Research

To Boldly Go

What science could learn from NASA’s Twins Study.

By Katy Human featured image Photo courtesy of NASA

Movies and video clips may show astronauts drifting slowly by windows, gazing into the quiet depth of space, but don’t kid yourself: human space flight is stressful. There’s the stress of radiation exposure, including cosmic rays unshielded by Earth’s atmosphere. There’s nutritional stress, because it’s hard to force yourself to eat enough prepackaged astronaut food to counter grueling exercise regimes. There’s also psychological stress, a seemingly inevitable consequence of space flight of any length.

NASA created the Human Research Program in 2005 to conduct studies that might help us understand and minimize risks to astronaut health and performance during space exploration. But the roots of the program go back decades deeper, to John Glenn’s first orbit of the planet in 1962 — arguably the agency’s first experiment with a human body in space.

Glenn’s trip lasted about five hours. By 1996 — the year NASA welcomed into its astronaut class two Navy pilots with Social Security numbers just two digits apart — people were spending months in space.

Those two Navy pilots, athletes originally from West Orange, New Jersey, were identical twins Scott and Mark Kelly. The men logged nearly 600 days of spaceflight combined. Mark retired in 2011 and Scott in 2016; Scott’s final mission on the International Space Station lasted 340 days.

Before that flight Scott asked a seemingly innocent question: Was NASA doing anything particular because he and Mark were identical twins? The agency put out a call for research proposals: Who could help the agency investigate the physiological and biochemical changes that might occur during the nearly one year Scott spent on the International Space Station (ISS) while his brother Mark stayed behind on Earth? Earthbound Mark could serve as an almost perfect control, similar in both nature and nurture to his space-bound brother.

“We are very fortunate to be studying other, unrelated, astronauts,” says Susan Bailey, a radiation biologist from Colorado State University. “But with the Twins Study, we can suddenly, remarkably, control for the genetics between [two] individuals. We can also align everything so we have the same time points to compare.”

NASA will soon begin publishing data from the agency’s Twins Study, a $1.5 million, three-year, 10-investigator study profiling the Kelly brothers for nearly everything imaginable: their metabolism; their hearts, eyes, bones, and muscles; the turning off and on of their genes; the length of their telomeres; their cognitive scores; and their gut microbiota.

The Twins Study involves precisely two subjects, creating an “N-of-1” problem that has sparked some criticism. With only one pair of twins, can results possibly be extrapolated more broadly?


THE TELOMERE STUDY

In 2014, NASA received 40 applications from researchers around the country, all proposing to study the Kellys before, during, and after Scott’s one-year mission aboard the ISS. Ten proposals made the cut; one led by Colorado State University’s Bailey was among them.

Bailey has been studying telomeres for more than three decades. She compares the chromosome-bound structures to the plastic tips at the end of some shoelaces, which help keep the laces from fraying with wear. Telomeres serve to protect our chromosomes; every time our cells divide — as occurs over and over again with aging — those protective tips get a tiny bit shorter. Like shoelace tips, as telomeres themselves shorten or fray, their protective abilities are compromised.

“We use telomeres as biomarkers of risk,” says Bailey. “If they’re shortening at an accelerated rate, we see increased risk of age-related degenerative pathologies like cardiovascular disease and cancer. Telomere-length dynamics capture our exposures, our experiences … they integrate our life stressors.”

Using a technique called fluorescence in situ hybridization (FISH), she can light up all individual telomeres to measure their length and map the distributions of their sizes over time. She and her team hypothesized that Scott’s telomeres would shorten in space, “as a result of the unique stresses astronauts experience: physical, psychological, nutritional.” But during his 340-day ISS flight, Scott’s telomeres actually lengthened; Mark’s did not. “We can see this shift in Scott, these populations of cells with longer telomeres,” Bailey says. “You couldn’t have surprised me more. I also couldn’t be more at a loss to understand why.”

“There’s [always] risk in doing challenging stuff, whether launching into space and building a space station, or personal risk involved in releasing my genome. To learn things, you take risks.”

She didn’t believe it at first. Maybe some-thing was mislabeled; maybe there was something about the transport of samples. But such factors would most likely degrade telomeres, not lengthen them. Bailey asked a colleague in an independent lab to rerun her samples. She also got access to additional samples from a fellow Twins investigator for analysis of more in-flight time points. The same pattern emerged, Bailey says. “They all show telomere lengthening while Scott was on station. That helped boost our confidence — it’s a real effect.”

Scott’s telomeres lengthened very quickly, within a couple of weeks of being in space. When he returned to Earth, they shortened again, within a week. Nine months later they had rebounded, ending by being slightly longer than they had been before he went to the space station.

Telomere lengthening is not exclusively good news, Bailey cautions: The downside of elongating cellular life is a greater risk of cancer: “This is what cancer does, and it does so by maintaining telomeres, usually by turning telomerase back on,” she says, referring to the enzyme that protects and extends telomeres. As we age, our cells generally stop dividing, providing an effective tumor suppressor. “Tumor cells figure out a way around that.”

Bailey says she remains baffled by the differences in Scott’s in-flight telomeres, but thanks to the Twins Study she has countless avenues to pursue to try to better understand them. She’ll be looking at levels of telomerase and its ability to help rebuild telomeres. Presumably the enzyme somehow played a role in Scott’s anti-aging tricks in space. Could it be harnessed to make long-distance space travel safer? Bailey also hopes to gain access to Scott’s radiation exposure history while on the ISS so she can better understand Scott’s space environment versus Mark’s ground environment.

Meanwhile, Bailey says, there also are the results of epigenetic studies to consider, as well as the likely role of microgravity on telomeres and telomerase. And perhaps she needs to consider emotional and behavioral responses. “Yes, there’s stress,” she says. “But these people have worked their whole lives to do this, to get to space. They are realizing a dream and you’ve got to wonder what that does.” Might the fun counter the stress at the level of the telomere?


THE POWER OF TWO

Mark Kelly did some genetic testing several years ago through the California-based company 23andMe. Scott did the commercial test more recently, not so much to learn about himself as to contribute to the broader database of genetic knowledge, he says. He also did it for fun.

The two learned that they share less in common with Neanderthals than most people do. “We’re 2 percent, and the average is more than that,” Scott says. “Well, I guess that’s pretty good?”

23andMe’s test also revealed the Kellys have Ashkenazi Jewish relatives, which was a surprise. But many families uncover such unexpected histories. Less surprising: The twins are, in fact, identical.

In the course of the NASA-funded genetics work, Scott and his brother learned they carry a very rare allele associated with a neurological disease. They learned that a few medicines may not work terribly well for them, including the blood thinner warfarin and interferon, which is used against hepatitis virus and other pathogens. And they learned that they do not carry a long list of diseases associated with specific genes. “It’s nice to find out that you can’t pass these things on,” says Scott.

But that’s just the beginning, says Stanford University’s Mike Snyder, another NASA-funded researcher on the Twins Study. (See the infographic about Snyder’s own biology in Genome’s summer 2017 issue, page 22.) Snyder, a geneticist, works in the broad field of “omics,” which combines increasingly powerful and data-rich fields such as genomics (the study of DNA), proteomics (the study of proteins involved in critical cellular functions), and metabolomics (metabolic research).

“We’re big believers that you can learn a lot from an N of 1,” says Snyder.


PUTTING IT ALL TOGETHER

Some of the power of NASA’s study, he and Bailey say, lies in the agency’s work to ensure that all investigators share all their data with one another. So, those studying detailed patterns of DNA methylation (methylation — the addition of a particular chemical group to DNA — can influence how and whether genes are expressed) can compare their data with those from biochemists who are measuring blood levels of proteins associated with, say, inflammation or the microbial makeup of feces.

Snyder is known for this kind of work, integrating multiple, repeated, and diverse measurements to make expected and unexpected connections. He might simultaneously measure physiological markers (say, heart rate, skin temperature, and activity levels), biochemical markers (levels of certain factors in the blood), and even exposure to psychological stressors (such as fatigue or emotional distress).

To do these kinds of investigations, Snyder has cohorts of patients using wearable medical technology “to see what it means to be healthy, at a level we’ve never seen before.” Snyder has studied himself as a patient and has made unexpected links, including how a viral respiratory infection awakened a latent genetic predisposition to diabetes.

“We’re using wearables in a way we think we can tell people are getting sick before they know,” Snyder says. He wanted to bring that to the astronauts. “They are dealing with all kinds of unique stressors,” Snyder says. “Start with the physical forces of getting shot up to space in the first place.” He cites nausea, concerns about bone and muscle deterioration and headaches, among other side effects of space travel.

Snyder has sequenced his own genome several times and has billions of data points on dozens of patients he’s followed over the years. “For me alone, I’ve got a petabyte of data,” he says. “We may not have that much on Scott and Mark, but there is a lot. This is essentially a two-person big-data project.”

Both he and Bailey attended a midyear meeting in Houston, organized by NASA, to begin crafting some of the group’s initial results into a paper that would be a sweeping overview of the Twins Study. Individual investigators will then begin sharing their results with one another and publishing their own findings.

One potential hitch to data release: Agency officials are struggling to balance the benefits of releasing data that could help inspire more great science with the risk of releasing exquisitely personal genetic information that could someday harm the Kellys’ kids or grandkids.

“There’s risk involved,” agrees Scott Kelly, though he remains unfazed. “There’s [always] risk in doing challenging stuff, whether launching into space and building a space station, or personal risk involved in releasing my genome. To learn things, you take risks.”

Agency officials have worried mostly about the astronauts’ kids, Scott says. “If we got rid of the Affordable Care Act and we had to worry about pre-existing conditions not being covered reliably or affordably, they could say, ‘He is your father. You may have that trait, therefore we will not cover you for that.’”

Scott says he and his brother have both talked with their girls (each has two, in their teens and early 20s) about these issues. “They understand it.”