What to know about CRISPR gene-editing technology
Scientists had tried to treat diseases by editing genes since the 1990s, but the methods were cumbersome and didn’t pay off.
Then in June 2012, the journal Science published a paper by two future Nobel Prize winners who had invented a new approach called CRISPR-Cas9.
It combined a bacterial enzyme called Cas9, which cuts DNA like a pair of scissors, with a synthetic RNA molecule that can be programmed to direct those scissors where to cut, like a genomic GPS.
The Food and Drug Administration on Friday approved the first drug that uses this technology to treat an illness, sickle cell disease. Called Casgevy, the medicine for the inherited blood disorder was developed by Boston-based Vertex Pharmaceuticals and CRISPR Therapeutics, which is headquartered in Zug, Switzerland, but has most of its employees in Boston.
The FDA on Friday also approved a rival sickle cell treatment called Lyfgenia, which uses a different technology. Developed by Somerville-based Bluebird Bio, Lyfgenia is a gene therapy that uses an engineered virus to insert a modified gene into the DNA of a patient’s blood cells. The FDA has approved at least eight gene therapies for mostly rare diseases since 2017.
Here’s a primer on CRISPR:
Who invented it?
The tool is credited to a scientific team led by American biochemist Jennifer Doudna of the University of California, Berkeley, and French microbiologist Emmanuelle Charpentier of the Max Planck Institute for Infection Biology. Doudna and Charpentier would be given the 2020 Novel Prize in chemistry for their pioneering work.
Other prominent scientists quickly advanced the field, including several
in Massachusetts. In January 2013, seven months after Doudna and Charpentier reported their discovery, the MIT molecular biologist Feng Zhang published another paper in Science on the tool’s potential. A similar paper from the Harvard geneticist George Church came out in the same issue of the journal.
Did those papers initially get much attention?
Not outside scientific circles. It wasn’t until an article in Forbes in March 2013 that media outlets began to pick up on the significance of CRISPR. But many scientists read the Doudna-Charpentier article and immediately knew it was a big deal.
“I don’t think it took special talent on my part to recognize that,” said Dr. Stuart Orkin, a researcher at Dana-Farber Cancer Institute and Boston Children’s Hospital and Howard Hughes Medical Institute Investigator.
In 2008, Orkin identified the gene that Casgevy snips to treat sickle cell, called BCL11A. No one had devised an efficient way to do it, Orkin said, but the approach laid out by Doudna and Charpentier appeared to provide a road map. “It was very elegant and innovative,” he said.
What is sickle cell disease?
Sickle cell is a group of inherited blood disorders that affect hemoglobin, the oxygen-carrying protein in red blood cells. It primarily affects people of African descent. White people are rarely diagnosed with it.
It occurs in about one out of 365 Black births in the United States, and one out of 16,300 Hispanic American births, according to the Centers for Disease Control and Prevention. About 100,000 Americans and millions of people worldwide have the condition.
The disease causes round, flexible red blood cells to deform into a sickle shape and stick to vessel walls. That deprives tissues of oxygen, resulting in excruciating pain and often necessitating blood transfusions. People with sickle cell inherit two faulty hemoglobin genes — one from each parent. If someone inherits just one defective copy, that person is said to have sickle-cell trait but can lead a normal life.
Does Casgevy edit the faulty hemoglobin gene?
No. It treats the disease through a workaround. Casgevy edits the BCL11A gene in a patient’s bone marrow stem cells to make high levels of fetal hemoglobin. That’s the healthy, oxygencarrying form of hemoglobin produced during fetal development that is replaced by adult hemoglobin soon after birth.
Unlike adult hemoglobin, fetal hemoglobin resists forming a crescent shape in sickle cell patients, and scientists have long wanted to find a way to restart it. The discovery of CRISPR made it possible to flip the genetic switch, with what appears to be remarkable effect.
The medicine completely relieved 29 of 30 sickle cell patients of debilitating episodes of pain for at least one year among clinical trial participants who were followed for at least 18 months, according to Vertex.
Now that the FDA has approved Casgevy, will scientists use CRISPR-derived gene editing to develop medicines to treat other diseases?
They’re already trying. CRISPR Therapeutics, for example, is working on using the approach to treat forms of cancer, among other diseases. Bill Lundberg, who served as chief scientific officer at the company from 2015 to 2018, said he believes CRISPR gene editing has the potential to treat a range of inherited and acquired diseases.
“This is an incredibly exciting time for patients,” said Lundberg, who now heads the Netherlandbased biotech Merus. “I’m no longer involved with [CRISPR Therapeutics], but I have deep personal excitement around this.”