Selected Passages from The Code Breaker
I’m in the process of writing a review of The Code Breaker, a book about Jennifer Doudna and the use of CRISPR in gene editing.
There are plenty of great quotes in the book, many of which won’t make it into the final draft of the review. It seems like a shame to not share them. If you’re interested in reading the book, this post might be a good sample to get a taste for the writing and content.
Below you’ll find every quote from the book that I highlighted. Bold sentences stood out to me as particularly good.
Two revolutions coincided in the 1950s. Mathematicians, including Claude Shannon and Alan Turing, showed that all information could be encoded by binary digits, known as bits. This led to a digital revolution powered by circuits with on-off switches that processed information.
Simultaneously, Watson and Crick discovered how instructions for building every cell in every form of life were encoded by the four-letter sequences of DNA. Thus was born an information age based on digital coding (0100110111001. ..) and genetic coding (ACTGGTAGATTACA...). The flow of history is accelerated when two rivers converge.
When it came time to go to graduate school, she did not initially consider Harvard, despite being the top student in her physical chemistry class. But her father pushed her to apply. "Come on, Dad,"she pleaded, “I will never get in."To which he replied, "You certainly won't get in if don't apply." She did get in, and Harvard even offered her a generous stipend.
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.
Mojica had been corresponding with Ruud Jansen of Utrecht University in the Netherlands, who was studying these sequences in tuberculosis bacteria. He had been calling them "“direct repeats," but he agreed that they needed to come up with a better name. Mojica was driving home from his lab one evening when he came up with the name CRISPR, for "clustered regularly interspaced short palindromic repeats." Although the clunky phrase was almost impossible to remember, the acronym CRISPR was, indeed, crisp and crispy. It sounded friendly rather than intimidating, though the dropped "e" gave it a futurist sheen. When he got home, he asked his wife what she thought of the name. "It sounds like a great name for a dog," she said. "Crispr, Crispr, come here, pup!" He laughed and decided it would work.
What Mojica had stumbled upon was a battlefront in the longest running, most massive and vicious war on this planet: that between bacteria and the viruses, known as “bacteriophages" or “phages," that attack them. Phages are the largest category of virus in nature. Indeed, phage viruses are by far the most plentiful biological entity on earth.
There are a trillion phages for every grain of sand, and more than all organisms (including bacteria) combined. In one milliliter (0.03 ounces) of seawater there can be as many as 900 million of these viruses. As we humans struggle to fight off novel strains of viruses, it's useful to note that bacteria have been doing this for about three billion years, give or take a few million centuries. Almost from the beginning of life on this planet, there's been an intense arms race between bacteria, which developed elaborate methods of defending against viruses, and the ever-evolving viruses, which sought ways to thwart those defenses.
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.
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 (CFRNA), 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!
Historians of science and technology, including myself, often write about what is called the "linear model of innovation." It was propagated by Vannevar Bush, an MIT engineering dean who cofounded Raytheon and during World War II headed the U.S. Office of Scientific Research and Development, which oversaw the invention of radar and the atom bomb. In a 1945 report, "Science, the Endless Frontier,'
Bush argued that basic curiosity-driven science is the seed corn that eventually leads to new technologies and innovations. "New products and new processes do not appear full-grown," he wrote. "They are founded on new principles and new conceptions, which in turn are painstakingly developed by research in the purest realms of science.
Basic research is the pacemaker of technological progress." Based on this report, President Harry Truman launched the National Science Foundation, a government agency that provides funding for basic research, mainly at universities.
The story of CRISPR at first seems to accord with the linear model.
Basic researchers such as Francisco Mojica pursued an oddity of nature out of pure curiosity, and that seeded the ground for applied technologies such as gene editing and tools to fight coronaviruses. However, as with the transistor, it was not simply a one-way linear progression.
Instead, there was an iterative dance among basic scientists, practical inventors, and business leaders.
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."
The source of the difficulty turned out to be that the sequencing of the bacteria's genome had been annotated incorrectly in textbooks and databases. "Blake realized that the reason we were having so much trouble was that they got the start wrong," Haurwitz explains. Once they figured out the problem, they were able to make Cas6 in the lab.
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.? "Until then, I didn't know much about biology and didn't find it interesting, because in seventh grade all they did was give you a tray with a frog and tell you to dissect it and identify the heart," he recalls. "It was all memorization and not very challenging."In the Saturday enrichment class, the focus was on DNA and how RNA carried out its instructions, with an emphasis on the role played in this process by enzymes, those protein molecules that act as catalysts to spark actions in a cell. "My teacher loved enzymes,"
Zhang says. "He told me that whenever you face a tough question in biology, just say 'Enzymes.' It's the correct answer to most questions in biology."
When his mother drove him in her Buick up to the 1964 World's Fair in New York, he became tantalized by the future. It made him feel impatient about being stranded in the present. "I wanted to get to the future, I felt that's where I belonged, and that's when I realized that it was something I had to help create," he says. As the science writer Ben Mezrich noted of Church, "Later in life, he would return to this moment as the instant when he first started to think of himself as a sort of time traveler. Deep down, he started to believe that he was from the far future, and had somehow been left in the past. It was his task in life to try to get back, to try to shift the world to where he had once been."
Some great discoveries and inventions — such as Einstein's theories 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 editing human cells — were accomplished by many groups at around the same time.
I believe that, on balance, American science has benefited from the current mix of federal funding and commercial incentives. To turn a basic scientific discovery into a tool or a drug can cost billions of dollars. Unless there is a way to recoup that, there won't be as much investment in research. The development of CRISPR and the therapies it led to are a good example.
To an unnecessary extent, the prolonged fight was driven by emotions and resentments. Instead, Doudna and Zhang could have followed the example of Jack Kilby of Texas Instruments and Robert Noyce of Intel who, after five years of wrangling, agreed to share the patent rights for the microchip by cross-licensing their intellectual property to each other and splitting the royalties, which helped the microchip business grow exponentially and define a new age of technology. 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.
In most cases, the biohackers are, like Zayner, accomplished scientists who forgo working at universities or corporations and instead become the rogue wizards of a rarefied part of the do-it-yourself maker's movement. In the drama of CRISPR, Zayner plays the role of one of Shakespeare's wise fools, such as Puck in A Midsummer Night's Dream, who speaks truth under the guise of showmanship, pokes fun at the pretensions of the high-minded, and pushes us forward by pointing out what fools these mortals be.
If scientists don't play God, who will?
-James Watson, to Britain's Parliamentary and Scientific Committee, May 16, 2000
[Huntington’s] victims often have children before they know they have the genetic disease. Therefore, it's not weeded out by natural selection. The evolutionary process cares little about what happens to us after we have children and get them to a safe age, so there are a whole bunch of middle-aged maladies, including Huntington's and most forms of cancer, that we humans would want to eliminate, even though nature sees no need to.
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. Examples include requirements that schoolkids be vaccinated and that people wear masks during a pandemic. The emphasis on societal benefits rather than individual rights can take the form of John Stuart Mill's utilitarianism, which seeks the greatest amount of happiness in a society even if that means trampling on the liberty of some individuals.
Or it can take the form of more complex social contract theories, in which moral obligations arise from the agreements we would make to form the society we want to live in.
These contrasting perspectives form the most basic political divide of our times. On the one side are those who wish to maximize individual liberty, minimize regulations and taxes, and keep the state out of our lives as much as possible. On the other side are those who wish to promote the common good, create benefits for all of society, minimize the harm that an untrammeled free market can do to our work and environment, and restrict selfish behaviors that might harm the community and the planet.
These design flaws are not mere exceptions. They are the natural consequence of the way evolution progresses. It stumbles upon and then cobbles together new features, sort of like what happened during the worst eras of Microsoft Office, rather than proceed with a master plan and end product in mind. Evolution's primary guide is reproductive fitness-what traits might cause an organism to reproduce more-which means it permits, and perhaps even encourages, all sorts of plagues, including coronaviruses and cancers, that afflict an organism once its childbearing use is over. This does not mean that, out of respect for nature, we should quit searching for ways to fight against coronaviruses and cancer.
When he got the assignment from Doudna to lead the lab, he sent around a quote from Tolkien's Lord of the Rings:
"I wish it need not have happened in my time," said Frodo.
"So do I," said Gandalf, "and so do all who live to see such times. But that is not for them to decide. All we have to decide is what to do with the time that is given us.
Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. The first known one was the Babylon flu epidemic around 1200 BC. The plague of Athens in 429 BC killed close to 100,000 people, the Antonine plague in the second century killed ten million, the plague of Justinian in the sixth century killed fifty million, and the Black Death of the fourteenth century took almost 200 million lives, close to half of Europe's population.
The COVID pandemic that killed more than 1.5 million people in 2020 will not be the final plague. However, thanks to the new RNA vaccine 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 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.
I was invited to moderate a panel about COVID, and I began by asking Zhang and Doudna about the possibility that the pandemic might create greater public interest in biology. When at-home testing kits become low-cost and easy to use, Zhang replied, they will democratize and decentralize medicine. The most important next steps will be innovations in "microfluidics," which involves channeling tiny amounts of liquid in a device, and then connecting the information to our cell phones. That will allow us all, in the privacy of our homes, to test our saliva and blood for hundreds of medical indicators, monitor our health conditions on our phones, and share the data with doctors and researchers.
Beginning in 2016, Liu began developing a technique known as “base editing," which can make a precise change in a single letter in DNA without cutting a break in the strands. It's like a very sharp pencil for editing. At the 2019 Cold Spring Harbor meeting, he announced a further advance called "prime editing," in which a guide RNA can carry a long sequence to be edited into a targeted segment of DNA. It requires making only a tiny nick in the DNA rather than a double-strand break. Edits of up to eighty letters are possible. "If CRISPR-Cas9 is like scissors and base editors are like pencils, then you can think of prime editors as like word processors," Liu explained.
Dozens of the presentations at the 2020 meeting involved young researchers who had found clever new ways to use base editing and prime editing. Liu himself described his latest discovery of how to deploy base-editing tools into the energy-producing region of cells. In addition, he was a co-author of a paper that described a user-friendly web-app that could be used to design prime-editing experiments."
COVID had not slowed the CRISPR revolution.
Before the pandemic, communication and collaboration between academic researchers had become constrained. Universities created large legal teams dedicated to staking a claim to each new discovery, no matter how small, and guarding against any sharing of information that might jeopardize a patent application. "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.
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.
Like any evolutionary trait, this new ability may help the species thrive and perhaps even produce successor species. Or it may not. 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.
Most of all, I want to convey the importance of basic science, meaning quests that are curiosity-driven rather than application-oriented.
Curiosity-driven research into the wonders of nature plants the seeds, sometimes in unpredictable ways, for later innovations. Research about surface-state physics eventually led to the transistor and microchip. Likewise, studies of an astonishing method that bacteria use to fight off viruses eventually led to a gene-editing tool and techniques that humans can use in their own struggle against viruses.
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
Competition drives discovery. Doudna calls it "the fire that stokes the engine," and it certainly stoked hers. Ever since she was a child, she was not embarrassed to appear ambitious, but she knew how to balance this by being collegial and forthright. She had learned about the importance of competition from reading The Double Helix, which describes how the perceived footsteps of Linus Pauling were a catalyst for James Watson and Francis Crick. "Healthy rivalries," she later wrote, "have fueled many of humankind's greatest discoveries."
Scientists are mainly motivated by the joy that comes from understanding nature, but most will admit that they are also driven by the rewards, both psychic and substantive, of being the first to make a discovery: papers published, patents granted, prizes won, and peers impressed. Like most humans (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.
In the upcoming decades, as we gain more power to hack our own evolution, we will have to wrestle with deep moral and spiritual questions: Is there an inherent goodness to nature? Is there a virtue that arises from accepting what is gifted to us? Does empathy depend on believing that but for the grace of God, or the randomness of the natural lottery, we could have been born with a different set of endowments? Will an emphasis on personal liberty turn the most fundamental aspects of human nature into consumer choices made at a genetic supermarket? Should the rich be able to buy the best genes? Should we leave such decisions to individual choice, or should society come to some consensus about what it will allow?
Likewise, suppose I'm an average height. If I were enhanced by eight inches, I'd be way taller than most people, and that could be a benefit to me. But if everyone else got the same eight-inch enhancement I did, then I would get no real benefit. The enhancement wouldn't make me or society as a whole better off, especially given the legroom of airline seats these days. The only sure beneficiaries would be carpenters who specialized in raising door frames. So enhanced height is a positional good, while enhanced resistance to viruses is an absolute good.
To what extent does dealing with mood swings, fantasies, delusions, compulsions, mania, and deep depression help spur, in some people, creativity and artistry? Is it harder to be a great artist without having some compulsive or even manic traits? Would you cure your own child from being schizophrenic if you knew that, if you didn't, he would become a Vincent van Gogh and transform the world of art?
(Don't forget: Van Gogh committed suicide.)
At this point in our deliberations, we have to face the potential conflict between what is desired by the individual versus what is good for human civilization. A reduction in mood disorders would be seen as a benefit by most of the afficted individuals, parents, and families.
They would desire it. But does the issue look different when asked from society's vantage point? As we learn to treat mood disorders with drugs and eventually with genetic editing, will we have more happiness but fewer Hemingways? Do we wish to live in a world in which there are no Van Goghs?
One moral issue that continues to loom large for her is inequality, especially if the wealthy are able to buy genetic enhancements for their children. "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."
Some of the scientific researchers I talked to were appalled by what Zayner did. But I found myself rooting for him. If his shadow has offended, think but this and all is mended: More citizen involvement in science is a good thing. Genetic coding will never become as crowdsourced and democratized as software coding, but biology should not remain the exclusive realm of a gospel-guarding priesthood.
Perhaps we will be able to improve our cognitive skills so that we can keep up with the challenges of using our technology wisely. Ah, but there's the rub: wisely. Of all the complex components that go into human intelligence, wisdom may be the most elusive. 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. Ingenuity without wisdom is dangerous.