Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing

PROLOGUE

Thanksgiving weekend, November 2018: I settled in for a fifteen-hour flight from New York to Hong Kong to attend a scientific conference. It was a long trek for a three-day gathering of bioethicists, and I wasn’t expecting any major fireworks. Even Alta Charo, a member of the organizing committee, worried it might be “a really boring summit.”¹

As we headed towards the Arctic Circle, I folded my laptop, ordered a Pot Noodle, and flicked through the in-flight entertainment menu before settling on an action film called Rampage. Following an explosion aboard the international space station, canisters containing a mysterious chemical crash to earth. Naturally, one lands in the San Diego Zoo, where Dwayne “The Rock” Johnson happens to work as a primatologist, contaminating his beloved albino gorilla, George. Two other animals—Lizzie the crocodile and Ralph the wolf—mutate overnight before converging on Chicago. This was all utterly ridiculous if mildly entertaining, but the material wreaking mutational mischief was the reason I was on this journey. “Have you heard of CRISPR?” Naomie Harris asks our chiseled hero.

He hadn’t. Nor indeed had I until a few years earlier. The summit in Hong Kong was the sequel to a gathering in 2015 in Washington, DC, to discuss the ethics of human genome editing. The debate had been prompted by the emergence of a revolutionary technology for fixing or modulating genes with a catchy acronym: CRISPR. Earlier that year, scientists in China had altered the genes of a human embryo in a dish for the first time. It was a preliminary experiment on non-viable embryos (no women were pregnant), but it sparked fears that someone, somewhere might attempt to rewrite the genetic code of the human species. One of the undisputed pioneers of the gene-editing technology, Jennifer Doudna, called for international debate on how this technology should be used, whether it should be restrained, or even banned altogether. The chair of the DC conference, Nobel laureate David Baltimore, referenced Brave New World to warn that we were facing “the prospect of new and powerful means to control the nature of the human population.” Three years later, I presumed many of the same characters would be sounding similarly abstract warnings.

I landed in Hong Kong in the early afternoon of Monday, November 26, and turned on my phone. As I scrolled through Twitter, it took a few seconds in my groggy state to register what I was reading. A science reporter named Antonio Regalado had published a sensational scoop that a Chinese scientist was overseeing the pregnancy of a gene-edited fetus. It strongly suggested that babies genetically altered using CRISPR might already have been born.² Within hours, those rumors were confirmed and then some by the Associated Press. The AP story revealed the birth of genetically edited twins.³ #CRISPRbabies was trending.

There was more: in a series of YouTube videos, a thirty-four-year-old Chinese scientist named He Jiankui described his historic feat. “Two beautiful little Chinese girls, named Lulu and Nana, came crying into this world a few weeks ago,” he said in halting English. “The girls are home now, with their mom Grace, and their dad, Mark.” The name He Jiankui didn’t mean anything to me but he was due to speak at the conference. Would he still show up? Would the organizers allow him to appear?

Two days later, He Jiankui did indeed try to explain what he had done, and more importantly, why. It was one of the most intensely watched scientific presentations in history, in front of hundreds of journalists and press photographers and close to two million viewers of the live webcast. And I had a front row seat. As He Jiankui entered the packed auditorium and walked across the stage, the only sound was the staccato clatter of about two hundred camera shutters. On social media, an American scientist was screaming this was a travesty and that the organizers were crowning a science celebrity. On the contrary, I felt we were watching a dead man walking. Indeed, by the time He Jiankui had left the stage and returned home to Shenzhen, his dreams of fame and national glory were in tatters. Instead, he faced house arrest, ignominy, and, one year later, prison.⁴

The #CRISPRbabies story marks an extraordinary turning point in human history. There’s a reason that the Ken Burns documentary The Gene, based on Siddhartha Mukherjee’s superb book of the same name, opens with a colleague of He Jiankui injecting CRISPR circumspectly into a human embryo. “The baby crisperer,” as the Economist dubbed him,⁵ had wrested control of heredity from nature, at least for one of the 20,000 genes that make up the human genome.

It was just fifteen years earlier that an international consortium of scientists completed the Human Genome Project (HGP), piecing together more or less every page of the book of life, a script of 3.2 billion letters comprised of a four-letter alphabet. A group of researchers at the University of Leicester printed the complete sequence as an encyclopedia of more than one hundred volumes, each chromosome bound in a different color. Those volumes of information are miraculously bundled into twenty-three pairs of chromosomes that reside in trillions of cells in your body. With the human genome sequence at hand, scientists could set about identifying the genes that go awry in literally thousands of rare hereditary diseases, as well as the DNA variants or misspellings that shape our predisposition to common diseases like diabetes, heart disease, and mental illness. Even before this genetic revolution, researchers dreamed of using specific DNA sequences as gene therapy, injecting healthy genes into patients’ cells to compensate for the faulty genes. But the idea of performing DNA surgery—fixing broken genes by cutting and pasting DNA directly into a patient’s genome—was a fantasy.

All that changed when the CRISPR craze erupted in the summer of 2012. Two scientists—French microbiologist Emmanuelle Charpentier and Doudna, an American biochemist—published a groundbreaking discovery. They stood on the shoulders of many researchers around the world who had been toiling out of the public eye to understand the biological purpose of CRISPR. These Clustered Regularly Interspaced Short Palindromic Repeats (the official acronym) were known to be the critical component of a natural bacterial immune system, a microbial missile defense shield to neutralize attack by certain viruses. Researchers in the Doudna and Charpentier labs reconfigured the molecular machinery to produce an ingenious method for precisely targeting and cutting genes and other DNA targets. Six months later, several groups, led by Feng Zhang at the Broad Institute and George Church at Harvard Medical School, showed that the DNA of mammalian cells could be edited using CRISPR. The prospect of being able to precisely edit almost any sequence of DNA, be it human, bacterial or of any other organism, was extraordinary. CRISPR’s ease of use was unlike anything seen before—a technical if not conceptual breakthrough that would transform science and medicine, and perhaps the very fabric of humanity.

Thanks to these researchers and many other scientists around the world, we can now exercise control of heredity with unprecedented ease and precision. We can erase or rewrite disease genes, one person or embryo at a time. We can change the genomes of livestock, plants, and parasites to improve the lives of millions of people, especially in developing countries ravaged by climate change. We can save species from extinction—and maybe even re-create some that have already left this mortal coil. And although we don’t know nearly enough about the complexity of the gene networks that underpin our predisposition to diabetes, heart disease, and mental illness, let alone shape our behavior, personality, and intelligence, we can imagine a day when we might be able to augment or manipulate some of those characteristics, too.

The beauty of CRISPR is that it is easier, faster, and much cheaper than earlier genome editing platforms. Researchers have edited a Noah’s Ark of plant and animal life: fruits and vegetables, insects and parasites, crops and livestock, cats and dogs, fruit flies and zebrafish, mice and men. Do-it-yourself biohackers began experimenting on themselves and their pets. A tsunami of research papers appeared in the most prestigious science journals as scientists CRISPR’d anything they could get their hands on. “The CRISPR Craze,” as Science dubbed it, swept over the popular press.⁶ The Economist’s cover featured an innocent crawling baby with a menu of potentially editable traits, including perfect pitch, 20/20 vision, and no baldness.⁷ The Spectator riffed on that with “Eugenics is back,” featuring a cartoon baby sitting on a petri dish (“not ginger” was the hair preference).⁸ MIT Technology Review labeled CRISPR “the biggest biotech discovery of the century.”⁹ And a WIRED cover story by Amy Maxmen stated: “No hunger. No pollution. No disease. And the end of life as we know it.”¹⁰

When I was training as a geneticist in the 1980s, I was part of a team desperately searching the human genome to find the faulty genes that cause Duchenne muscular dystrophy (DMD) and cystic fibrosis (CF). We were literally genetic detectives, hunting for clues to the whereabouts of genes and mutations that compromise and curtail human life.^I We met patients in our lab at St Mary’s Hospital in London, including teenagers with CF who would be lucky to see their 20th birthday. The identification of the genes mutated in patients with CF, DMD, and other disorders gave us hope that cures were just around the corner. “From gene to drug” and “From bench to bedside” were the memes of the day, heralding a revolution in molecular medicine. Every few years the future of medicine would get a new name—personalized medicine, precision, genomic, or individualized medicine, as if changing the name would change fortunes.

In 1990—the year of the launch of the HGP—I hung up my lab coat for the last time. My personal eureka moment came when I chanced upon a classified advertisement for a job with Nature magazine. Well, I thought, that’s one way to get my name in the pages of the world’s most famous science journal. I was offered the job by the editor, Sir John Maddox. Two years later, Maddox handed me the chance to helm the first spin-off journal bearing the Nature nameplate—Nature Genetics.¹¹ At a conference in 1993 to mark our first birthday, I mingled with a handpicked all-star cast, including Francis Collins, Craig Venter, and Mary-Claire King, who over dinner inspired me to write my first book.

Written with my friend the late Michael White, Breakthrough told of the brilliant Berkeley geneticist who, in 1990, mapped the so-called breast cancer gene, BRCA1. A few weeks after Myriad Genetics scooped King in the race to isolate the gene in 1994, the organizers of a major genetics conference in Montreal convened a plenary session to celebrate Myriad’s highly publicized success. King stole the show, presenting the results from multiple families in which her team had documented specific BRCA1 mutations capable of wreaking what the British journalist John Diamond called the “cytological anarchy of cancer and death.”

King insisted she didn’t care who won the race to identify BRCA1: win or lose, her team would be in the lab studying mutations in families. It was important, she said, to distinguish reality from the media frenzy. “Fantasy has been New York Times profiles, 60 Minutes, guys on motorcycles in Time magazine”—a jab at Francis Collins, her former collaborator. Reality, she said,

is having the gene, not knowing what it does, and the realization that in the twenty years since we have been working on this project, more than a million women have died of breast cancer. We very much hope that something we do in the next twenty years will preclude another million women dying of the disease.¹²

King received a standing ovation. Two decades later, a lawsuit that stemmed from a dispute over BRCA1 genetic testing resulted in the U.S. Supreme Court outlawing gene patents in a unanimous decision.¹³

My next book, Cracking the Genome, covered the biological equivalent of the moon landing—the HGP—which became a fierce partisan feud between the international consortium led by Collins and a privately funded hostile takeover led by Craig Venter.¹⁴ The command center at his company, Celera Genomics, looked more like the bridge of the starship Enterprise, with two massive video screens streaming DNA sequences rather than photon torpedoes. With the draft sequence in hand, we had the parts list of the human body and could systematically identify the mutations that underlie not only dominant and recessive (Mendelian) disorders but also begin to crack the genetic basis of more common diseases such as asthma and depression.

The ink had barely dried on the genome project when I heard Venter call for a new sequencing technology to speed-read DNA that could deliver the “$1,000 genome.” As the first draft had cost $2 billion, this really did sound like science fiction. But the seeds were sown one Sunday afternoon in February 2005, when Clive Brown emailed his colleagues at a British biotech company called Solexa with the subject line: “WE’VE DONE IT!!!!” Using a new technology invented by a pair of Cambridge University chemistry professors,^II Brown’s team had sequenced the genome of the smallest virus known, ΦX174. The next year, another company, Illumina, acquired Solexa, setting it on course to reach the mythical $1,000 threshold a decade later.¹⁵ By then, we saw the first cases of genome sequencing saving lives, ending the diagnostic odysseys of patients like Nicholas Volker suffering mystery genetic diseases. The plummeting cost of sequencing was accompanied by major advances in speed. For example, Stephen Kingsmore at Rady Children’s Hospital in San Diego recently set a Guinness World Record by sequencing and processing the complete genome of a newborn baby in just twenty hours.¹⁶

Each of these stories chronicled a massive leap forward in genetics propelled by advances in sequencing DNA. We are on course for the $100 genome, with new sequencing platforms offering incredible new possibilities for speed-reading DNA.^{III 17} One in particular, nanopore sequencing, is housed in a portable device smaller than a smartphone and has found its way onto the International Space Station.

Along with reading DNA, we are also seeing tremendous progress in synthesizing or writing DNA. Church and other scientists have digitally encoded books and films in DNA sequences¹⁸ and engineered a yeast cell by fusing the organism’s natural complement of sixteen chromosomes into a single mosaic chromosome.¹⁹ Synthetic biology has an exciting future designing DNA circuits and customizing organisms for a host of applications from bioengineered fragrances and petrochemicals to the next generation of antibiotics and antimalarial drugs. Scientists have even expanded the original four-letter genetic alphabet by synthesizing novel chemical building blocks that can substitute for the naturally occurring ones in the double helix. This paves the way for designing synthetic proteins containing novel building blocks.²⁰

Advances in reading and writing are very important. But if I could only read and write this book without an ability to edit, search, and replace, the result would never see the light of day. So too with genome engineering, or editing: It allows scientists and even nonscientists to rewrite the genetic code as easily as I can change money to honey or gnome to genome on my computer.

In 2014, I was invited by the Nobel laureate Jim Watson to help update a popular science book that he’d written with Andrew Berry a decade earlier, simply called DNA.²¹ As I reflected on the major advances in genetics, there was no escaping CRISPR. In November 2014, at the annual Breakthrough Prize ceremony, televised live from a NASA hangar in California, I watched Cameron Diaz handing Doudna and Charpentier the most lucrative science prize in the world, worth $3 million apiece.^IV Barely thirty months after their landmark study, the scientific establishment and the titans of Silicon Valley had crowned the women as scientific royalty.

Neither Doudna nor Charpentier were physicians, but CRISPR holds the prospect to taking gene therapy to a new level. Both women launched biotech companies to deliver CRISPR-based therapies designed to fix mutations that cause sickle-cell disease, blindness, DMD, and many other disorders. “For the past decade, I’ve been making GMO humans,” says Fyodor Urnov, a colleague of Doudna’s who helped develop genome editing at Sangamo Therapeutics in California. In 2019—seventy years after Linus Pauling proposed sickle-cell anemia as the first “molecular disease”—Victoria Gray, an African American mother from Mississippi, became the first American patient to receive a gene-editing therapy for sickle-cell disease.²² A year later, she is healthy, blessedly free of complications, her blood cells rejuvenated. Many more genome editing trials are getting underway, mostly using CRISPR. We are truly on the verge of a new era in medicine.

But genome editing has gone much further. The actions of He Jiankui crossed a red line, a scientific Rubicon that virtually all scientists deemed sacrosanct. Heritable genome (or germline) editing is no longer the domain of dystopian science fiction movies and panicked stories of designer babies. The genie is well and truly out of the bottle and cannot be put back. Will germline editing find a niche in treating genetic disorders? Will couples want to use CRISPR to genetically enhance their children? Why should we stop at correcting genetic diseases? Can we not entertain the idea of applying CRISPR technology for enhancement? How about tuning a gene to reduce the amount of sleep we need, or provide protection against the onset of dementia, or shield astronauts against radiation poisoning? Or is heritable genome editing, as Urnov argues, “a solution in search of a problem”?

CRISPR “is a remarkable technology with many great uses,” said Broad Institute director Eric Lander. “But if you are going to do anything as fateful as rewriting the germline, you’d better be able to tell me there is a strong reason to do it. And you’d better be able to say that society made a choice to do this—that unless there’s broad agreement, it is not going to happen.”²³

Editing Humanity is the story of one of the most remarkable scientific revolutions we have ever seen—the CRISPR revolution. My original intent in this book, supported by a science writing fellowship from the Guggenheim Foundation, was to focus on CRISPR—the science and the scientists. In 2017, I conceived the launch of a new journal called The CRISPR Journal, and began meeting the scientists leading this exciting research. Our journey begins with the stories of a band of unheralded microbiologists and biochemists—the true “heroes of CRISPR”—trying to fathom the function of obscure lines of genetic code in bacterial DNA. CRISPR demonstrates emphatically the immense value of funding basic academic and investigator-driven research. Big science consortia like the HGP can do great things, but lest we forget, so too can humble scientists with modest financial support. Few could have predicted that studies of how bacteria vanquish their viral nemeses would spawn a multi-billion-dollar industry that could cure disease and alleviate world hunger.

In Part II, I discuss the rise and fall of genetic therapy, which is undergoing a renaissance after years of despair. One of the great hopes of genome editing is the possibility of treating patients with a wide range of debilitating diseases including muscular dystrophy, hemophilia, blindness, and sickle-cell disease. The term “Holy Grail” is overused in science, but if fixing a single letter in the genetic code of a fellow human being isn’t the coveted chalice of salvation, I don’t know what is.

In the second half of the book, I turn to the CRISPR babies and the extraordinary story behind this reckless experiment. I lift the veil on He Jiankui’s secretive ambitions. I question whether He Jiankui was the rogue scientist that he has been painted and assess the fallout of his actions. In the closing chapters, I present some of the exciting new directions that CRISPR might take us, from gene drives to eradicate malaria to de-extinction to resurrect species we have lost, and separate truth from fiction in the debate over designer babies.

This is biology’s century. As Urnov points out, there is a huge gap between a genius idea and its practical realization. In 1505, Leonardo da Vinci designed a model of an ornithopter—a flying machine. It was almost four centuries later, in December 1903, when Orville Wright defied gravity for twelve seconds and the length of a baseball diamond (120 feet). It took several decades more for that landmark flight to usher in commercial air travel, let alone carry the first man into earth orbit and beyond.

Siddhartha Mukherjee says it well in The Gene: “The challenge with all these technologies is that DNA is not just a genetic code, it is in some sense also a moral code. It doesn’t just ask questions about what we will become. Now that we have these tools, we have the capacity to ask the question, what can we become?”

This book is about the origins, development, uses and misuses of CRISPR, the technology adapted from some of the most ancient organisms on earth, which bring us to the precipice of editing humanity.

I. In the mid-1980s, Francis Collins posed for a newspaper photographer in a lab coat holding a needle in front of a large haystack—the literal metaphor for DNA detectives scouring the genome for a single spelling mistake among three billion letters.

II. Both professors, Shankar Balasubramanian and David Klenerman, have since been knighted.

III. In nanopore sequencing, the DNA is unzipped to allow a single strand to be threaded through a nanopore—a bacterial protein shaped like a ring donut. By measuring the electrical current as the DNA speeds through the pore like a subway train, Oxford Nanopore can translate those electrical squiggles into the underlying DNA sequence.

IV. The annual Breakthrough Prize of $3 million per recipient is worth about ten times a one-third share of the Nobel Prize, which has a total purse of $900,000.