Scientific ’breakthrough of the year’ edits DNA,
‘Transformational’ CRISPR technology could soon be used to treat genetic diseases
Gavriel Rosenfeld lives with his family in northwest London, England. Ten years ago, when he was 3, his mother Kerry noticed something strange about his gait. By 4, he was waking up with terrible leg cramps.
The doctor who delivered the news was so distressed she had a red rash creeping up her neck. Gavriel was diagnosed with Duchenne muscular dystrophy, an aggressive muscle-wasting disease caused by a genetic mutation.
“There is no treatment. There is no cure. Boys generally lose their ability to walk in their early teens, and their hearts and lungs then deteriorate,” Kerry Rosenfeld remembers the doctors telling her. “The message was very short, sharp and clear: that he would unlikely live past his early 20s. And that there was nothing more we could do.”
Today, at13, the boy from northwest London cannot walk. His upper body is weakening. But not all of Gavriel is in London. Some of his cells are in the laboratory of Dr. Ronald Cohn at Toronto’s Hospital for Sick Children. And those cells no longer bear the traits of muscular dystrophy.
Using a genome-editing technology called CRISPR, Cohn and his collaborators corrected the DNA error that was causing Gavriel’s muscles to fail. A duplicated DNA segment leaves his cells unable to make a crucial protein called dystrophin. The lab’s edit snipped out the duplication, restoring the gene’s function. CRISPR was declared “Breakthrough of the Year” by the journal Science this week. Because of its simplicity and power, commentators have described CRISPR as “transformational” and “a potentially society-altering technology.” It is both hailed and feared for its widereaching applications.
After a Chinese team announced CRISPR experiments on human embryos, scientists held an international summit earlier this month to discuss the ethics and safety of modifying human germ cells — changes that would be inherited by future generations. In another case cited by Science as an example of the tool’s power and risks, British scientists used a CRISPR-powered “gene drive” to rapidly spread infertility in a laboratory population of the mosquito species that carries malaria. The technique could wipe out the species in the wild, but with unknown effects on ecosystems.
Gene therapies and other biomedical applications of CRISPR, on the other hand, are still a work in progress. Cohn and other investigators, who want to edit non-heritable or “somatic” cells to treat disease in a single individual, face many challenges — chief among them how to transfer discoveries from a petri dish to an actual living person such as Gavriel.
Yet the exhilaration in the field is palpable.
“It’s going to take a little bit more work to figure this all out, but there is so much excitement and energy around this technology, I expect solutions will be forthcoming,” says Matt Porteus, a professor of pediatrics at the Stanford School of Medicine in California who specializes in genome editing.
Cohn calls CRISPR “the most exciting technology in my professional career.” He says, “I can start to devel- op a concept of treatment for patients with genetic disorders who are alive — patients I see in my clinic, patients I have been taking care of for many, many years, and I could never offer anything.”
CRISPR isn’t the only genome-editing technology. In November, doctors in London announced they had used enzymes called TALENs to successfully treat a 1-year-old girl with leukemia and no remaining treatment options. They engineered a donor’s T cells, which target the cancer, to disable genes that would fight with the girl’s body. Other researchers are using a tool called zinc-- finger nucleases to edit HIV patients’ T cells and remove a receptor the virus relies on to infect cells, with promising results.
But using these technologies is like trying to pick up marbles with $500 chopsticks. It works, but so inefficiently and expensively that most scientists don’t try it. CRISPR — cheap, fast, simple — is like handing the marble-picker a big fat scoop.
“What CRISPR has really done is not change the idea of what one might do, but instead made it possible for a wider range of people to adopt the idea. The ease of designing a CRISPR has really opened up the possibility to a lot more people who previously couldn’t access this technology,” says Porteus.
Cohn’s lab, after successfully engineering Gavriel’s genome, is now turning to another CRISPR application: highly specific, rapidly created animal models.
Already, they are close to engineering a mouse that replicates Gavriel’s disease-causing genetic duplication, bumping the research from a dish to a living organism in a fraction of the usual time. More work needs to be done by labs everywhere, including finding the right mechanism to deliver a potential gene therapy to a human recipient’s muscle cells (disorders of the blood, which can be removed from the body, are easier to tackle).
But Porteus calls this a “technical” problem, rather than a biological one. And he points out that if we could develop successful therapies for somatic cells, we might avoid the need to edit germ cells or embryos. Cohn, meanwhile, has already assembled a group of regulatory, ethics, policy and industry collaborators to discuss the safest way to take the next steps toward a therapy.
After Gavriel was diagnosed, the Rosenfeld family founded the Duchenne Research Fund to try to find a cure for the disease. Cohn became the fund’s chief scientific adviser, and then a close family friend. The Sick Kids CRISPR study, published in the American Journal of Human Genetics, was funded in part by another trust started by a family whose son has Duchenne.
The two funds have joined in the past to advance research into gene therapy, which they believe has the best hope of saving the most children. But Kerry Rosenfeld always thought they were working to preserve Gavriel’s legacy — not his life.
“It was never going to hit in time to save our own child. And this discovery, and this optimism and enthusiasm, and the speed with which Prof. Cohn was pushing this through and moving with it, meant that we had to do a whole paradigm shift in our heads and start to think of a future for our child.”
Cohn talks realistically to families about timelines, and manages the pressures his own team faces. But he feels hope, too. “It’s good to have hope,” he says. “It’s something very powerful.”