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

CHAPTER 24 BASES LOADED

CRISPR genome editing is not yet a decade old but, as I’ve tried to show in this book, it is poised to transform myriad areas of science, medicine, and agriculture. But there are many scientific, regulatory, and ethical challenges ahead. One setback in a clinical trial could precipitate another decade in the dark ages, as happened to gene therapy. Tim Hunt, Editas’s former head of corporate affairs, is refreshingly honest about the business challenges ahead for “cash-eating machines” like Editas commercializing somatic genome editing. “We’ve raised $500–600 million. We’ll need $1–1.5 billion before we have a product on the market,” he said in early 2020. “CRISPR is often described as fast, cheap, and easy. But making a medicine is not fast, not cheap, and not easy. It’s a long journey.”¹

From building a company, managing preclinical research and clinical trials, bankrolling manufacture, enhancing delivery, and navigating regulatory red tape, the road to commercial success is tortuous. And in some cases, genome editing is targeting a very niche market. The numbers of patients receiving some therapies, such as those with orphan diseases, are very small. All of these factors drive up the price of potentially life-saving drugs. Ross Wilson and Dana Carroll exhorted genome editing companies and regulators “to accept the challenge to make genome editing therapeutics affordable and accessible, which would represent a massive contribution to global health justice.”²

There may come a time when it makes sense to perform germline editing, but not now, not yet. Maybe in a decade or two, we might consider heritable genome editing to be technically safe, ethically sound, medically justified, and publicly supported. I believe that day will come eventually. Perhaps by 2032, the centennial of Brave New World. Or 2053, the one hundredth anniversary of the double helix. Or 2078, when Louise Brown turns one hundred. Or 2100, a century since we first cracked the sequence of the human genome.

No drug comes without side effects; no surgery is completely safe. Genome editing won’t be any different, but scientists are well advanced in overcoming those issues. What is ethically appropriate will depend on a deep discussion about values and beliefs involving a host of stakeholders, not just scientists and physicians. Medically justified will be rare for genetic disorders given the prevalence of PGT, and other applications appear frivolous or fictional. Public and government approval is also in question: CRISPR clinics could become an extension of the burgeoning medical tourism industry. Perhaps some nations will sanction genome editing for their citizens, even if the rest of the world isn’t ready.

Scientists and physicians, ethicists and lawyers, sociologists and politicians have been debating the merits and dangers of CRISPR since 2015. But every day, babies, children, and adults are being diagnosed with deadly genetic disorders. For these patients and their families, genome editing offers a powerful life-saving medical technology with no bounds. In late 2019, after NIH director Francis Collins gave a public address in a Washington, DC, hotel, a woman in the audience named Neena Nizar navigated her wheelchair to the microphone. Nizar is president of the Jansen’s Foundation and one of only two dozen patients in the world (and two adults in the United States) with that rare genetic disease. Patients like Nizar suffer weakened bones and cartilage, and endure multiple rods, pins, and clamps to hold their brittle bones together.

Nizar challenged Collins, demanding to know why more wasn’t being done to help patients like her suffering one of thousands of genetic disorders. “Science and medicine have a responsibility to try to find answers” to rare diseases, Collins assured her. But the need for germline editing, for Jansen’s or a plethora of other conditions, was “uncompelling to me,” because of the availability of PGT to create and test embryos. “So why not just implant those? We don’t need a gene-editing solution.”³

Afterwards, Nizar smiled ruefully when I asked her if that was answer she was looking for. Both her sons have inherited the same disease. “It’s easy to get on your high horse when you’re not in our position. If editing an IVF embryo is the best option to mitigate the pain that a child would otherwise suffer, then give us the choice,” she said. “Let them say we’re playing God.”⁴ Debates over ethics and eugenics, hyperagency and human flourishing are all well and good. But patients just want a chance for a normal, healthy life. If modern science offers them hope, who is going to dare take that away?

Indeed, there are signs of hope as we enter a new era of hyper-personalized medicine, where patients with ultra-rare gene mutations can receive a customized therapy with FDA approval. At Boston Children’s Hospital, pediatric neurologist Tim Yu has developed bespoke drugs for children with Batten disease⁵ and ataxia telangiectasia.⁶ Yu has also advised a group including Yale University’s Monkol Lek to devise a custom CRISPR therapy for Terry Horgan, a 24-year-old patient with Duchenne muscular dystrophy. Horgan’s mutation is in the first exon of the dystrophin gene, not part of the group of mutations addressed by drugs currently on the market or in the clinic. Terry’s brother Rich is the founder of Cure Rare Disease, a nonprofit spearheading hyper-personalized medicine. Encouraging, but each of these personalized drugs requires about $1–2 million at a minimum.

Like many researchers in the CRISPR spotlight, Jennifer Doudna receives regular emails from patients and their family members, desperately looking for hope. One message (shared publicly by Urnov) was written by a thirty-six-year-old woman whose cheerful salutation—“Hi Dr. Doudna”—belied the plea that followed. “Time is quickly running out for me.” She explained she has a single-nucleotide mutation that causes a severe lethal disease. Fixing it should be easy. “I’ve watched the continued development and the work you’ve done,” she continued. She’d read a magazine profile of Doudna. “I’m a very good candidate for CRISPR trials. I would be more than happy to be a study participant.”⁷

Deftly handling emails from desperate patients is just one of many new challenges that Doudna has had to take on since the world changed in 2012. She is famous now, one of the most recognizable scientists in the world. Time with her students and postdocs is increasingly precious. No longer just the most valuable player in the Doudna lab, she’s also the team president, coach, and general manager. She dons a multitude of hats—researcher, teacher, grant writer, mentor, administrator, accountant, evangelist, ethicist, entrepreneur, author, commentator, advisor, and public speaker—sometimes all in the same day. A team of assistants helps her budget and manage lab operations and vet media requests. Every hour of Doudna’s day is charted on a laminated daily calendar, juggling group meetings, advisory boards, budget planning, and interviewing the next wave of students and postdocs who will further advance the CRISPR revolution. After another frantic day, she texts her husband to schedule the drive home.

In late 2019, Doudna flew to Washington, DC, for an especially important appointment. Every five to seven years, HHMI summons its 250 investigators to a closed-door review in which they must highlight their research accomplishments and outline their future plans before a panel of a dozen or more members of the scientific elite. After answering questions, a limousine waits to drive her back to the airport while the advisors vote whether to extend support (more than $1 million/year) for another term. For most investigators, it’s the most nerve-wracking ninety minutes of their professional lives. Doudna felt a few butterflies as she entered the room but the thought of the institute severing ties with one of the most celebrated scientists in the world was unthinkable.

A few months later, Doudna faced a new and unexpected public health crisis from of all things a virus: the novel coronavirus.⁸ As she and her colleagues prepared to shutter their labs for the pandemic, Doudna felt an overwhelming responsibility to help the local community. On March 13, she addressed her IGI colleagues with pronounced fire and emotion and told them it was time to step up. “Folks, I have come to the conclusion that the IGI must rise and take on this pandemic,” she said.⁹ With a gaping shortfall in COVID-19 testing capacity, Doudna and colleagues decided to turn a 2,500-square-foot space into a COVID-19 test center. The response to a call for volunteers was stunning: hundreds of people volunteered to help in any way they could.

In less than three weeks, dozens of volunteers from Berkeley and industry partners fitted out a new genetic testing lab on the first floor of the IGI capable of running more than 1,000 diagnostics tests every twenty-four hours.¹⁰ A pair of Doudna’s top postdocs, Jennifer Hamilton and Lin Shiao, stepped up to become the lab’s technical directors. For the first time, as Megan Molteni observed, Shiao felt that “all those years spent moving tiny bits of liquid around might actually directly change someone’s life for the better.”¹¹ Urnov rallied the troops with a quote from 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.”

On April 6, 2020, Dori Tieu, a fire prevention inspector from the Berkeley Fire Department, delivered the first samples on ice in a large polystyrene box to a nervous Urnov. For a few weeks or maybe months, CRISPR could wait.

Eighteen months before the pandemic hit pause on his lab’s activities, Feng Zhang was asked if there was a chance that his CRISPR editing tour de force in 2013 could end up being the biggest discovery of his career. “I hope not!” Zhang replied, aghast at the prospect that he had peaked already. “It’s a very lucky position to be in,” he continued. “There are many, many more problems we need to solve.”¹² From a young age, his parents had told him: “You should make yourself useful.” How could he make a difference against COVID-19?

In his meager spare time, Zhang personally set about adapting his SHERLOCK diagnostic method to develop a relatively simple diagnostic test for COVID-19. The test received emergency FDA approval—the first for a CRISPR diagnostic—in May 2020.¹³ There’s even an at-home version called STOPCovid,^I designed to work in about an hour for less than $10 (not counting the outlay for a sous vide to substitute for a lab water bath).¹⁴ And he formed a team with the CEO of Pinterest, Ben Silbermann, that took just three weeks to develop and release an app called How We Feel for people to track their personal health and symptoms in real time.¹⁵ Zhang and Silbermann have been friends since they met in high school in Des Moines, Iowa, a lifetime ago.

Other gene editing luminaries also retooled to tackle the COVID-19 crisis. In March 2020, a venture capitalist in Boston named Tom Cahill, who had launched a $125 million fund backed by a small group of billionaires including Peter Thiel and Stephen Pagliuca, co-owner of the Boston Celtics, organized a conference call to discuss COVID-19. Word spread fast. Cahill knew something was amiss when he couldn’t dial in because the call was over-subscribed with hundreds of listeners. “There was a sense of desperation among these masters of the universe” about the threat posed by the virus to their families and businesses, said Rob Copeland, who broke the story.¹⁶

Cahill decided to convene a 21st century Manhattan Project, the Justice League of scientists to vanquish the virus. Team captain was Stuart Schreiber, a distinguished chemist at Harvard, who created the Scientists to Stop COVID-19. The dozen experts included his colleague David Liu and a Nobel laureate, Michael Rosbash, who said he was the least qualified person on the team. Their report on the best prospects to defeat the virus from a pool of two hundred candidates¹⁷ was sent via some well-placed connections to the White House. Schreiber even attached superhero names to his group, including Batman (Ben Cravatt) and Wonder Woman (Akiko Iwasaki). Iron Man is part of a different superhero universe, so Liu is Cyborg—half man, half machine, genius intellect.

Alas, humans don’t have their own version of CRISPR superpower to cut down the coronavirus—but perhaps one day they could receive it. At Stanford, Stanley Qi leads an effort to deploy CRISPR-Cas13 in a method called PAC-MAN, designing CRISPR guide RNAs to seek out and destroy coronavirus RNA sequences.¹⁸ After all, why wouldn’t the most popular, versatile tool in the biotechnology arsenal be used to vanquish the virus?

The irony of this emergency call to arms was not lost on Doudna, Zhang, or any of their colleagues. CRISPR evolved to vanquish a particular group of viruses, the bacteriophages. Now a particularly malevolent virus was spreading around the world by feasting on the airways of a different host. “Bacteria have been dealing with viruses forever,” Doudna observed. “They’ve had to come up with creative ways to fight them. And now here we are, humans, in a pandemic facing this challenge.”¹⁹

As we contemplate the future of genome editing, I can’t help but think of the remarkable progress geneticists have made over the past fifty to seventy-five years, unraveling the secrets of the gene and the genome like the Cas enzyme unzipping the double helix. Francis Crick and Jim Watson’s classic 1953 letter to Nature consisted of eight hundred words and one diagram—a beautiful, elegant pencil drawing of the double helix courtesy of Crick’s wife Odile. CRISPR has given us the means to modify the DNA code as easily (almost) as a deft flick of Odile’s pencil eraser.

Odile Crick was a professional painter with a penchant for nudes. She wasn’t as enamored with the double helix breakthrough as her husband. “You were always coming home and saying things like that, so naturally I thought nothing of it,” she recalled. Nevertheless, her double helix became not only the most famous scientific drawing of the 20th century but also the universal symbol of humankind’s quest to understand, repair, manipulate, and control the code of life—to read, write, and edit DNA.

Odile only drew one other scientific illustration in her life.²⁰ Her granddaughter Kindra, an accomplished artist in her own right, told me where to look. It appeared in a book by neuroscientist Christof Koch called The Quest for Consciousness.²¹ The simple drawing was of a woman with shoulder-length hair in a short dark dress running, a static picture depicting motion. To where exactly is left to our imagination.

CRISPR is moving faster than society can keep up. To where is up to all of us.

I. “STOP” stands for SHERLOCK Testing in One Pot.