Genia Brin’s Double Parkinson’s Mutation
By Nadine Epstein
Eugenia Brin was 48 when she first noticed that her left leg was dragging. It took two years for doctors finally to diagnose her with early onset Parkinson’s disease, because she didn’t have tremors or other easily identifiable symptoms. The diminutive Brin, trained as an applied mathematician in the Soviet Union and then working as a meteorological analyst at NASA’s Goddard Space Flight Center in Maryland, knew there was no cure for the degenerative disorder of the central nervous system, which affects about one in every 250 people over 40 and more than one in 100 in people over 65. All she could do was work with her physicians to find the right combination of drugs and dosages to help relieve the symptoms—at least temporarily.
In 2008, she was tested through 23andMe, a start-up launched by Anne Wojcicki, who is married to Brin’s eldest son, Sergey, a co-founder of Google. Among the variants the company’s basic consumer package tests for is a mutation on the LRRK2 gene that can lead to Parkinson’s, because, says Wojcicki, “our scientists recognized that LRRK2 was an important finding.” While visiting California, Brin, known to friends and family as Genia, provided a DNA sample. “Our family was one of the first to be tested,” she says. “We were trying it out.” The result was completely unexpected: She had the mutation on not one but both LRRK2 genes. “When I got the results I thought ‘that’s why,’” she recalls. “There was some sense of relief to know there was a reason behind the illness.”
Parknson’s doesn’t only strike Jews, but it does have a Jewish connection. Ashkenazi Jews such as Brin, says Susan Bressman, chair of the department of neurology at Beth Israel Medical Center in New York City and professor of neurology at Albert Einstein College of Medicine, do not develop Parkinson’s at a higher rate than any other group, but they are more likely to carry the LRRK2 mutation, the most common of the six or so mutations that cause increased incidence of the disease. “Two to five percent of Parkinson’s worldwide is due to LRRK2,” she says. “If you look at Ashkenazi Jews, 15 percent of Parkinson’s is due to LRRK2.” She stresses that the mutation does not necessarily mean someone will develop Parkinson’s; a variety of environmental factors are also thought to play a role. “All we can say for sure is that LRRK2 mutation as a cause is more prevalent in people who have Parkinson’s,” she says. “We don’t know why 30 percent of LRRK2 mutation carriers get the disease.” Nor does the absence of the mutation guarantee not developing the disease: The vast majority of the millions of people who suffer from Parkinson’s worldwide do not have a known mutation.
Everyone has two copies of the LRRK2 gene, but it is unlikely that one, let alone both, will have the mutation, says Neil Risch, director of the Institute for Human Genetics at the University of California, San Francisco. “It’s really rare, probably in the ballpark of one in 20,000 or 40,000.” While the double copy doesn’t make Brin’s symptoms worse or affect her treatment plan, “the big downside is that it means both of her kids have a copy,” Risch says. “Usually they’d have a 50-50 chance but if a parent has two mutations it is 100 percent.” As a result, both Sergey, 38, and Brin’s younger son Sam, 25, each have a single copy.
The Parkinson’s Institute in Sunnyvale, CA, asked the Brins to donate skin cells to a lab at Stanford University. Researchers there were most interested in Genia’s cells, which they used to create induced pluripotent stem cells that can reproduce themselves, says bioengineer and stem cell biologist Blake Byers, who directs this research at Stanford and wrote his doctoral dissertation on it. “This is the only homozygous mutant [double gene mutation] line that we have in our lab,” he says. “It is valuable because we know it contains a Parkinson’s-inducing factor unlike lines of other genetic backgrounds, where the initiation of Parkinson’s might require an environmental trigger.”
Byers and others then successfully grew the stem cells into mature neurons that secreted dopamine and generated normal neural signaling. They sped up the progression of Parkinson’s—which usually takes about 50 years in the human body—by subjecting the neurons to stress until they exhibited the telltale signs of the disease: the elevated levels of proteins that are thought to clog and kill the cells, halting necessary dopamine production. “It was the first time we were able to investigate what Parkinson’s neurons look like when they are alive for more than a few days, then watch them get sick and die,” says Byers. By comparing these neurons to healthy ones taken from a control group, the researchers were able to understand how the diseased cells behaved. “The paper we wrote on Genia’s genes shows increased accumulation of alpha-synuclein protein and increased oxidated stress levels and increased susceptibility to oxidated stress induced cell death,” says Byers. The next step is to bombard the neurons with drugs that may prevent or cure the disease, he says, adding that additional research results will be published in about six months.
“Genia’s genes were very instrumental for doing this work,” says Byers, explaining that usually researchers don’t know the identity of the person whose genes they are studying but that in this case, the family went public with the information. “I wanted to disclose it to put a face on a scientific finding for the reading audience to bring more attention to Parkinson’s,” explains Brin.
Brin’s Parkinson’s has progressed slowly but has begun to make everyday tasks more difficult, especially when she is tired or stressed. Nevertheless, she pushes herself to live normally, continuing to travel, ski and serve on the Michael J. Fox Foundation for Parkinson’s Research Patient Council. Meanwhile, her sons have shown no signs of developing the disease. Sam exercises regularly, and Sergey follows the regimen of others at increased risk: In addition to exercising, he drinks caffeine and takes good care of his immune system, says Byers, adding that he does not smoke, even though smoking has also been found to help stave off the development of the disease.
Sergey underwrote 23andMe’s Parkinson’s Disease Genetics Initiative, which provides free testing to people who suffer from Parkinson’s in the hopes of learning more about the disease and someday finding a cure. Says Byers: “The reality is, unfortunately, that most Parkinson’s patients don’t get tested,” adding that if Genia Brin’s homozygous cell line had not been discovered, it would have taken far longer for researchers to learn what they now know about the disease.