Can superhuman athletes provide genetic clues on heart health?
San Jose Mercury News
The room is small and spartan, with beige walls pleading for a makeover and a treadmill occupying the right side.
Unremarkable in appearance, this Trackmaster TMX425 has the same display and settings as those found in gyms and hotel fitness centers. Its purpose, however, is anything but typical.
The TMX425 is the whirring heart of a five-year-old
In exam room 10, and at partner clinics across the globe, test subjects undergo an impossibly difficult treadmill test designed to identify athletes with freakishly high cardiovascular efficiency. If the score meets the study's otherworldly threshold, the athlete's DNA is sampled and sequenced.
"There's a broader implication of studying the extreme,'' said Dr.
Once the DNA is sequenced, researchers on the ELITE project -- the name is an acronym for Exercise at the Limit: Inherited Traits of Endurance -- sift through the genetic data.
By comparing the results from approximately 800 athletes around the globe, the ELITE team hopes to pinpoint a handful of genetic mutations responsible for the superhuman heart-pumping power.
At that point, drugs could be manufactured to mimic the beneficial mutations and, eventually, rid the world of the killer of killers:
"Some people have certain genes that allow them to do things better than other people, like build muscle or use energy,'' said Dr.
"If we understand what genes make elite athletes, we could turn them on in people who are sick. It's not too far-fetched. It could work, and it's potentially ground-breaking."
Ashley grew up in
A slender man with a narrow face and wide smile, Ashley played soccer and the saxophone and graduated with honors from the
"It's called the Langendorff heart, and you (remove it from the body) and tie the blood vessel and hang it,'' he said. "Incredibly, it beats. It beats for hours.
"I stared at it that day and thought, 'This is the most incredible thing I've ever seen. I need to understand this. I need to spend my life studying this.' ''
Ashley did his residency at Oxford, then fused his inner geek -- he loves big data -- with a passion for cardiovascular medicine. He joined the
Out of discussions with co-workers came ELITE. Created in 2012, it has four primary researchers and dozens of assistants, all based at
"We're looking at the fittest people on the planet and trying to figure out what makes them so good,'' said Dr.
Cardiovascular disease is the alpha killer, the leading cause of death in
The global picture is equally bleak: Heart disease killed approximately 18 million in 2015, the
"The prognosis is worse than most cancers, yet we don't really have great treatments,'' Ashley said. "We have treatments for the secondary effects, but we don't have anything that makes the heart strong again.''
ELITE goes where no cardiovascular research has gone before. Instead of studying the sick, it uses a data-driven, high-threshold test of the healthy -- the freakishly healthy.
The threshold for the study is so high, in fact, that
The Splash Brothers wouldn't qualify.
"That's a very different type of performance," Mattsson said of NBA and NFL players. "They don't need high (testing) numbers to perform in their sport.
"If they trained that amount, the hours needed to reach that level, they would lose training in other aspects."
Instead, ELITE targets endurance athletes, with 19 test sites in 11 countries. In some cases, the national teams have results on file from testing performed during tryouts and training.
The sports most likely to produce athletes who meet the threshold are rowing, cycling and, above all, cross-country skiing.
Marathoners, on the other hand, don't produce qualifying test scores at the rate you might expect because of the nature of their training: The body overheats before the heart reaches its most efficient level.
"There's likely something about training in the cold that helps,'' said Dr.
Why bother with test scores in the first place? Why wouldn't ELITE simply sequence the DNA of Olympic champions?
"Performance is messy,'' Mattsson said. "We can't be sure, based on performance, who would qualify.''
Performance can be affected by race conditions. And training methods. And coaching. And equipment.
And, ahem, blood doping.
Asked about the potential for test results to be skewed by dopers, Matteson noted that saliva samples must be submitted for genetic sequencing.
The cheaters, he said with a smile, "usually opt out."
The human genome has three billion base pairs of DNA molecules, which are grouped to form some 20,000 genes.
The key to superior heart efficiency could be a handful of mutations within the millions of base pairs that are grouped into the thousands of genes in a few dozen freakish endurance athletes.
The ELITE team likes to joke that the search for relevant mutations is like looking for needles in haystacks of needles. But it's more like needles in a mountain range of needles.
"You have genetic variation in the whole population, and then you have one person who's way out there,'' Wheeler said. "You can learn a lot from that person."
The finely-tuned athlete gasping for air on the Trackmaster is
"Still increasing," Mattsson yells over the whir of the TMX425. His role as lead investigator occasionally involves a bit of motivational coaching.
"Good job! New increase in 20 seconds."
With a monitor strapped to his chest and mask covering his mouth, Davis powers on. He seemed like a good candidate for the study: A former triathlete, the 30-year-old ditched the swimming discipline and became a national-class performer in the duathlon, which combines running and cycling in a three-stage combination.
The brutish treadmill test underway is not designed to measure Davis' speed or stamina but his VO2 max: His maximum oxygen uptake, or maximum aerobic capacity.
"The better the heart, the more oxygen uptake,'' Mattsson explained. "Find the genes that are important for high oxygen uptate, you find the genes that are important for a good heart.''
VO2 max has been used by physicians for decades to measure cardiovascular degeneration. Scores are assigned on a 1-to-100 scale and strongly correlate to survival rates. Below 14, and it's time for a heart transplant. At the other end of the scale, Wheeler noted, "VO2 max is a pure measurement for endurance potential."
A healthy, untrained man typically has a VO2 max in the 30s or 40s, an equivalent woman slightly lower.
For national team athletes in endurance sports, the scores jump into the 50s or 60s.
ELITE's bar is 75 for men and 63 for women.
Those thresholds, Mattsson explained, narrow the qualifying pool to 0.02 percent of the population: Not just the fit -- the superhuman.
"The reason (the threshold) is so high and not 50, for example, is that some people could train to get to 50 and some could be born with it, so it dilutes the sample,'' Mattsson said. "If it's super high, then you have to have a lot of training and a beneficial genetic profile ...
"We've excluded people with world championships in the 10k because they don't have a high enough VO2 max.''
On the Trackmaster, Davis' long legs churn away.
He began the evening with a warm-up session, stopped briefly to put on the testing equipment, then plunged into the interval workout.
The Trackmaster was pre-programmed with a starting pace of 6:40 per mile. From there, the speed steadily increased to the current 5:27-per-mile clip. One interval left: Five minutes per mile, at four percent incline.
"Good job,'' Mattsson bellows again. He claps, but after a minute, Davis is done. He stops and lurches forward, grabbing the treadmill for support.
The monitors tracking his heart rate and oxygen consumption spit out a VO2 max score on the computer screen: 65.
Good enough for a national team, but not good enough for ELITE.
Doubled over, Davis is too exhausted to speak.
"I wasn't disappointed,'' he said later. "I was pretty realistic of my abilities and what a score of 75+ really takes."
The highest VO2 max score ever measured is believed to be 97.5, by Norwegian cyclist
So dominant was Mantyranta in the 1960s that he was hounded by accusations of blood doping. Then genetic testing revealed Mantyranta and numerous family members carried a mutation that caused their bodies to produce astounding levels of oxygen-carrying red blood cells.
In a sense, Mantyranta's body was doping ... with its own blood.
The VO2 max test provides researchers with an entryway into a warehouse of genetic clues. Qualifying scores have trickled in -- from the Stanford Trackmaster and partner clinics -- to the point that ELITE has samples from approximately 800 athletes.
"If you're a national champion in an endurance sport, the odds of you qualifying are 25 to 30 percent,'' Mattsson said.
"Tell your friends."
ELITE does it much faster and much, much cheaper.
"It's been a million-fold change in the cost,'' Ashley said of the sequencing process. "That's what allows us to consider doing this. At
Once a qualifying VO2 max score is identified, researchers request a saliva sample. The athlete spits into a tube, and the DNA is sent to a vendor for sequencing.
A month later, the results are placed on a hard drive and sent to
"I'm looking for more rare things than you would expect to see by chance,'' Waggott said. "It's like gambling, and you never know when you'll get the winning ticket. Each new algorithm is like pulling the arm on a slot machine. Sometimes, you get a great finding.''
Waggott described his success thus far -- five years into the study -- in baseball terms: He knows there are plenty of base hits in the data and is hoping to find a few home runs.
The ELITE team hopes to publish in a few months. If the results are positive -- if enough genetic clues are uncovered -- the drugs would come next.
It seems unrealistic to think a treadmill study could lead to the creation of medicine capable of curing heart disease. But a similar process is underway in the fight against high cholesterol.
A decade ago, researchers discovered an aerobics instructor in the
Genetic testing revealed the woman, who used the name
Instantly, pharmaceutical companies sprinted to manufacture drugs mimicking her mutation -- drugs that "turn on" the genes that direct the body to gobble bad cholesterol 24/7.
Years later, two so-called PCSK9-inhibitors hit the market: Praluent (Sanofi) and Repatha (Amgen), which have produced encouraging results.
If ELITE succeeds, the same process could be used on ailing hearts. Drugs would activate the genes responsible for beneficial cardiovascular functions, whether that's producing more red blood cells or making the heart beat faster or spurring a more efficient transfer of oxygen.
"That's the hard thing but the amazing thing,'' Ashley said. "The answer could be found any one of those places. Extrapolating from what we know of an athlete's heart seems like a good place to look."
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