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.

The invention of CRISPR and the plague of COVID will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery, beginning just over a century ago, of the three fundamental kernels of our existence: the atom, the bit, and the gene.

Now we have entered a third and even more momentous era, a life-science revolution. Children who study digital coding will be joined by those who study genetic code.

When Doudna was a graduate student in the 1990s, other biologists were racing to map the genes that are coded by our DNA. But she became more interested in DNA’s less-celebrated sibling, RNA. It’s the molecule that actually does the work in a cell by copying some of the instructions coded by the DNA and using them to build proteins.

the key to innovation is connecting a curiosity about basic science to the practical work of devising tools that can be applied to our lives—moving discoveries from lab bench to bedside.

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?

“Maybe that explains my fascination with science, which is humanity’s attempt to understand the longest-running mystery we know: the origin and function of the natural world and our place in it.”

Darwin and Wallace had a key trait that is a catalyst for creativity: they had wide-ranging interests and were able to make connections between different disciplines.

From an evolutionary perspective, both the simplest coronavirus and the most complex human are essentially protein-wrapped packages that contain and seek to replicate the genetic material encoded by their nucleic acids.

“Hypocrisy in search of social acceptance erodes your self-respect.”

The easiest of these viruses to study are the ones that attack bacteria, and they were dubbed (remember the term, for it will reappear when we discuss the discovery of CRISPR) “phages,” which was short for “bacteriophages,” meaning bacteria-eaters.

But The Double Helix painted a more vibrant picture. “It made me realize that science can be very exciting, like being on a trail of a cool mystery and you’re getting a clue here and a clue there. And then you put the pieces together.”

In chemistry class at college, most of the experiments were conducted by following a recipe. There was a rigid protocol and a right answer. “The work in Don’s lab wasn’t like that,” she said. “Unlike in class, we didn’t know the answer we were supposed to get.” It gave her a taste of the thrill of discovery.

Her experiments gave her a glimpse of how basic science can be turned into applied science. Yeast cells are very efficient at taking up pieces of DNA and integrating them into their genetic makeup. So she worked on a way to make use of this fact. She engineered strands of DNA that ended with a sequence that matched a sequence in the yeast. With a little electric shock, she opened up tiny passageways in the cell wall of the yeast, allowing the DNA that she made to wriggle inside. It then recombined into the yeast’s DNA. She had made a tool that could edit the genes of yeast.

RNA interference operates by deploying an enzyme known as “Dicer.” Dicer snips a long piece of RNA into short fragments. These little fragments can then embark on a search-and-destroy mission: they seek out a messenger RNA molecule that has matching letters, then they use a scissors-like enzyme to chop it up. The genetic information carried by that messenger RNA is thus silenced.

The scientist does not study nature because it is useful. He studies it because he takes pleasure in it, and he takes pleasure in it because it is beautiful. —Henri Poincaré, Science and Method, 1908

CRISPR, for “clustered regularly interspaced short palindromic repeats.”

Enzymes are a type of protein. Their main function is to act as a catalyst that sparks chemical reactions in the cells of living organisms, from bacteria to humans. There are more than five thousand biochemical reactions that are catalyzed by enzymes. These include breaking down starches and proteins in the digestive system, causing muscles to contract, sending signals between cells, regulating metabolism, and (most important for this discussion) cutting and splicing DNA and RNA.

Science can be the parent of invention. But as Matt Ridley points 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.”

“Small meetings, where unpublished data and ideas can be shared and everyone helps everyone, can change the world,” Banfield later noted.

The year of the inaugural conference produced a major advance. Luciano Marraffini and his advisor Erik Sontheimer of Northwestern University in Chicago showed that the target of the CRISPR system was DNA. In other words, CRISPR did not work through RNA interference, which had been the general consensus when Banfield first approached Doudna. Instead, the CRISPR system targeted the DNA of the invading virus.

That had a holy-cow implication. As Marraffini and Sontheimer realized, if the CRISPR system was aimed at the DNA of viruses, then it could possibly be turned into a gene-editing tool.

“If it could target and cut DNA, it would allow you to fix the cause of a genetic problem.”

This transition from player to coach happens in many fields. Writers become editors, engineers become managers. When bench scientists become lab heads their new managerial duties include hiring the right young researchers, mentoring them, going over their results, suggesting new experiments, and offering up the insights that come from having been there.

These two elements are the core of the CRISPR system: a small snippet of RNA that acts as a guide and an enzyme that acts as scissors.

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.

In-person meetings can produce ideas in ways that conference calls and Zoom meetings can’t. That had happened in Puerto Rico, and it did so again when the four researchers got together for the first time in Berkeley.

Physical meetings are especially useful when a project is in an early phase. “There’s nothing like sitting in a room with people and seeing their reactions to things and having a chance to bat around ideas face to face,” Doudna says. “That’s been a cornerstone to every collaboration that we’ve had, even those where we are conducting a lot of the work by electronic communication.”

“Without the tracrRNA, the crRNA guide does not bind to the Cas9 enzyme.”

“In other words, we could add a different crRNA and get it to cut any different DNA sequence we chose.”

“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.

Competition drives discovery.

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

CRISPR in Action If ever man fell ill, there was no defense —no healing food, no ointment, nor any drink— but for lack of medicine they wasted away, until I showed them how to mix soothing remedies. —Prometheus, in Aeschylus’s Prometheus Bound

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.

Despite the dangers, there could be benefits if biotech followed this route. During a pandemic, it would be useful if societies could tap the biological wisdom and innovation of crowds. At the very least, it would be good to have citizens who could test themselves and their neighbors at home. Contact tracing and data collection could be crowdsourced. Today, there is a sharp line dividing officially sanctioned biologists from do-it-yourself hackers, but Josiah Zayner is dedicated to changing that. CRISPR and COVID could help him blur those lines.

This was a new room, rich with hope, terrible with strange danger. A dim folk memory had preserved the story of a greater advance: “the winged hound of Zeus” tearing from Prometheus’ liver the price of fire. Was the world ready for the new step forward? Certainly, it will change the world. You have to make laws to fit it. And if plain people did not understand and control it, who would? —Excerpted from James Agee’s cover story, “Atomic Age,” on the dropping of the atom bomb, Time, August 20, 1945

Focusing mainly on philosophical rather than safety concerns, the authors discussed what it meant to be human, to pursue happiness, to respect nature’s gifts, and to accept the given. 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. “We want better children—but not by turning procreation into manufacture or by altering their brains to gain them an edge over their peers,” they wrote. “We want to perform better in the activities of life—but not by becoming mere creatures of our chemists or by turning ourselves into tools designed to win or achieve in inhuman ways.” One can almost sense a congregation nodding “Amen” while a few people in the back mutter, “Speak for yourself.”

CRISPR Babies A new species would bless me as its creator and source; many happy and excellent natures would owe their being to me. —Mary Shelley, Frankenstein; or, The Modern Prometheus, 1818

If scientists don’t play God, who will? —James Watson, to Britain’s Parliamentary and Scientific Committee, May 16, 2000

The issue is one of the most profound we humans have ever faced. For the first time in the evolution of life on this planet, a species has developed the capacity to edit its own genetic makeup. That offers the potential of wondrous benefits, including the elimination of many deadly diseases and debilitating abnormalities. And it will someday offer both the promise and the peril of allowing us, or some of us, to boost our bodies and enhance our babies to have better muscles, minds, memory, and moods.

That doesn’t answer the question of whether we should allow genetic enhancements. But as we grope for a set of principles to include in our moral calculus, the distinction does point to a factor we should consider: favoring enhancements that would benefit all of society over those that would give the recipient a positional advantage.

So now we can see a problem with simply leaving such decisions to individual choice. A liberal or libertarian genetics of individual choice could eventually lead us—just as surely as government-controlled eugenics—to a society with less diversity and deviation from the norm. That might be pleasing to a parent, but we would end up in a society with a lot less creativity, inspiration, and edge. Diversity is good not only for society but for our species. Like any species, our evolution and resilience are strengthened by a bit of randomness in the gene pool.

The problem is that the value of diversity, as our thought experiments showed, can conflict with the value of individual choice. As a society, we may feel that it is profoundly beneficial to the community to have people who are short and tall, gay and straight, placid and tormented, blind and sighted. But what moral right do we have to require another family to forgo a desired genetic intervention simply for the sake of adding to the diversity of society? Would we want the state to require that of us?

For all of history, humans (and every other species) have been battling rather than accepting nature’s poisoned offerings. Mother Nature has produced massive suffering and distributed it unequally. Thus we devise ways to combat plagues, cure diseases, fix disabilities, and breed better plants, animals, and children.

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.”

She is confident that the good that can come from CRISPR will eventually outweigh the dangers. “Science doesn’t move backwards, and we can’t unlearn this knowledge, so we need to find a prudent path forward,” she says, reprising the phrase in the title of the report she wrote after her 2015 Napa Valley meeting. “We’ve never seen anything like this before. We now have the power to control our genetic future, which is awesome and terrifying. So we must move forward cautiously and with respect for the power we’ve gained.”

Here’s to the crazy ones. The misfits. The rebels. The troublemakers. The round pegs in the square holes. The ones who see things differently. They’re not fond of rules. And they have no respect for the status quo. You can quote them, disagree with them, glorify or vilify them. About the only thing you can’t do is ignore them. Because they change things. They push the human race forward. And while some may see them as the crazy ones, we see genius. Because the people who are crazy enough to think they can change the world are the ones who do. —Steve Jobs, Apple’s “Think Different” ad, 1997

Coronavirus I have no idea what’s awaiting me, or what will happen when this all ends. For the moment I know this: there are sick people and they need curing. —Albert Camus, The Plague, 1947

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.