A year on the space station has an undeniable impact across the human body, but many of the body's systems recover after a return to Earth.
Human bodies did not evolve to float in microgravity or to thrive under the radiation levels in space. When NASA astronaut Scott Kelly spent nearly a year on the International Space Station, in a mission launching in 2015, his body was put under incredible stress: Fluids swelled his upper body and head, his genes activated in different ways, and his immune system jumped into overdrive compared to that of his identical twin, Mark Kelly. Mark has also flown in space, but he remained on the ground during that long-duration mission. Over time, Scott experienced decreased body mass, instability in his genome, swelling in major blood vessels, changes in eye shape, metabolism shifts, inflammation and alterations in his microbiome — as well as a strange lengthening of his telomeres, the protective structures at the ends of chromosomes. (They shortened again after he landed.)
Ten teams working on NASA's Twins Study — encompassing 12 universities and 84 researchers — followed the duo before, during and after the flight, tracking the twins' biology to see how the brothers changed over the course of the study. While the research was very limited in scope, scientists planning to send astronauts on long trips to the moon, Mars and beyond will find this data on long-duration spaceflight invaluable.
"Early on in our astronaut career, my brother and I had kind of wondered about it — hey, I wonder if they'll ever do an experiment with the two of us, being genetically nearly identical," Scott Kelly told Space.com.
But there was no interest for years after the twins' selection as astronauts in 1996, since the sample size would be so small — until Scott brought it up again in 2013 ahead of his record-breaking space station mission, which he shared with Russian cosmonaut Mikhail Kornienko. "When it came to the fact that I was going to spend a year in space, it was so unique that I actually thought maybe there was some merit to it … [and] it turns out there was some interest once people started talking about it."
That discussion snowballed into the massive Twins Study, whose summary paper is being published in full for the first time after releases about preliminary results in 2017 and 2018. This new collection of information, gleaned with intensive, meticulous testing on orbit and on Earth — including for several months after Scott landed — traces the twins' full trajectories for the first time.
"This is really probably the most in-depth study, certainly at the biochemical level, that's ever been done in people in space," Mike Snyder, the chair of genetics at Stanford University and a co-author on the publication of the Twins Study, said during a press teleconference Tuesday (April 10). "So, we're literally making thousands of measurements at a level that hasn't been done before. And as such, we get to see a system-wide view that really hasn't been done either."
The integrated report from all the Twins Study researchers was released today (April 11) in the journal Science.
In the genes
Some of the most interesting changes occurred in which of the spacefaring twin's genes were expressed. To be clear, this isn't changes in DNA itself — it's changes in which genes are activated to make proteins, in reaction to a subject's environment. Researchers didn't directly compare Scott's genes to Mark's, but rather documented the amount of changes in Scott's gene expression throughout his journey and compared them to how many changes in expression Mark experienced as he remained on the ground.
"As soon as [Scott] got into space, there was a large-scale shift in over 1,000 genes that are actually dynamically changing … so, clearly the body and cells were adapting," Christopher Mason, a geneticist at Weill Cornell Medical Center in New York and co-author on the study, said during the teleconference.
"We saw enrichment — the kinds of genes that were becoming activated include things that regulate DNA damage response, activate DNA repair [and] maintain telomere lengths," he added, "and also, most notably, the most enriched set of genes [were] almost all involved in the immune system regulation, which indicated to us that the immune system is almost on a high alert as a way to try and understand this new environment."
Mason added that even more genes began changing levels of activity — up to six times more — in the second half of the space mission compared to the first.
Looking closely at the epigenetics, or changes in the physical structure of DNA to alter gene expression, of both twins (again, not changes to the DNA letters themselves), researchers saw a similar level of change in each. In fact, Mark showed slightly higher levels, the researchers said. (His more chaotic life on Earth — with travel, changing environments, and changing food and drinks — could have played a role, they added.)
But the individual genes being expressed more or less, for Scott, were consistent with the changes he was undergoing: "things having to do with telomere length, with inflammation, with immune response and with the activity of bones," Andrew Feinberg, the director of the Center for Epigenetics at Johns Hopkins University and a co-author on the study, said during the teleconference.
The researchers also measured a curious thing: Many of the protective caps on Scott's chromosomes, called telomeres, lengthened during his flight, as measured in blood sent back to Earth for analysis — although his cells' telomeres returned to about the same average length, with some a bit shorter, once he returned to the ground.
"Telomeres [are] the ends of our chromosomes that shorten as we get older," Susan Bailey, a researcher at Colorado State University and co-author on the new work, said during the teleconference. "And they can serve as a biomarker of accelerated aging or some of the associated health risks, like cardiovascular disease or cancer. So, certainly we imagined, going into the study, that the unique kinds of stresses and extreme environmental exposures like space radiation and microgravity, all of these things, would act to accelerate telomere loss."
To understand their unusual lengthening, and the rapid shortening again within two days of landing on Earth, Bailey said she is looking to the other researchers' work, including the work on gene expression and other physiological changes, for potential causes. But, she cautioned, "I don't think that [the elongation] can really be viewed as the fountain of youth and that people might expect to live longer because they're in space." In fact, the overall slight shortening of telomeres on average after Scott landed is more of a long-term consequence of spaceflight, as shorter telomeres can be risk factors for aging-associated diseases.
Bailey and other researchers also observed DNA damage, including chromosome rearrangements called inversions, as well as an elevated DNA-repair response. Although the International Space Station isn't showered with as much radiation as deep space — it's still within Earth's protective Van Allen radiation belts, which deflect energetic particles — it does get an elevated amount compared to the ground. DNA damage from radiation exposure would likely increase for astronauts who ventured beyond low Earth orbit; astronauts traveling to Mars would experience about 8 times the radiation as Scott did.
The researchers noted that many effects Scott experienced, including 91.3% of his gene activity-level changes, reverted to normal within six months of his return to Earth. His immune response (to a flu vaccine) remained normal throughout the flight, despite increased stress on that system; his spatial orientation and motor accuracy, thrown off-kilter by his stay in space, returned to normal, as did his body mass.
The ratio of microbes in Scott's gut, called the microbiome, changed during flight but returned to normal after his return, and its diversity stayed constant. (Yes, to track this, he had to send regular fecal samples down from the space station.)
According to Scott, he felt back to 100 percent after about eight months at home, which was longer than for his previous spaceflights.
"I would say, subjectively, to me, the time in space tracks very well with the symptoms upon return, having flown flights of increasing duration throughout my career: seven days; 13; 159 and 340," Scott told Space.com. "I was kind of surprised, actually, that I felt — I was in space more than twice as long [as last time] — I felt more than twice as bad when I got back."
Overall, though, his biggest hurdle after flight might have been psychological, Scott said: "You've experienced this significant event where you're living in a very controlled environment for a really long time, and then you don't have that anymore. To get readjusted back to — not just physically readjusted, but generally adjusted to life back on Earth — seemed to take me about eight months."
Of course, prospective space travelers will also have to contend with longer-lasting effects, which the researchers found — lingering DNA damage due to the radiation exposure, for one. Changes due to long-term shifts in fluids, because of microgravity, also led to a thickening of the carotid arteries that deliver blood to the brain, which can be a marker for heart disease. That same fluid shift caused changes in eye shape and other issues that hurt Scott's vision. The researchers are also tracking genes that are still showing differences in activation, such as some associated with DNA repair.
Scott also showed a decrease in cognitive speed and accuracy six months after he returned to Earth, according to the paper. And there could be increased risk for heart disease and some cancers in the cells which ended up with shortened telomeres.
Many of these changes will be more significant for even longer flights, or ones that travel outside low Earth orbit. So the researchers hope to do more yearlong studies on more individuals, both in low Earth orbit, around the moon and someday farther out, to continue to track these changes. The researchers emphasized that technology has changed since Scott's mission; now, an astronaut has sequenced DNA in space, and a new technique has also come out to analyze epigenetics in flight, the researchers said. All of these tools could enhance future studies.
"I mean, I'm a geneticist. I wish every single person had a twin that was always doing something different and that we were always tracking them, but I don't think we would get IRB approval to copy everyone," Mason joked about his ideal research.
"The Twins Study represents a significant first step in using novel research approaches to better understand the challenges to crewmembers undertaking interplanetary missions," Bill Paloski, the director of NASA's Human Research Program, said in a statement provided to Science. "Results are consistent with previous data and observation from long-duration missions aboard Russian space vehicles."
"We in NASA's Human Research Program plan to continue this line of investigation for years to come, including aboard the space station during the Integrated One-Year Mission Project, currently under development," he added.
From Scott's perspective as an astronaut, the study findings are promising, he told Space.com. "The bottom line is, from all these studies — and, granted, this is an experiment with one data point … would be that there's nothing that we saw that would prevent us from going to Mars," he said.
"Certainly, there's some stuff that they're going to continue to look at — gene expression, telomeres, other issues astronauts have with their vision," he added, "but no showstoppers that jumped out at anyone."
Scott said that, based on his experience, he thinks the time scales needed for a journey to Mars would be doable for astronauts. But for even-longer-duration flights, some new technology may be necessary, he said.
"I think it's when we're going to consider spending many years in space that we would have to probably consider some type of artificial gravity to alleviate some of the negative impacts of living in that environment for an extended period," Scott said. "Otherwise, you'll have people that get to the moons of Jupiter or Saturn and not be able to function well, or get back to Earth after being in space for 10 years and be complete basket cases.
"But I don't think we'll have to worry about that anytime soon," he added.
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