In late 2013, Nessan Bermingham, a rambunctious venture capitalist with Atlas Venture, conceived a new gene editing company. Bermingham grew up on an army base in County Kildare. After earning his PhD in London at St Mary’s Hospital Medical School—something we have in common—he did postdoctoral research at Baylor College of Medicine before moving into finance. During an Atlas retreat in Miami, Bermingham struck up a conversation at the salad bar with John Leonard, a physician who had just retired after a successful career in big pharma.
Leonard moved to industry early in his career after his wife was diagnosed with multiple sclerosis. In the early 1990s, he ran the antiviral program at Abbott Laboratories during the AIDS crisis. “Our mission was absolute, and from that I learned how empowering belief can be,” he said.19 His team developed ritonavir, one of the first HIV protease inhibitors, and later Humira. After retiring as head of R&D at AbbVie in 2013, he dabbled in a couple of more low-key entrepreneurial ventures, including a craft cider company in Michigan. The trip to Miami was just a networking opportunity, or so he thought. A few months later, Bermingham flew to Chicago to take Leonard to lunch and lay out his ideas for Intellia Therapeutics. (The company’s name came from the Greek “entelia,” a state of pristine excellence.) “I couldn’t think of a more promising and exciting technology than CRISPR,” he said. Bermingham was confident he could secure Doudna’s intellectual property (IP), which was good enough for Leonard, who joined as chief medical officer.20
In May 2014, Bermingham officially founded Intellia as CEO in partnership with Doudna’s first company Caribou,IV which holds Doudna’s IP (and owns a stake of Intellia). Intellia’s cofounders include Barrangou, Sontheimer, and Marraffini. Caribou is led by Rachel Haurwitz, who was the first student in Doudna’s lab to work on CRISPR, but determined to launch a biotech company even before she finished her thesis. The other cofounders were Jínek and James Berger (now at Johns Hopkins).
Intellia emerged from stealth six months later, with support from Novartis before another round raised $70 million. In May 2015, officially divorced from Editas, Doudna joined the cofounder group along with stem cell biologist Derrick Rossi. A year later, Intellia went public, outperforming Editas by reaping some $110 million in the largest IPO for a Boston biotech that year. Haurwitz and Barrangou joined the team celebration as Bermingham ran the opening bell on the Nasdaq exchange.
Bermingham is a fierce competitive athlete, reveling in ultramarathons, boxing, and mountain biking. During an after-dinner speech at a medical conference in Washington, DC, in 2017, Bermingham drew parallels between extreme sports and precision medicine, presenting his vision to develop a one-and-done treatment paradigm where “freedom from genetic disorders is no longer an inherited privilege.” His motivation came from the patients he hoped one day to cure:
When I climb a hill in the final stages of a marathon, I push through because I know that my lungs will never have to fight harder for oxygen than those patients living with alpha-1 lung disease. When I step into the boxing ring, I’m fearless because I know that I’ll not experience the pain children with sickle-cell disease fear every day. When continuing the race demands I choose to suffer, I remind myself it is by my choice and I will never have to face a preventative double mastectomy and living under the sword of breast cancer.21
Bermingham needed every piece of inspiration six month later competing in his first Roving Race in Patagonia. Athletes run twenty-five miles for four consecutive days, followed by a fifty-mile overnight leg and a trivial six miles on the final day, while carrying their own gear.22 He placed in the top half out of more than three hundred competitors (dozens of whom didn’t finish) in a time of thirty-nine hours—only nineteen hours behind the winner. Barrangou, no slouch as an entrepreneur, can only doff his hat. “Ness scares me! I can run with those guys, but this guy’s in a different league,” he laughed.
Perhaps exhausted, Bermingham resignedV as Intellia’s CEO a short time later, passing the torch to Leonard. Barrangou thinks he’s the ideal CEO: “John has done it before. It’s not about being first in the clinic, it’s about being best in the clinic.”23
Intellia’s biggest bet is on a liver disease called transthyretin amyloidosis (ATTR), which affects about 50,000 patients worldwide. (In 2016, Regeneron paid Intellia $75 million for rights in ten therapeutic areas, including ATTR.) This disease is adult-onset, typically fatal, caused by toxic amyloid protein deposits leading to heart failure and neuropathy. Patients typically survive just a few years after diagnosis. The plan is to use CRISPR-Cas9 to deactivate the TTR gene in the liver using a lipid nanoparticle for delivery, which unlike some viruses does not trigger an immune response. The strategy avoids leaving Cas9 hanging around too long, minimizing the risk of any off-target mistakes. If results in nonhuman primates hold up, this could represent a cure for patients with ATTR.
Eric Olson, a professor at the University of Texas, may not be an expert in genome editing, but he knows muscle.24 Olson started his own lab in the early 1980s at MD Anderson Cancer Center, and taught himself molecular biology. His first two grant applications were trashed by reviewers but it was third time lucky. Olson receives letters and emails almost daily from parents searching for hope, if not a cure, for muscular dystrophy. Olson’s company, Exonics, is on course to make a difference.
Duchenne muscular dystrophy (DMD) is the most common and severe form of inherited muscular dystrophy. It is caused by one of thousands of different mutations in the largest gene in the human genome. As an X-linked disease, DMD affects mostly boys—about 300,000 around the world. The corresponding protein, dystrophin, sits under the membrane of muscle cells and acts like a giant shock absorber; without it, the membranes start to leak, resulting in muscular weakness. Replacing dystrophin is a formidable task, but attempts to find a workaround, such as supplying a “mini” dystrophin gene or switching on a dormant related protein called utrophin, have met with little success.
The dystrophin gene consists of seventy-nine coding sequences, or exons, spread over 2.6 million letters on the X chromosome. Many of the 4,000 catalogued DMD mutations congregate in the middle of the gene between exons 45–50. These frequently result in a “frameshift” mutation, shifting exon 51 out of frame, which in turn compromises production of dystrophin. Interestingly, the middle portion of dystrophin—the spring, if you will—is less critical than the ends of the giant protein. We know this because patients with a milder form of DMD, Becker muscular dystrophy, have shortened springs but otherwise a partially functional protein, and have a longer life expectancy than DMD patients.
Olson’s plan essentially is to use CRISPR to convert some of the DMD mutations in the central exons to the milder Becker form of muscular dystrophy. By using CRISPR-Cas9 to engineer a cut in exon 51 to excise one particular mutation, the resulting protein should be close to fully functional. Just as Jean Bennett found a canine model to test her gene therapy for LCA, Olson’s team turned to another canine model. The beagle colony at the Royal Veterinary College near London looks and sounds as happy and healthy as their normal cousins, with tricolor coats and a trademark howl. But the affected dogs noticeably drag their hind legs.VI
Leading the Exonics team is an expat from Moldova, Leonela Amoasii. The initial results in 2018 put a smile on everyone’s face.25 Amoasii treated one-month-old puppies and then compared results with controls two months later. The muscle fibers of the treated dogs express newly restored dystrophin protein, as much as 80 percent of normal. But the most compelling evidence is to watch the treated dogs run, jump, and play as happily as their wild-type cousins. “We’re really excited,” says Amoasii. So too is Vertex Pharmaceuticals, which acquired Exonics in June 2019 in a deal potentially worth up to $1 billion—not bad for a company founded less than three years earlier.