Several months after deciphering his genetic code last year, Stanford bioengineer Stephen Quake approached a cardiologist colleague. Early analysis of his DNA had flagged a rare genetic variant as potentially linked to heart problems. The variant, in fact, was located in a gene linked to sudden cardiac death in athletes, so physician Euan Ashley suggested Quake visit his office for some follow-up screening. Inspired by that meeting, the scientists spent the next year figuring out how to examine his genome in a way that would be meaningful to both Quake and his doctor.
The result–published today in The Lancet–is the most comprehensive clinical analysis of a human genome to date, highlighting both the medical potential of genomics and the hurdles that remain. “We wanted to try to answer the question of what a physician should do when a patient walks into the office with a copy of his genome and says ‘treat me,’ ” says Quake, who was named one of Technology Review’s top young innovators in 2002.
As the cost of sequencing has plummeted in the last few years–from about $3 billion for the Human Genome Project to less than $5,000 today–the number of complete human genomes has blossomed. Hundreds have now been sequenced, though only about 13 have been made public. Scientists are moving their focus from the technical hurdles of sequencing itself to what they say that will be a much more difficult task: analyzing the content of genomes to better understand human disease and the health risks of the individual.
Quake and 13 other “genome pioneers”–a select group who have had their entire genomes sequenced–described their efforts to use their genomes to better manage their health at a conference in Cambridge, MA, this week. The early adopters included James Watson, co-discoverer of the structure of DNA, Harvard professor Henry Louis Gates, Jr., entrepreneur Ester Dyson, 17-year-old Anne West, and a handful of genomics executives.
Despite the complexity and remaining mystery of the human genome–scientists still don’t know the function of 90 to 95 percent of human genes–many of the pioneers at the event described using their genomic information to make medical decisions. John West, former CEO of Solexa, a sequencing company that was acquired by genomics giant Illumina, recently had his genome sequenced along with that of his wife and two children. West and his wife discovered they have higher risk of a certain type of glaucoma, which sent them to the ophthalmologist for screening. “Now we know there is something to look for, and the test is easy and relatively inexpensive,” he said at the conference. (Daughter Anne presented the results of her analysis of her family’s genomes to the illustrious audience.)
Seong-Jin Kim, director of the Lee Gilya Cancer and Diabetes Institute at Gachon University of Medicine and Science, in South Korea, discovered after genome sequencing that he has a tenfold increased risk of macular degeneration, the leading cause of blindness in people over age 60. “I am diligently taking preemptive steps in everyday life to prevent it,” he said at the conference. He takes high doses of antioxidants, which have been shown to slow progression of the disease, has regular eye exams, and avoids activities that tend to overexert the eyes. (The scientist is also trying to convince his wife to switch to an LED television, because they may be less damaging to the eyes than LCD.)
While individual genetic tests could have been performed for each of the medical conditions in these cases, the cost of genome sequencing is dropping so quickly that it will soon be cheaper to sequence the whole genome rather than various parts. Quake, who published his own genome sequence, without interpretation, in 2009, can now go back to his genome anytime a new publication describes the possible implications of one of his variations.
In the Lancet paper, Quake and his collaborators undertook a comprehensive analysis of his genome. The researchers focused on variants that had been linked to risk of disease in previous studies, and those thought to play a role in a patient’s response to drugs. Beginning with an average risk for a particular disease of someone of Quake’s age and background, they added or subtracted risk using the genetic information. “That’s the most challenging thing, there is no accepted method for how to do that,” says Ashley. “We tried to prioritize what would be the most important thing to discuss with a doctor.”
Highlighting just how difficult it is to analyze a genome, Quake points out that it took just a few weeks to sequence his genome, which was published in a scientific paper with three authors. Analyzing the genome for its clinical relevance took a year, and the resulting paper has 20 authors.
The rare variant that led Quake to Ashley’s office in the first place provides an illustrative example of the state of genome interpretation. The variant is located in a gene that is well-known to be linked to sudden death. But it turns out that Quake’s particular variation is fairly common and present in some healthy people. Combining that knowledge with the results of screening tests–all perfectly normal–led the team to conclude it isn’t dangerous. The team also found a completely new variant in that gene, which they haven’t yet been able to interpret. “At the moment our tools are relatively limited,” says Ashley.
In addition, researchers found variants in other genes linked to cardiomyopathy, a disease that weakens and enlarges the heart, which may help explain a history of sudden death in the family. “Maybe I could have guessed it based on family history,” says Quake. “But it’s one thing to know there is a family history and another to know I had the allele. That sent me to a cardiologist.”
Quake says he hasn’t listened to all the medical advice derived from his genome. While he learned that he has a higher-than-average genetic risk for other types of heart disease, he found via the traditional way that physicians use to calculate risk–which doesn’t include genetic information–that he’s just under the threshold for statin use. Ashley felt the genetic risk factors were enough to put him over the line and suggested he start taking the drugs. “I haven’t followed that yet,” says Quake. “I’m still thinking about it.”
If Quake does start taking the drugs, his genome suggests he will respond to them and is unlikely to suffer one of the drug’s more serious side effects, muscle pain.
Some experts are already concerned that widespread genetic testing will lead to unnecessary medical follow-ups, driving high medical costs even higher. But Quake hopes that genome sequencing will ultimately lower costs. “I think this will provide a way to ration health care so that people at risk can get [screening tests] more frequently and those who aren’t get it less frequently,” he says.