The Code Breaker

by Walter Isaacson

It was fitting that a virus-fighting team would be led by a CRISPR pioneer. 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. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses—just what we humans need in an era that has been plagued, as if we were still in the Middle Ages, by repeated viral epidemics.

One of the leaders she tapped was a postdoc named Jennifer Hamilton who, a few months earlier, had spent a day teaching me to use CRISPR to edit human genes. I was pleased, but also a bit unnerved, to see how easy it was. Even I could do it!

What none of the participants discussed was a longer-range prospect: using CRISPR to engineer inheritable edits in humans that would make our children, and all of our descendants, less vulnerable to virus infections. These genetic improvements could permanently alter the human race. “That’s in the realm of science fiction,” Doudna said dismissively when I raised the topic after the meeting. Yes, I agreed, it’s a bit like Brave New World or Gattaca. But as with any good science fiction, elements have already come true. In November 2018, a young Chinese scientist who had been to some of Doudna’s gene-editing conferences used CRISPR to edit embryos and remove a gene that produces a receptor for HIV, the virus that causes AIDS. It led to the birth of twin girls, the world’s first “designer babies.”

Our newfound ability to make edits to our genes raises some fascinating questions. Should we edit our species to make us less susceptible to deadly viruses? What a wonderful boon that would be! Right? Should we use gene editing to eliminate dreaded disorders, such as Huntington’s, sickle-cell anemia, and cystic fibrosis? That sounds good, too. And what about deafness or blindness? Or being short? Or depressed? Hmmm… How should we think about that? A few decades from now, if it becomes possible and safe, should we allow parents to enhance the IQ and muscles of their kids? Should we let them decide eye color? Skin color? Height? Whoa! Let’s pause for a moment before we slide all of the way down this slippery slope. What might that do to the diversity of our societies? If we are no longer subject to a random natural lottery when it comes to our endowments, will it weaken our feelings of empathy and acceptance? If these offerings at the genetic supermarket aren’t free (and they won’t be), will that greatly increase inequality—and indeed encode it permanently in the human race? Given these issues, should such decisions be left solely to individuals, or should society as a whole have some say? Perhaps we should develop some rules.

But in 2012 Doudna and others figured out a more earth-shattering use: how to turn CRISPR into a tool to edit genes. CRISPR is now being used to treat sickle-cell anemia, cancers, and blindness. And in 2020, Doudna and her teams began exploring how CRISPR could detect and destroy the coronavirus. “CRISPR evolved in bacteria because of their long-running war against viruses,” Doudna says. “We humans don’t have time to wait for our own cells to evolve natural resistance to this virus, so we have to use our ingenuity to do that. Isn’t it fitting that one of the tools is this ancient bacterial immune system called CRISPR? Nature is beautiful that way.”

(The elevator pitch: A Beautiful Mind meets Jurassic Park.)

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?

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

arrogance, a ruthlessness, and an impatience with sloppy thinking came naturally to both of us,”

the four bases in DNA: adenine, thymine, guanine, and cytosine, now commonly known by the letters A, T, G, and C.

the Human Genome Project, and its goal was to figure out the sequence of the three billion base pairs in our DNA and map the more than twenty thousand genes that these base pairs encode.

Having a map of DNA did not, it turned out, lead to most of the grand medical breakthroughs that had been predicted. More than four thousand disease-causing DNA mutations were found. But no cure sprang forth for even the most simple of single-gene disorders, such as Tay-Sachs, sickle cell, or Huntington’s. The men who had sequenced DNA taught us how to read the code of life, but the more important step would be learning how to write that code. This would require a different set of tools, ones that would involve the worker-bee molecule that Doudna found more interesting than DNA.

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 a society or organization. But like many famous siblings, DNA doesn’t do much work. It mainly stays at 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. Instead of just sitting at home curating information, it makes real products, such as proteins. Pay attention to it. From CRISPR to COVID, it will be the starring molecule in this book and in Doudna’s career.

“messenger RNA” facilitates the assembly of the proper sequence of amino acids to make a specified protein. These proteins come in many types. Fibrous proteins, for example, form structures such as bones, tissues, muscles, hair, fingernails, tendons, and skin cells. Membrane proteins relay signals within cells. Above all is the most fascinating type of proteins: enzymes. They serve as catalysts. They spark and accelerate and modulate the chemical reactions in all living things. Almost every action that takes place in a cell needs to be catalyzed by an enzyme. Pay attention to enzymes. They will be RNA’s costars and dancing partners in this book.

Doudna became a rising star in the rarefied realm of RNA research. That was still a bit of a biological backwater, but over the next two decades the understanding of how little strands of RNA behaved would become increasingly important, both to the field of gene editing and to the fight against coronaviruses.

In the age of coronaviruses, there is another role that RNA interference may play. Throughout the history of life on our planet, some organisms (though not humans) have evolved ways to use RNA interference to fight off viruses.5 As Doudna wrote in a scholarly publication back in 2013, researchers hoped to find ways to use RNA interference to protect humans from infections.6 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.

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 1031 of them—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.7 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.

“I like to hire people who have their own creative ideas and want to work under my guidance and as part of my team, but not with daily direction.”

Let’s pause for a quick refresher course. 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 (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!

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.”

Genentech, a mash-up of “genetic engineering technology.” It began making genetically engineered drugs and, in August 1978, blasted into hypergrowth when it won a bet-the-company race to make a synthetic version of insulin to treat diabetes. Until then, one pound of insulin required eight thousand pounds of pancreas glands ripped from more than twenty-three thousand pigs or cows. Genentech’s success with insulin not only changed the lives of diabetics (and a lot of pigs and cows); it lifted the entire biotechnology industry into orbit.

By the time Genentech began recruiting Doudna in late 2008, the company was worth close to $100 billion. Her former colleague, who was now working on genetically engineering cancer drugs at Genentech, told her that he was loving his new role. His research was much more focused than when he was an academic, and he was working directly on problems that were going to lead to new therapeutics.

Socratic:

1 For much of the twentieth century, most new drugs were based on chemical advances. But the launch of Genentech in 1976 shifted the focus of commercialization from chemistry to biotechnology, which involves the manipulation of living cells, often through genetic engineering, to devise new medical treatments. Genentech became the model for commercializing biotech discoveries: scientists and venture capitalists raised capital by divvying up equity stakes, then they entered into agreements with major pharmaceutical companies to license, manufacture, and market some of their discoveries.

California Institute for Quantitative Biosciences (QB3), which had as its goal “a catalytic partnership between university research and private industry.”

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. This government-business-university partnership produced the great innovations that propelled the U.S. economy in the postwar period, including transistors, microchips, computers, graphical user interfaces, GPS, lasers, the internet, and search engines.

She hated the phrase “work-life balance” because it implied that work competes with life.

In the history of science, there are few real eureka moments, but this came pretty close. “It wasn’t just some gradual process where it slowly dawned on us,” Doudna says. “It was an oh-my-God moment.” When Jinek showed Doudna his data demonstrating that you could program Cas9 with different guide RNAs to cut DNA wherever you desired, they actually paused and looked at each other. “Oh my God, this could be a powerful tool for gene editing,” she declared. In short, they realized that they had developed a means to rewrite the code of life.4

It was immediately obvious that this single guide would make CRISPR-Cas9 an even more versatile, easy-to-use, and reprogrammable tool for gene editing. What made the single-guide system particularly significant—from both a scientific and an intellectual property standpoint—was that it was an actual human-made invention, not merely a discovery of a natural phenomenon.

By studying a phenomenon that evolution had taken a billion or so years to perfect in bacteria, they turned nature’s miracle into a tool for humans.

How beauteous mankind is! O brave new world, That has such people in’t! —William Shakespeare, The Tempest

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.

Competition drives discovery. Doudna calls it “the fire that stokes the engine,” and it certainly stoked hers.

But the benefits of competition are great. If it hastens the discovery of a way to fix muscular dystrophy, prevent AIDS, or detect cancer, fewer people will die early deaths. To take an example relevant to these days, the Japanese bacteriologist Kitasato Shibasaburō and his Swiss rival Alexandre Yersin both rushed to Hong Kong in 1894 to investigate the pneumonic plague epidemic and, working with different methods, discovered the responsible bacteria within days of each other.

CRISPR is also being used as a detection tool to identify precisely what type of cancer a patient has. Mammoth Biosciences, a company that Doudna founded with two of her graduate students, is designing diagnostic tools based on CRISPR that can be used on tumors to identify quickly and easily the DNA sequences associated with different types of cancers. Then precision treatments can be tailored for each patient.10

Coming soon Work is also underway on some more ambitious uses of CRISPR gene editing that could make us less vulnerable to pandemics, cancers, Alzheimer’s, and other diseases. For example, a gene known as P53 encodes for a protein that suppresses the growth of cancerous tumors. It helps the body respond to damaged DNA and prevents cancerous cells from dividing. Humans tend to have one copy of this gene, and cancers proliferate if something goes wrong with it. Elephants have twenty copies of this gene, and they almost never get cancer. Researchers are currently exploring ways to add an extra P53 gene into humans. Likewise, the gene APOE4 raises the risk of the devastating disease of Alzheimer’s. Researchers are looking for ways to convert it into a benign version of the gene.

published in 1895, a traveler to the future discovers that humans have evolved into two species, a leisure class of Eloi and a working class of Morlocks.

The title of the gathering was “Engineering the Human Germline,” and it focused on the ethics of making genetic edits that would be inherited. These “germline” edits were fundamentally different, medically and morally, from somatic-cell edits that affect only certain cells in an individual patient. The germline was a red line that scientists had been reluctant to cross.

The most important was almost identical to what had been decided at the small Napa meeting at the beginning of the year. Human germline editing should be strongly discouraged until stringent conditions were met, but the words “moratorium” and “ban” were avoided. Among the conditions the group adopted was that germline editing should not proceed until “there is broad societal consensus about the appropriateness of the proposed application.” The need for a “broad societal consensus” was one that would be invoked often in discussions of the ethics of germline editing, as if a mantra. It was a laudable goal. But as the debate over abortion has shown, discussions do not always lead to broad societal consensuses.

liberal.

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.”

The births happened so early that Jiankui had not yet submitted the official description of his clinical trial to Chinese authorities. On November 8, after the twins were born, it was finally submitted. It was written in Chinese, and for two weeks it went unnoticed in the West.29 He also finished the academic article he had been working on. Titled “Birth of Twins after Genome Editing for HIV Resistance,”

“One thing is clear,” he said. “If this guy really did what he claims to have done, this is actually not very hard to do. That’s a sobering thought.”

He strongly believed that CRISPR could be used someday to make inheritable edits; research was then underway at Harvard to study germline edits in sperm that might prevent Alzheimer’s.

“We’re trying to plan the world we’re going to leave for our children,” he said. “Is it a world where we’re deeply thoughtful about medical applications, and we’re using it in serious cases, or is it a world where we just have rampant commercial competition?” Zhang made the point that the issues surrounding gene editing needed to be settled by society as a whole and not by individuals. “You can imagine a situation where parents will feel pressure to edit their children because other parents are,” he said. “It could further exacerbate inequality. It could create a total mess in society.”

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.

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

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. The calls for a moratorium on germline gene editing receded. Just as bacteria have spent millennia evolving ways to develop immunity to viruses, perhaps we humans should use our ingenuity to do the same.

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.

The primary concern is germline editing, those changes that are done in the DNA of human eggs or sperm or early-stage embryos so that every cell in the resulting children—and all of their descendants—will carry the edited trait. 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.