Every year, headlines report the sudden deaths of teens and young adults who were healthy by all outward appearances. When the ensuing autopsies fail to pinpoint a cause, each death adds to a centuries-long medical riddle that only in recent years has begun to generate new insights.
Eric Topol (Col ’75) is helping untangle the mystery. In what is expected to be the largest effort of its kind, Topol, the director of the Scripps Translational Science Institute in La Jolla, California, is collaborating with medical examiner offices in San Diego and Los Angeles to identify sudden-death victims and, in turn, conduct “molecular autopsies” that can expose genetic risk factors that traditional autopsies don’t reveal. Over time, he hopes to work with medical examiners around the country and develop a database of his findings.
“This is a big public health problem, and now we have a way to unravel it,” says Topol, who analyzes blood and heart-muscle samples for clues. Family members also provide saliva samples.
Since starting the project in November 2014, he’s conducted roughly eight autopsies and says those have turned up some telling indicators. For instance, two victims exhibited defects in their ion channels, a series of valves on cell membranes that help maintain a healthy heartbeat. “It’s something that you can only find through this detective work,” Topol says.
And it can help save lives. The defect causes arrhythmia, which creates an abnormal rhythm in the heart. Topol says family members could be tested for the condition and receive treatment, which could range from medication to having a defibrillator implanted.
There are no reliable statistics on how many sudden deaths occur each year among those 45 and younger in the United States. Estimates range widely—from 3,000 to 10,000—according to Michael Ackerman, a pioneer in sudden-death research at Minnesota’s Mayo Clinic.
Ackerman, who conducted the first molecular autopsy in 1999, says that drawing conclusions from genetic autopsies is fraught with risk for researchers and physicians. He says he’s seen instances in which family members of a sudden-death victim received implantable defibrillators because of a purported finding in a genetic autopsy, only to discover later that a genetic mutation should not have been called the cause of death.
“Molecular autopsies are a great advance, but the enthusiasm has to be kept in check so we roll it out carefully,” Ackerman says.
Topol’s team, funded in part by a $29 million grant through the National Institutes of Health, works at analyzing the more than 6 billion genes of sudden-death victims, along with those of their family members, in an effort to filter out mutations that might be linked to the sudden death.
The process is laborious, and doesn’t always reveal a smoking gun. “We’re talking about 250 billion data points, and to get it down to the one root cause mutation isn’t always possible,” Topol says. “Understanding unexplained sudden death is a big data story. That’s where it gets to be detective work. We can, in some families, get the insights we need, but that’s uncommon. We need much bigger samples to be able to confidently explain to a family what they don’t know.”