.
[k4585] If ever there was a case for editing a human gene, it would be for getting rid of the mutation that produces the cruel and painful killer known as Huntington’s disease.
[k4591] Huntington’s is a rare dominant disease; even one copy of the mutation spells doom.
[k4596] Fixing Huntington’s is not a complex edit.
[k4610] Sickle-cell anemia is an interesting next case to consider because it raises two complexities, one medical and the other moral. Like Huntington’s, sickle cell is caused by a simple mutation.
[k4619] Well, as with many such genes, there’s a complexity. People who get a copy of the gene from only one parent do not develop the disease, but they do develop immunity to most forms of malaria.
[k4651] Challenges and so-called disabilities often build character, teach acceptance, and instill resilience.
[k4664] In [Jory Fleming’s] 2021 memoir, How to Be Human, he reflects on whether gene editing should be used, if it becomes feasible, to eliminate some of the causes of autism. “You’d be removing an aspect of the human experience,” he writes, “but for what benefit exactly?” Autism, he argues, is a difficult condition to have, but the challenges largely come because the world is not good at accommodating people whose emotional lives are different.
[k4671] Once a vaccine was discovered to stop polio, we humans quickly and easily decided to use it to eliminate that disease from our species, even at the risk of allowing future Franklin Roosevelts to remain unforged.
[k4683] What if the embryo was typical, but they edited it to be deaf? Woult that be okay? What if they asked a doctor to punch out the child’s eardrums after birth?
[k4688] How do we distinguish between traits that are true disabilities and ones that are disabilities mainly because society is not good at adapting for them? Take the case of the deaf lesbian couple, for example. Some people may consider both the fact that they are deaf and the fact that they are lesbian as disadvantages.
[k4692] Likewise, being born Black in America could be considered a disadvantage. A single gene, SLC24A5, has a major influence on determining skin color. What if a set of Black parents considers their race to be a social handicap and wants to edit that gene to produce light-skinned babies?
[k4696] The disadvantages from being deaf, for a human or any other animal, are very real. In contrast, any disadvantages to being gay or Black are due to social attitudes that can and should be changed.
[k4705] Add to this mix a rare gene mutation that was discovered in the Olympic champion skier Eero M
ntyranta. 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.
[k4716] But there’s a problem with this fairness argument. Most successful athletes have always been people who happened to have better athletic genes than the rest of us. Personal effort is a component, but it helps to be born with the genes for good muscles, blood, coordination, and other innate advantages.
For example, almost every champion runner has what is known as the R allele of the ACTN3 gene. It produces a protein that builds fast-twitch muscle fibers, and it is also associated with improving strength and recovery from muscle injury. Someday it may be possible to edit this variation of the ACTN3 gene into the DNA of your kids. Would that be unfair? Is it unfair that some kids are born with it naturally? Why is one more unfair than the other?
[k4744] So enhanced height is a positional good, while enhanced resistance to viruses is an absolute good.
[k4753] DARPA already has a project going, in conjunction with Doudna’s lab, to study how to create genetically enhanced soldiers.
[k4800] Understanding the genetic components of wisdom may require us to understand consciousness, and I suspect that’s not going to happen in this century. In the meantime, we will have to deploy the finite allocation of wisdom that nature has dealt us as we ponder how to use the gene-editing techniques that we’ve discovered.
[k4822] Twitter, unsurprisingly, is not the best forum to discuss bioethics.
[k4832] On most great moral issues, there are two competing perspectives. One emphasizes individual rights, personal liberty, and a deference to personal choice.
[k4836] The contrasting perspectives are those that view justice and morality through the lens of what is best for the society and perhaps even (in the case of bioengineering and climate policy) the species.
[k4925] Diversity is good not only for society but for our species.
[k4926] The problem is that the value of diversity, as our thought experiments showed, can conflict with the value of individual choice.
[k4933] But the fact that inequality already exists is not an argument to increase or permanently enshrine it.
Permitting parents to buy the best genes for their kids would represent a true quantum leap in inequality.
[k4945] There are practices we cannot fully control, from shoplifting to sex trafficking, that are kept to a minimum by a combination of legal sanctions and social shaming.
[k4944] Despite such objections, it’s possible to aim for some social consensus on gene editing rather than simply leaving the issue totally to individual choice. There are practices we cannot fully control, from shoplifting to sex trafficking, that are kept to a minimum by a combination of legal sanctions and social shaming.
[k4953] As one Catholic theologian said at a National Academy of Medicine panel, “When I hear someone say that we shouldn’t play God, I’d guess that ninety percent of the time they are atheists.”
[k4964] Darwin wrote about “the clumsy, wasteful, blundering, low, and horridly cruel works of nature.” Evolution, he discovered, bears no fingerprints of an intelligent designer or benevolent God.
[k4968] 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.
[k4976] “What the drive to mastery misses and may even destroy is an appreciation of the gifted character of human powers and achievements,” Sandel writes. “To acknowledge the giftedness of life is to recognize that our talents and powers are not wholly our own doing.”
[k4981] When we create chemotherapies to fight cancer or vaccines to fight coronaviruses or gene-editing tools to fight birth defects, we are, quite properly, exercising mastery over nature rather than accepting the unbidden as a gift.
But Sandel’s argument should nudge us, I think, toward some humility, especially when it comes to trying to design enhancements and perfections for our children.
[k4998] [Doudna says,] “I am not sure how to make a sharp distinction in medicine between what is natural and what is unnatural, and I think it’s dangerous to use that dichotomy to block something that could alleviate suffering and disability.”
[k5005] “How could you not want to make progress on coming up with ways to prevent such a thing?” Doudna asks. “My heart broke.”
[k5016] Once you’ve seen the face of someone with a genetic disease, she says, especially one like Huntington’s, it’s hard to support why we would refrain from gene editing.
[k5020] The evolution in her thinking made her more sympathetic to the view that many gene-editing decisions should be left to individual choice rather than to bureaucrats and ethics panels. “I’m an American, and putting a high priority on personal freedom and choice is part of our culture,” she says. “I also think that as a parent I feel that I would want to have that choice to make about my own health or own family’s health as these new technologies come along.”
[k5028] “We could create a gene gap that would get wider with each new generation,” she says. “If you think we face inequalities now, imagine what it would be like if society became genetically tiered along economic lines and we transcribed our financial inequality into our genetic code.”
[k5050] While attending the 2019 CRISPR Conference in Quebec, I am struck by the realization that biology has become the new tech.
[k5056] As I wandered around reporting dispatches from the front lines of their revolution, I noticed that even as they pursue their new discoveries they feel tugged, sooner than the digital techies did, to engage in a moral reckoning about the new age they are creating.
[k5112] “Look at what parents are willing to do to get kids in college,” Zhang says. “Some people will surely pay for genetic enhancement. In a world in which there are people who don’t get access to eyeglasses, it’s hard to imagine how we will find a way to have equal access to gene enhancements. Imagine what that will do to our species.”
[k5139] (Later, I go online to see. The IDT website advertises “all of the reagents needed for successful genome editing,” with kits designed for delivery into human cells beginning at $95. Over at a site called GeneCopoeia, a Cas9 protein with a nuclear location signal starts at $85.)
[k5512] He got a response from the FDA on February 20 informing him that, in addition to sending his application electronically, he had to mail in a printed copy along with a copy burned onto a compact disc (remember what those were?) to FDA headquarters in Maryland. In an email he wrote to a friend that day describing the FDA’s bizarre approach, Greninger vented, “Repeat after me, emergency.”
A few days later, the FDA responded by requiring him to do more trials to see if the test he was using inadvertently detected the MERS and SARS viruses, even though they had been dormant for years and he had no samples of those viruses to test. When he called the CDC to see if he could get a sample of the old SARS virus, it refused. “That’s when I thought, ‘Huh, maybe the FDA and the CDC haven’t talked about this at all,’ “ Greninger told reporter Julia Ioffe. “I realized, Oh, wow, this is going to take a while.”
[k5537] 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.
[k5794] “We could create a STOP-flu or a STOP-HIV or have many detection targets on the same platform. The device is agnostic about what virus it’s looking for.”
Mammoth has the same vision of making it easy to reprogram its own tool to detect any new virus that comes along. “The beauty of CRISPR is that once you have the platform, then it’s just a matter of reconfiguring your chemistry to detect a different virus,” Chen explains.
[k5840] Vaccinations were pioneered in the 1790s by an English doctor named Edward Jenner who noticed that many milkmaids were immune to smallpox. They had all been infected by a form of pox that afflicts cows but is harmless to humans, and Jenner surmised that the cowpox had given the milkmaids immunity to smallpox. So he took some pus from a cowpox blister, rubbed it into scratches he made in the arm of his gardener’s eight-year-old son, and then (this was in the days before bioethics panels) exposed the kid to smallpox. He didn’t become ill.
[k5912] An RNA vaccine has certain advantages over a DNA vaccine. Most notably, the RNA does not need to get into the nucleus of the cell, where DNA is headquartered. The RNA does its work in the outer region of cells, the cytoplasm, which is where proteins are constructed. So an RNA vaccine simply needs to deliver its payload into this outer region.
[k5935] Lacking Pfizer’s resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, the government’s infectious disease expert, was supportive. “Go for it,” he declared. “Whatever it costs, don’t worry about it.” It took Moderna only two days to create the desired RNA sequences that would produce the spike protein, and thirty-eight days later it shipped the first box of vials to the NIH to begin early-stage trials. Afeyan keeps a picture of that box on his cell phone.
As with CRISPR therapies, a difficult part of the vaccine development was creating the delivery mechanism into the cell. Moderna had been working for ten years to perfect lipid nanoparticles, the tiny synthetic capsules that can carry molecules into a human cell. This gave it one advantage over BioNTech/Pfizer: its particles were more stable and did not have to be stored at extremely low temperatures. Moderna is also using this technology to deliver CRISPR into human cells.
[k5949] Specifically, [Zayner] decided to make and test a potential vaccine that had been described that May in a Science paper by researchers at Harvard.
[k5952] With the recipe in hand, Zayner ordered the ingredients and went to work.
From his garage lab in Oakland, just seven miles south of Doudna’s at Berkeley, Zayner launched a YouTube streaming course–named Project McAfee, after the anti-virus software–so that others could follow along and perform the experiments on themselves. “Biohackers can be like the test pilots of the modern world by doing the slightly crazy shit that needs to be done,” he declared.
[k5959] Also Skyping in was Dariia Dantseva, a student in Dnipro, Ukraine, who created her country’s first biohacking lab. “Ukraine is pretty easy about regulating biohacking, because the state literally does not exist,” she says. “I believe that knowledge is not just for the elites, it’s for all of us. That’s why we do this.”
[k5966] “If a bunch of scrubs like us can do this, hundreds of people could be doing it and moving science forward more quickly,” he says. “We want everyone to have the opportunity to create this DNA vaccine and test if it creates antibodies in human cells.”
[k5972] On Sunday, August 9, the three biohackers appeared together–from California, Mississippi, and Ukraine–in a live video-stream to inject into their arms the vaccines they had been concocting over the past two months.
[k5981] Some of the scientific researchers I talked to were appalled by what Zayner did. But I found myself rooting for him.
[k6021] “It was a bad day for viruses,” Moderna’s chair Afeyan says about the Sunday in November 2020 when he got the first word of the clinical trial results. “There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.”
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.
[k6254] If COVID doesn’t kill us, Zoom will.
[k6332] Until 2020, only five women, beginning with Marie Curie in 1911, had won a Nobel for chemistry, out of 184 honorees.
[k6345] “I was told more than a few times that girls don’t do chemistry or girls don’t do science. Fortunately, I ignored that.”
[k6374] By honoring CRISPR, a virus-fighting system found in nature, in the midst of a virus pandemic, the Nobel committee reminded us how curiosity-driven basic research can end up having very practical applications.
[k6383] “They’ve turned every interaction scientists have with each other into an intellectual property transaction,” says Berkeley biologist Michael Eisen. “Everything I get from or send to a colleague at another academic institution involves a complex legal agreement whose purpose is not to promote science but to protect the university’s ability to profit from hypothetical inventions that might arise from scientists doing what we’re supposed to do–share our work with each other.”
[k6436] People of my generation became fascinated by personal computers and the web. We made sure our kids learned how to code. Now we will have to make sure they understand the code of life.
One way to do that is for all of us older kids to realize, as the interwoven tales of CRISPR and COVID show, how useful it is to understand the way life works. It’s good that some people have strong opinions about the use of GMOs in food, but it would be even better if more of them knew what a genetically modified organism is (and what the yogurt-makers discovered). It’s good to have strong opinions about gene engineering in humans, but it’s even better if you know what a gene is.
[k6480] Or, to flummox those who would label gene editing as “unnatural” and “playing God,” let’s put it another way: Nature and nature’s God, in their infinite wisdom, have evolved a species that is able to modify its own genome, and that species happens to be ours.
[k6483] It could be one of those evolutionary traits that, as sometimes happens, leads a species down a path that endangers its survival. Evolution is fickle that way.
That’s why it works best as a slow process. Every now and then, a rogue or rebel–He Jiankui, Josiah Zayner–will prod us to go faster. But if we are wise, we can pause and decide to proceed with more caution. Slopes are less slippery that way.
[k6487] This is why it is useful, I think, for all of us to try to understand this new room that we are about to enter, one that seems mysterious but is rich with hope.