It’s hard for Jimi Olaghere to remember what life was like two years ago, just before he got an experimental treatment for sickle cell disease. The genetic condition causes unpredictable episodes of severe pain, which had kept him in and out of the hospital his whole life — with as many as 20 overnight visits to the emergency room and three trips to the ICU a year. “Life was bleak,” Olaghere said.
That changed thanks to CRISPR, a revolutionary gene editing tool that enables scientists to make precise changes to DNA. About two years ago, Olaghere received an infusion that flipped a genetic switch to restore his blood cells’ ability to carry oxygen throughout his body. He hasn’t been to the hospital or emergency room for a pain crisis since.
“I wasn’t expecting the change to be so dramatic and almost instantaneous.” Olaghere said. “It really feels like a miracle.”
The technology that turned Olaghere’s life around is young by scientific standards. Ten years ago on Tuesday, a small team of scientists published an unassuming paper describing a simple but powerful invention for cutting specific sequences of DNA. It became known as CRISPR gene editing.
Dozens of biotech companies are building their businesses on CRISPR’s potential. But the CRISPR therapies in the most advanced clinical trials, including the one that Olaghere received, are all from Boston companies.
The technology has taken the scientific world by storm. Thousands of research labs use CRISPR in experiments to probe biology. And biotech companies have collectively raised billions of dollars to develop CRISPR therapies to treat cancer, genetic diseases, viral infections, and more.
“It is extraordinary,” said Jennifer Doudna, a biochemist at the University of California Berkeley, who invented CRISPR gene editing. “I don’t know of another technology that within ten years of its genesis was something that had already led to positive clinical outcomes.”
“The clinical development is really nothing short of amazing,” said Feng Zhang, a scientist who also invented CRISPR gene editing in his lab at the Broad Institute of Harvard and MIT.
Crispr Therapeutics and Vertex Pharmaceuticals, which made Olaghere’s infusion, plan to submit their CRISPR therapy to the Food and Drug Administration later this year.
While a decade from concept to FDA-approved therapy may seem slow, it is fast compared to other biotechnologies such as antibodies, gene therapies, and even mRNA vaccines, which all required two or three decades of refinement and testing before becoming FDA approved products.
Earlier this month Crispr and Vertex said that all 31 people with sickle cell disease who got their treatment no longer experience severe episodes of pain. “I would have been happy with just a little less pain and fewer hospitalizations,” Olaghere said. “This completely overshot that.”
Sickle cell disease is caused by a mutation in the gene for hemoglobin, an oxygen-carrying protein in the blood. To correct the problem, scientists collected Olaghere’s blood, used CRISPR to turn on the production of so-called fetal hemoglobin, which we all make as babies, and then reinfused the blood cells back into his body.
In another trial testing the same gene editing therapy for a similar blood disease called beta-thalassemia, 42 out of 44 people who got the treatment no longer required blood transfusions they used to need to stay healthy. The other two people require far fewer transfusions than they used to.
Dr. Jean-Antoine Ribeil, clinical director of the Sickle Cell Center for Excellence at Boston Medical Center who was not involved in the trials, said the results “are really promising and convincing,” especially the therapy’s ability to reduce pain crises in people with sickle cell. “It is a transformative therapy for the patients.”
Another Cambridge biotech firm, Intellia Therapeutics, recently revealed promising data for its CRISPR therapy designed to treat a rare genetic liver disease by stopping a gene from producing a toxic protein. A low dose of the therapy reduced that protein by about 90 percent for at least a year — the most recent data point. It was a better outcome than many experts hoped for.
“It is incredible how effective these first out-of-the-gate therapies have actually been,” said Doudna, who is a cofounder of Intellia.
These potentially curative therapies have humble origins. In 2012, a small team of scientists led by Doudna and Emmanuelle Charpentier, now at the Max Planck Unit for the Science of Pathogens in Berlin, created CRISPR gene editing by combining a bacterial enzyme called Cas9, which cuts DNA like a pair of scissors, with a synthetic RNA molecule that can be programmed to tell those scissors where to cut, like a genomic GPS.
Initially, Doudna and Charpentier used CRISPR to cut DNA in a test tube. The experiment was simple, but offered a new way for easily manipulating DNA. “There was a sense, very quickly, that this would transform the way we did biology,” Doudna said.
Eight years later, she and Charpentier shared the Nobel Prize in Chemistry in 2020 for the invention. Scientists have used CRISPR on everything from butterflies to bananas to human blood cells.
Addgene, a Watertown nonprofit that makes and distributes genetic tools, has shared CRISPR tools with scientists at more than 4,800 organizations across 90 countries.
“We can do things to DNA that we couldn’t do before, in a cheaper, faster, targeted way,” said Eric Perkins, a scientist at Addgene since 2008. “It really changed everything for people working with DNA.”
The development of CRISPR therapies was accelerated by previous work on technologies such as engineered viruses and lipid nanoparticles, which are used to deliver DNA and RNA into cells. “There was a wonderful foundation in place that when CRISPR came to be, we could call on those preexisting technologies,” said Dr. John Leonard, chief executive of Intellia.
Although there haven’t been any issues with CRISPR’s safety in humans yet, scientists will need to watch patients who get the therapies to make sure unintended consequences don’t arise in the future. Olaghere admits he was unsure about how safe the therapy would be. “But it seemed a lot more risky to do nothing, so I did not find it hard to make that decision,” he said.
The CRISPR therapy gave him energy that he’s never known before — his body wasn’t used to having so much oxygen — which helps him play with his three young children. That is aggravating his hips, which have grown weak from years of poor blood flow. He still has hip pain, but not the kind that used to send him to the hospital.
“I don’t have those intense almost mind bending crises that you expect with sickle cell,” he said. He doesn’t know how long the treatment will last, but he hopes that it’s permanent.
“We are not supposed to call it a cure,” he said, “but it feels like one.”
Ryan Cross can be reached at firstname.lastname@example.org. Follow him on Twitter @RLCscienceboss.