Asked what he thinks about the possibility of fixing his disease using CRISPR, potentially eradicating the scourge of sickle cell altogether, Sanchez says, “Hmmn… that sounds cool.” Then he pauses. “There’s a lot of things that I learned having sickle cell,” including patience and keeping a positive outlook. “I don’t think I’d be me if I didn’t have sickle cell.”
A new biotech industry is rising fast in the belief that genome editing will provide the ultimate new weapon to deliver precision medicine. The industry is centered in Kendall Square, where the first three publicly traded CRISPR genome editing companies—Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics—jostle for space and research talent with dozens of innovative biotech and gene therapy firms.
In July 2019, CRISPR Therapeutics (working with Vertex Pharmaceuticals) became the first company to launch a CRISPR-based clinical trial for a genetic disease in the United States. A thirty-four-year-old mother of four from Mississippi, Victoria Gray, was the first of dozens of volunteers in the trial. Diagnosed with SCD as a baby, her faith has sustained her during tough times. “I always knew that something had to come along and that God had something important in store for me,” she told National Public Radio’s Rob Stein.10 At a clinical center in Nashville, Tennessee, doctors removed her bone marrow cells and administered chemotherapy. On July 2, 2019, hematologist Haydar Frangoul injected some two billion of Gray’s gene-edited “supercells” back into her body.
After weeks in hospital, Gray was finally able to return home, leaving hospital wearing a blood-red T-shirt with I AM IMPORTANT emblazoned on the front and proudly sporting an invisible genetic modification. “I’m a GMO. Isn’t that what they call it?” she said.11 A month later, she returned to Nashville to receive her preliminary results, this time modeling a black sweatshirt that said simply, WARRIOR. Frangoul could not disguise his excitement.12 Almost half of Gray’s hemoglobin consisted of the fetal form, a spectacular result. That was still the case nine months after her therapy, with 80 percent of her bone marrow cells displaying the desired edit. Another patient with beta thalassemia in Germany has not needed a blood transfusion in fifteen months.13 But it is still too soon to call it a cure.
CRISPR Therapeutics was the brainchild of Emmanuelle Charpentier. “I always had in mind that one day it would be nice if my research could lead to anti-infective strategies,” she told me. “But the right application for me was human gene therapy.”14As she was setting up her new lab in Berlin, Charpentier called her old friend, Rodger Novak, an executive at Sanofi who had been a postdoc with her at Rockefeller in the mid-’90s. “What do you think about CRISPR?” she asked. Novak didn’t know what she was talking about. He suggested Charpentier talk to an investor friend, Shaun Foy, to appraise the technology. “Maybe you think I’m crazy?” Charpentier asked Foy. A month later, Foy called Novak with a simple suggestion: “You need to leave your job!” he said.
Charpentier partnered with Novak and Foy to create Inception Genomics in November 2013, which later became CRISPR Therapeutics. They initially selected Basel, Switzerland, as their pharma-friendly headquarters before relocating to Kendall Square for closer access to investors and talent. (They also founded another company, ERS Genomics—the name assembled from the initials of the three cofounders—to handle Charpentier’s patent rights.) Charpentier had initially approached Doudna and Zhang about potentially teaming up to form a CRISPR company. Doudna demurred, agreeing instead to join forces with George Church and Zhang. Two other big names in Boston joined the band: Keith Joung, a pathologist at Mass General Hospital who had deep experience working on zinc fingers, and David Liu, a Harvard chemistry professor and Zhang’s friend at the Broad Institute. The company’s initial name was Gengine, but it was sensibly retired in favor of something with a bit more, um, gravitas: Editas Medicine.
The all-star quintet met in Boston for a company photoshoot but by the time Editas was announced, something appeared to have gone awry. One reporter noted that Doudna was notably absent from the official photos, a wisp of auburn hair in one photo the only evidence she’d been there at all. The reason soon became apparent: The Broad Institute had scooped Doudna and Charpentier by expediting Zhang’s patent application. In May 2014 Zhang was awarded the big CRISPR-Cas9 patent. Doudna quickly cut ties with Editas. She later offered family reasons and the burden of travel, but the patent defeat, even if only the first round of a marathon contest, stung.
Editas was backed by three giant venture capital firms working together for the first time—Polaris, Flagship and Third Rock. Bill Gates joined the second round of investors who put up more than $100 million. Gates was fascinated by the potential of genome editing not only to treat genetic diseases but also to combat infectious diseases such as malaria and improve food production in developing nations.15 As CEO Editas appointed Katrine Bosley, who had spent twenty-five years in biotech, most recently as chief executive of a cancer drug company, Avila Therapeutics, which is where I first met her.16 When BosleyII first heard about genome editing, it sounded like science fiction. But during a few months as an entrepreneur-in-residence at the Broad Institute, she got to know Zhang and learn about CRISPR’s potential. She was impressed by the technology’s ease of use and wide applicability—something in common with the novel chemistry her team developed at Avila.III
The lead program at Editas is for another form of Leber’s congenital amaurosis (LCA type 10). The attraction of LCA10 as a target was for many of the same reasons that Bennett identified: because the eye is both small and accessible as a delivery target. Moreover, the desired gene edit—a small deletion—has a lower degree of difficulty. LCA10 is caused by a single-letter mutation in a gene called CEP290, first characterized in a consanguineous French-Canadian family. CEP290 is expressed in the photoreceptors behind the retina; in LCA10 patients, the loss of the protein leads to degeneration of the outer segment of the photoreceptors. The LCA10 mutation, which resides in an intron that is normally spliced out of the gene transcript, results in an extra chunk of sequence being inserted into the RNA message. This cryptic exon includes a premature stop codon: so all of these RNA messages fail to produce a functional protein.
The Editas plan is to use CRISPR-Cas9 to deliver a pair of precise cuts flanking the mutation to restore normal gene splicing, thus producing the normal protein and rebuilding the photoreceptors. Like Spark Therapeutics, Editas uses an AAV vector to deliver the CRISPR machinery, dubbed EDIT-101. In July 2019, together with Allergan, Editas announced enrollment of the first patients in the Brilliance clinical trial.17 The first surgery was performed in an hour-long procedure at the Casey Eye Institute at the Oregon Health & Science University in Portland in early 2020. It was called a new era in medicine—the first time CRISPR had been injected directly into a human patient, as opposed to the ex vivo approach employed for Victoria Gray.18
In early 2019, Bosley surprisingly stepped down as CEO. During her career, she had experienced the thrill of seeing drugs impact patients’ lives, but she was foregoing that opportunity at Editas. (She did admit in one interview that five years at the helm seemed like a thousand.) She signed off on Twitter saying: “I’m proud of everything we achieved and built together, and I’ll always be cheering them on—now as Editas Emeritas, as we say.”