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

“We all see nature’s wonders every day, whether it be a plant that moves or a sunset that reaches with pink fingers into a sky of deep blue. The key to true curiosity is pausing to ponder the causes. What makes a sky blue or a sunset pink or a leaf of sleeping grass curl?”

One of the most important themes of The Code Breaker is the wonder that nature inspires. However, the text doesn’t stop at marveling at nature’s miracles; it prioritizes figuring out how these miracles work. Jennifer Doudna’s life as a scientist is testimony to the fact that true curiosity inspires invention. As a child, Doudna stopped to ponder the root cause behind each natural phenomenon she observed. As a chemist, she still carries that childlike sense of curious wonder, chasing the how and why of phenomenon to the deepest level. It is important to know how CRISPRs work and to discover what happens to tracrRNA after it creates crRNA. Ever-deepening curiosity molds scientists into visionaries.

“Franklin was a focused scientist, sensibly dressed. As a result she ran afoul English academia’s fondness for eccentrics and its tendency to look at women through a sexual lens, attitudes apparent in Watson’s descriptions of her. ‘Though her features were strong, she was not unattractive and might have been quite stunning had she taken even a mild interest in clothes,’ he wrote. ‘This she did not. There was never a lipstick to contrast with her straight, black hair, while at the age of thirty-one her dresses showed all the imagination of English bluestocking adolescents.’”

Though she came to be called the “godmother of gene editing” in the 21st century, the brilliant structural biologist and crystallographer Rosalind Franklin experienced considerable sexism in the 1950s. She lived in a time when her university had separate faculty lounges for women and men, and the former were dingy in comparison. Franklin was judged heavily for her refusal to conform to dominant mores of femininity, and her work appropriated by Watson and Crick. Doudna was inspired by Franklin’s life story and later came to apply Franklin’s crystallography method to determine the structure of RNA. Thus, a thread links Franklin and Doudna, showing that inheritance is more than biological.

“But her reactions when she first read his book as a sixth-grader were far different. It sparked the realization that it was possible to peel back the layers of nature’s beauty and discover, as she says, ‘how and why things worked at the most fundamental and inner level.’ Life was made up of molecules. The chemical components and structure of these molecules governed what they would do.”

James Watson’s The Double Helix was a life-changing book for Doudna. It introduced her to her hero Rosalind Franklin and crystallized her general interest in science to the specific field of structural chemistry. Chemistry was the perfect fit for Doudna’s avid, unending curiosity; it would help her unravel how things worked at the deepest, smallest, molecular level.

“Today we are learning the language in which God created life.”

The Human Genome Project aims to list all the more than 3 billion base pairs of nucleotides that make human DNA. When the project was celebrated at the White House in 2000, Bill Clinton described it as the language of life. Clinton’s grandiose announcement was emblematic of the hype, funding, and testosterone-soaked culture informing the project. As it played out, learning the genetic code was not enough to cure disease or help humanity. One also needed to learn to write and edit the code before approaching those milestones.

“DNA may be the world’s most famous molecule, so well-known that it appears on magazine covers and is used as a metaphor for traits that are ingrained in society or organization. But like many famous siblings, DNA doesn’t do much work. It mainly stays home in the nucleus of our cells, not venturing forth. Its primary activity is protecting the information it encodes and occasionally replicating itself. RNA, on the other hand, actually goes out and does real work.”

Though RNA is the star molecule of CRISPR-related gene editing, The Code Breaker, and Jennifer Doudna’s career, it was historically ignored in favor of DNA. So ubiquitous is DNA to collective imagination that phrases like “acting is in my DNA,” or “camaraderie is part of our company’s DNA” are de rigueur. No one makes such statements about RNA (yet). Isaacson uncovers RNA’s true scope of work and potential in his text, focusing on why RNA is so suited to gene editing. Because DNA sits in a cell’s tough nucleus, it is harder to target and manipulate into a gene-editing vehicle. RNA is far more approachable and versatile. Isaacson also busts the myth that the RNA’s only function is to act as DNA’s messenger, showing how RNA also acts as an enzyme that can splice itself and even replicate. RNA’s unassuming versatility is symbolic of the work of women scientists, who are often denied their due. Therefore, it is poetic justice that Jennifer Doudna and Emmanuelle Charpentier helped put the spotlight on RNA.

“Szostak had a guiding principle: Never do something that a thousand other people are doing.”

Canadian American biologist Jack Szostak was instrumental in Doudna’s career. As a doctoral student in his lab at Harvard, Doudna learned the importance of forging her own trail as well as Szostak’s other maxim: ask big questions. Unlike the DNA-obsessed crowd of the 1980s, Szostak wanted to work on the RNA molecule, igniting a similar passion in Doudna, who would be the first of his doctoral students to study RNA. Her ability to take risks and think outside the box have come to define Doudna, qualities she believes Szostak nurtured.

“What Mojica had stumbled upon was a battlefront in the longest-running, most massive and vicious war in this planet: between bacteria and the viruses, known as ‘bacteriophages’ or ‘phages,’ that attack them.”

Jennifer Doudna and Emmanuelle Charpentier earned the Nobel Prize for their inventions in CRISPR, but many scientists contributed equally to the development of this technology. The first of these was Francisco Mojica, who actually discovered repeat spaced-out sequences in bacteria in 1990 and came up with the catchy acronym CRISPR. Bacteria uses CRISPRs to destroy attacking viruses. It is significant that the text focusses on Mojica’s discovery and acknowledges that he could have been a third winner of the 2020 Nobel that went to Doudna and Charpentier. This stresses the textual theme that scientific discoveries rarely occur in isolation; rather, they are a result of intergenerational advances.

“Science can be the parent of invention. But as Matt Ridley point out in his book How Innovation Works, sometimes it’s a two-way street. ‘It is just as often the case that invention is the parent of science: techniques and processes are developed that work, but the understanding of them comes later,’ he writes. ‘Steam engines led to the understanding of thermodynamics, not the other way round. Powered flight preceded almost all aerodynamics.’”

Isaacson dismantles the notion that all applications and inventions grow from discoveries made by scientists. He does not view industry and research labs as adversaries either. Though scientific progress is linear in the sense that researchers build upon the work of others, it is also iterative and radial. Sometimes inventions are made before a science is even formulated, as in the case of aerodynamics. That is why a healthy synergy between pure and applied sciences and industry is in society’s best interest.

“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 they had developed a means to rewrite the code of life.”

CRISPR-Cas9 is such a powerful gene-editing tool because of its adaptability. Later chapters show this adaptability in action, when the platform is used to create fast diagnostics tests for COVID-19. That’s just the tip of the iceberg: The technology can be adapted to diagnose anything from viral infections to cancers. Work is also in progress on CRISPR-based viral therapies, a game-changer because they target viruses, not the immune system.

“‘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.’”

Although the relationship between Emmanuelle Charpentier and Jennifer Doudna has endured strain, Charpentier admires Doudna’s ambition. Charpentier’s statements are especially pertinent because a competitive streak is viewed negatively in scientists, especially in women scientists. Notions of scientists as noble-minded creatures working for the pure love of their pursuits are widespread but false. Like all human beings, scientists are driven by a desire for recognition and achievement. Further, competition spurs discovery and innovation. In the text male scientists like Eric Lander are quoted as casting aspersions on Doudna’s chasing of laurels. However, as a woman in science, Charpentier knows women scientists often have to shout to be heard. Hence, Doudna’s ambition is a necessary engine.

“In gene editing, you have to know whether or not it cleaves in cells. I always worked directly in cells. Not in vitro. Because the environments in cells is different than the biochemistry environment.”

The rivalry between Jennifer Doudna and Feng Zhang of the Broad Institute is an important motif in The Code Breaker. Things took a sharp turn for the bitter when Zhang and Doudna competed over the patent to use CRISPR in human cells. Zhang believed he deserved the patent since his team made CRISPR work in human cells; Doudna’s work was in test tubes. Doudna’s argument was that unless the technology existed, Zhang would never have been able to make it work in human cells. It’s an unsolvable chicken-and-egg problem, but Isaacson posits that both Zhang and Doudna were right. Biochemistry and structural chemistry are natural complements. If anything, Zhang’s critique of Doudna shows that the sciences are increasingly convergent. This also ties into the text’s larger push for an interdisciplinary approach toward research.

“Some great discoveries and inventions—such as Einstein’s theory of relativity and the creation of the transistor at Bell labs—are singular advances. Others—such as the invention of the microchip and the application of CRISPR to edit human cells—were accomplished by many groups around the same time.”

January 2013 saw the publication of as many as five different papers on CRISPR-Cas9 editing in animal cells. Does this imply the move from bacteria to animal cells was actually as “obvious” as Doudna had said all along? Now that the components of the CRISPR-Cas9 system had been isolated in a test tube, could a minor innovation easily transplant the system into animal or even human cells? Or was the publication of the papers simply following the pattern of discoveries like the microchip? Isaacson leaves these questions open-ended, but there is another aspect to consider. Singular discoveries are less common in the information age, when data can easily be searched online. Perhaps science has entered the time of parallel discoveries.

“‘There is something mesmerizing about an evil genius at the height of his craft, and Eric Lander is an evil genius at the height of his craft,’ he wrote and posted publicly a few days after the article appeared. He called the piece ‘at once so evil and yet so brilliant that I find it hard not to stand in awe even as I picture him cackling loudly in his Kendall Square lair, giant laser weapon behind him poised to destroy Berkeley if we don’t hand over our patents.’”

Why did Eric Lander infamously undermine Doudna’s achievements in his controversial 2016 paper “Heroes of CRISPR”? According to Doudna’s friend and genetics professor Michael Eisen, Lander’s motive was a bid to promote Feng Zhang (Doudna’s rival and Lander’s colleague at the Broad Institute). Other scientists and commentators detect more than a whiff of sexism in Lander’s framing of CRISPR history, which aimed to edit out Doudna. However, since Lander celebrated Charpentier’s inventions, the article was probably motivated out of a misplaced sense of protectiveness for Zhang.

“Don’t fight over divvying up the proceeds until you finish robbing the stagecoach.”

Along with collaborations, sometimes science needs compromises. Zhang and Doudna’s bitter wrangle over patents proves this thesis. Their battle ensured both sides were fighting to monetize their CRISPR technologies for several years. In retrospect, Doudna thinks she and Zhang could have come together to save each side a lot of time, money, and pain. They could have learned from the example of Jack Kilby of Texas Instruments and Robert Noyce of Intel, who agreed to share the patent rights for the microchip. Shrewder than Zhang and Doudna, that duo first made sure they followed the old adage: they finished robbing the coach before fighting over its spoils.

“‘We have 100,000 people in the U.S. affected by sickle cell,’ one senator pointed out. ‘How are we going to afford that if its $1 million per patient? That just breaks the bank.’”

Since sickle-cell anemia is caused by a single mutation in DNA, it is one of the best candidates for CRISPR genes-editing in somatic cells. Yet when Doudna discussed including the treatment option in public healthcare with a group of US senators, the biggest barrier they envisioned was not ethical but financial. Gene editing is an expensive affair and could bankrupt the public health system. However, making such treatments available on the free market will worsen the world’s inequality crisis, one of the key issues the text examines. The best solution is to make gene-editing treatments, like those for sickle cell, affordable.

“No great technology has flourished until people had complete access to it.”

Should gene-editing technology be made available to everyone, in the manner of digital coding? Many scientists believe otherwise, but biohackers like Josiah Zayner contest their objections. According to Zayner, putting technology in an ivory tower only enables its misuse and creates knowledge inequality. He believes people should be free to edit their genetic material in their homes, as he did when he injected himself with a cocktail meant to disable the gene that stops muscle growth in adulthood. Zayner’s contention that technology must be democratized to thrive has a point. More problematic are his views around being able to edit the DNA for one’s offspring to enhance traits like IQ and height.

“‘Have we created a toolbox for future Frankensteins?’ she asked herself. Or perhaps even worse, future Hitlers?” 

In December 2014, Jennifer Doudna had a nightmare where she met someone who wanted to learn about gene editing; that someone turned out to be Adolf Hitler with the face of a pig, readying to take notes from Doudna. To Doudna, the nightmare seemed like a premonition: What if she had helped create a toolkit for terrorists, genocidal dictators, and evil scientists? The question reveals something about Doudna’s character. Unlike someone like James Watson, for whom the high of progress obliterates most questions around ethics, Doudna is more thoughtful and measured. Different voices repeat versions of Doudna’s question throughout the book, and there is no singular answer. However, Isaacson posits approaching the question from a different angle: Would it not be evil to refrain from using gene editing as a cure for terrible conditions? Doudna’s views on gene editing have evolved since the 2014 nightmare, especially as the coronavirus crisis snowballed. The toolbox of gene editing cannot be locked up, but like all tools, its offerings must be handled with caution.

“‘Here we report the first birth from human gene editing: twin girls who had undergone CCR5 gene editing as embryos were born normal and healthy in November 2018.’ In the article, Jiankui defended the ethical value of what he had done. ‘We anticipate that human genome editing will bring new hope to millions of families seeking healthy babies free from inherited or acquired life-threatening conditions.’”

Nightmares about the dubious use of gene editing came true when Chinese scientist He Jiankui performed gene editing in viable twin embryos and implanted them in a mother, leading to the birth of the world’s first “designer” babies. While the world condemned Jiankui, he insisted his actions were altruistic. He had ensured the babies would never be infected with HIV, which afflicted their father. HIV is far more stigmatizing in China than in the West, with many HIV-positive children abandoned by families. Though Jiankui was incarcerated for his breach of international medical conventions, his experiment renewed the argument around the ethics of gene editing. It also showed that the idea of what is considered “medically necessary” may not be the same across cultures and countries.

“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?”

When is gene editing, especially in embryonic cells, medically necessary? Some ethicists draw the line at diseases that profoundly impact the quality of life, such as Huntington’s disease, while others think gene editing can be used to help the broader category of “disabilities.” The problem with the latter approach is that everyone’s idea of a disability may not be the same. Perhaps being visually or hearing impaired is a clear disability (though many who are so impaired may not identify as disabled). However, some disabilities are influenced by cultural norms. James Watson problematically said that a parent should be able to abort a fetus if they don’t want it to be a female or “homosexual” (though, of course, there is no gene for sexuality). What if some parents consider a female child a disadvantage in a patriarchal society? Thus, Isaacson suggests that gene editing, an ethical minefield, is best navigated with the help of humanities experts in ethics, philosophy, sociology, economics, and other disciplines.

“The idea that germline editing was ‘unnatural’ began to recede in her thinking. All medical advances attempt to correct something that happened naturally, she realized. ‘Sometimes nature does things that are downright cruel, and there are many mutations that cause enormous suffering, so the idea that germline editing was unnatural began to carry less weight for me,’ she 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.’”

As Doudna’s views on the ethics of gene editing have evolved, she raises a very pertinent point: Is everything natural necessarily beneficial? Is that true of debilitating autoimmune conditions and terrible cancers? And to take the corollary of an “unnatural” treatment further, isn’t all treatment unnatural since it interferes with the course of nature? Doudna suggests that dismissing gene editing as sacrilegious or unnatural is a dangerous notion that robs many sufferers of the chance for a better life. A parent whose child suffers from debilitating pain or needs monthly blood transfusions to survive may see a gene-editing cure as a miracle, a gift from nature or God. After all, CRISPR-related gene editing is inspired by nature.

“‘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 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.’”

The strongest argument against making gene editing available in the free market comes from scientists like Feng Zhang, and it is purely secular: Gene editing can, and will, aggravate inequality unless monitored very closely. The globe’s inequality problem is already monstrous. Imagine a world where some parents can’t buy their children shoes and even nutritious food, but others can buy theirs a higher IQ and more muscular strength. Zhang predicts that the availability of gene-editing technologies will ultimately mean the availability of genetic enhancements, which will create catastrophic inequalities that will be further exacerbated by prejudices around race, gender, sexuality, national origin, disabilities, and more.

“The COVID pandemic that killed more than 1.5 million people in 2020 will not be the final plague. However, thanks to the RNA technology, our defenses against most future viruses are likely to be immensely faster and more effective. ‘It was a bad day for viruses,’ Moderna’s chair Afeyan says about the Sunday in August 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 viruses can do. We may never have a pandemic again.’”

While Moderna’s speculation that RNA gene editing will lead to the end of pandemics may be a tad optimistic, gene editing does give hope for better diagnostic tests, antiviral therapies, and vaccines. In the coronavirus pandemic, RNA-based vaccines, such as those produced by Pfizer and Moderna, are proving among the most effective. These novel RNA-based vaccines contain mRNA that directs cells to make a part of the coronavirus’s trademark spike protein. In response, the body also builds antibodies. Now that mRNA vaccine platforms are available, they may be adapted to viruses of the future. The COVID-19 pandemic has laid to rest some questions about the ethics of gene-editing treatments. In the face of such an enormous medical crisis, there is not much time to dither. People must use all available technologies to fight crises like COVID-19.

“If COVID doesn’t kill us, Zoom will. As Steve Jobs emphasized when he built a headquarters for Pixar and planned a new Apple campus, new ideas are born out of serendipitous encounters. In-person interactions are especially important in the initial brainstorming of new ideas and the forging of personal bonds. As Aristotle taught, we are a social animal, an instinct that cannot fully be satisfied online.”

While writing their biographies, Isaacson closely followed inventors like Steve Jobs and Jennifer Doudna. One aspect of their work that made an impression on him was that much of it occurred through a dynamic exchange of ideas in offline, real-world settings. Though technologies like Zoom enabled people to stay connected during the coronavirus pandemic, Isaacson fears they will inhibit scientific progress due to the lack of spontaneity. While Isaacson’s apprehensions are relevant, it is also possible scientists will evolve a hybrid offline-online model to brainstorm new ideas.