More than one small step: NASA twin study reveals the effects of spaceflight on the human body

In an unprecedented, year-long project, astronaut Scott Kelly spent 342 days in space, whilst twin brother, Mark, remained on earth. The aim was to produce the most comprehensive study of the effects of spaceflight on the human body to date.

A groundbreaking NASA study has brought together 84 researchers from ten separate research teams, across 12 universities to create the most comprehensive study of the effects of space travel on the human body to date.

The research investigated physical traits such as cardiovascular health, protein regulation, ocular degeneration and cognition. Delving right down to a genetic level — examining his telomeres — the ‘caps’ that prevent chromosomes from ‘fraying’. Researchers even studied the effect of long-term spaceflight on Scott’s gut bacteria.

The results begin to fill in gaps in our knowledge of potential health consequences for astronauts who remain in space for longer than six months, and the effects of associated hazards such as exposure to radiation and microgravity. Thus far, the way these risks impact health during extended stays in space has been unclear.

Lead author of the study, Francine Garrett-Bakelman, Assistant Professor of Biochemistry and Molecular Genetics at Weill Cornell Medical College and her colleagues ceased on Scott Kelly’s year in space aboard the International Space Station (ISS) between 2015 and 2016. scott would be leaving his twin brother, Mark — a former astronaut himself — behind on Earth as a near-perfect control group.

John Hopkins Medicine Q&A with Andrew Feinberg and Lindsay Rizzardi.

[Credit: Johns Hopkins Medicine]

Steve Platts, PhD, deputy chief scientist at the NASA Human Research Program, says: “The Twins Study provided the most comprehensive and integrated molecular view to date of how a human responds to spaceflight.

“Results will help expand our understanding of the physiological and psychological adaptations to space.”

The researchers discovered that there were no long-lasting major ill-effects on Scott’s body despite him spending almost a year orbiting at 400 km above his brother. They also discovered that many of the changes that did occur returned to normal six months after his return to Earth.

As Jenn Fogarty, PhD, chief scientist at the program, points out: “The Twins Study demonstrated on the molecular level the resilience and robustness of how one human body adapted to the spaceflight environment.

“This study was a stepping stone to future biological space research focusing on molecular changes and how they may predict health and performance of astronauts.”

Scientists collected blood samples, physiological data and cognitive measurements from Scott and Mark at various time points over 27 months before, during and after Scott’s near one-year space mission. The samples taken from Scott during the flight were collected on the ISS when shipments from Earth arrived on a Soyuz rocket and, the same day, shipped back to Earth ensuring that the samples were processed within 48 hours.

As Brinda Rana, PhD at UC San Diego School of Medicine, points out, even this had to be an operation of extraordinary precision: “Blood volume drops in space and the astronauts are chronically dehydrated. These factors add to the difficulty of obtaining samples in space.

“The challenge was to collect enough biofluids onboard the ISS at multiple time points throughout the year for all 10 investigative teams to conduct this comprehensive view of the human body in space.”

These challenges have also highlighted the need for NASA to develop methods that allow astronauts to perform gene-sequencing ‘on the -go’ and may lead to exciting new research into portable DNA sequencing tools.

Why choose twins? It’s in the genes.

Identical twin brothers: retired astronaut Mark Kelly (left) and Scott Kelly ( NASA/ Robert Markowitz)

The twin study provided NASA with a unique opportunity to use Scott’s twin brother, Mark, as a baseline control here on Earth.

With Mark and Scott being so genetically similar, researchers were able to sift out changes that occurred to Scott as a result of his exposure to space travel from any changes that may have occurred naturally to the twins as a result of their genome.

Dr Christopher Mason, an associate professor of physiology and biophysics at Weill Cornell Medicine, says: “It is likely that these two astronauts have been studied at a greater depth than any other person in history.

“They give us a really in-depth view of cellular, molecular and physiological changes that can help us learn what is in the range of what a human can endure.”

The study is amazing but should be viewed with caution

Scott Kelly at work on ISS maintenance with the station’s solar arrays visible in the background (NASA)

It should be noted, that due to the rarity of twin astronauts, the study has an extremely small sample size. As Andrew Feinberg, M.D., the Bloomberg Distinguished Professor of Medicine, Biomedical Engineering and Mental Health at The Johns Hopkins University, warns: “Since we only have two people in our study, we can’t say that these changes are due to space travel itself.

“We need more studies of astronauts to draw such conclusions.”

In addition to this, as the ISS is in a low-Earth orbit it means that Scott was not exposed to the levels of radiation that an astronaut on a trip to the Moon or Mars would experience.

The results, despite not being completely conclusive, point towards areas of interest that will need to be focused on if humanity is to embark on longer space missions — particularly 2–3-year missions to Mars.

Markus Löbrich writes in relation to the study in the latest edition of Science:

“Undoubtedly, the study by Garrett-Bakelman et al. represents more than one small step for mankind in this endeavour.”

Conclusions at a glance

Key areas of research included

Heart and ocular health

Effect on gut bacteria and health

The effectiveness of vaccines for astronauts

Changes in the length of Scott’s telomeres — caps on chromosomes which scientists believe are responsible for ageing and ageing-related illness.

Effect on cell mitochondria

Key findings from the research

Scott experienced dramatic shifts in telomere length dynamics, a biomarker that can help evaluate health and potential long-term risks of spaceflight.

Scott experienced thickening of the carotid artery, thickening of the retina, and weight loss. As well as a reduction in cognitive abilities.

There was some DNA damage: 91% of Scott’s gene expression levels returned to normal or baseline levels within six months of landing back on Earth. About 7% of gene expression changes persisted after six months on Earth.

the flu vaccine administered in space worked exactly the same as on Earth. Good news if future missions require vaccinations to be performed

changes in Scott’s diversity of gut flora in space were no greater than stress-related changes scientists observe on Earth

proper nutrition and exercise while in space resulted in decreased body mass and increased folic acid, which is vital for making red blood cells

The majority of radical changes in gene expression occurred during the latter six months of the space mission rather than the first six month period.

NASA attributed most of the key findings and effects to the stresses placed on the human body by spaceflight rather than an external effect such as exposure to radiation.

NASA concludes:

“Given that the majority of the biological and human health variables remained stable, or returned to baseline, these data suggest that human health can be mostly sustained over this duration of spaceflight.”

What follows is a brief description of some of the individual studies that make up this groundbreaking research.

The heart of NASA’s concerns: Examining Scott’s Heart and Eyes

Brinda Rana, PhD at UC San Diego School of Medicine, and her team were responsible for monitoring cardiac changes in Scott occurring as a result of space flight.

Senior author Brinda Rana, PhD, professor in the Department of Psychiatry at UC San Diego School of Medicine ( UC San Diego)

Rana says: “Cardiovascular changes akin to atherosclerosis have also been observed in astronauts after a long duration flight. Cardiovascular issues are major physiological hurdles which NASA wants to address before they can embark on longer space flight missions, such as the proposed mission to Mars in the 2030s.”

The team noted a cardiac output increase of about 10% and a moderate decrease in both systolic and diastolic blood pressure which persisted throughout the mission. They also noticed thickening of the carotid artery, but this resolved shortly after Scott’s return to earth. An increase in collagen proteins in urine in space flight, measured by Rana, correlates to physiological measures indicating vascular remodelling during space flight.

The team of investigators demonstrated the resilience and robustness of how a human body can adapt to a multitude of changes induced by the spaceflight environment (UC San Diego)

One of this team’s other concerns was the effect of space travel on astronauts’ vision. Rana explains: “A primary issue that astronauts have in space is Space-Associated Neuro-ocular Syndrome or SANS.

“Many astronauts develop SANS-related vision impairment that may be the result of multiple hits on the vascular system involving microgravity-related fluid shifts, environmental changes, and possibly a genetic predisposition.”

The team noticed several ocular changes in Scott that were not reflected by Mark — and thus are not suspected to be genetic or natural — so a likely effect of spaceflight. These are believed to be a result of thickening in Scott’s forehead and throughout the eye as well as the aforementioned drop in blood pressure.

Rana concludes:

“The overall Twins Study demonstrated the resilience and robustness of how a human body can adapt to a multitude of changes induced by the spaceflight environment, such as microgravity, radiation, circadian disruption, elevated CO2, isolation from friends and family and dietary limitations.”

The effects of space flight on gut bacteria

Moving down the body, it was the responsibility of Northwestern’s Fred W. Turek and his team to measure the effect’s of extended spaceflight on the human gut microbiome.

Scott Kelly’s personal living quarters on the ISS (NASA)

The researchers found a significant shift in the ratio of two major categories of bacteria in his gut microbiome. The diversity of bacteria in his microbiome, however, did not change during spaceflight, which the Northwestern University-led research team found encouraging.

Turek says: “We cannot send humans to Mars without knowing how spaceflight affects the body, including the microbes travelling with humans to Mars.

“And we need to know sooner rather than later. The plan is to send people to Mars in 2035, so we cannot wait until 2033 to gain this information.”

Gut health affects digestion, metabolism and immunity; and, more recently, changes in the microbiome have been linked to changes in bones, muscles and the brain.

The gut’s microbiome is a complex community of microorganisms — including bacteria, viruses and fungi — that live in the digestive tract. In the past 10 years, researchers have finally started to realize how the microbiome’s health and diversity has an effect on the rest of the human body.

The study’s finding could help physicians and researchers pinpoint and implement ways to protect astronauts’ and space tourists’ microbiomes during long bouts of space travel like during the much-anticipated mission to Mars, mentioned above.

Vitaterna, a research professor of neurobiology at Northwestern, says: “There are studies that link changes in the gut microbiome with neurological and physiological conditions, like Alzheimer’s disease, Parkinson’s disease, autism and schizophrenia.

“By protecting the gut, we can protect all these other systems. The influence that bacteria have on all other systems of the body is really remarkable.”

A number of variables could have influenced Scott Kelly’s microbiome while in space, including microgravity, increased radiation, shifts in circadian rhythms, decreased sleep time, lack of air circulation, the stress of living in an enclosed space and an altered diet.

Turek and Vitaterna were concerned that Scott’s diet in space — comprising mostly of freeze-dried, irradiated, pre-packaged foods — would decrease the diversity in his microbiome. Initially, diet does not appear to matter as much as the researchers suspected.

This result mirrored mouse studies the Northwestern pair conducted in the past. Whereas Scott and Mark Kelly did not eat the same foods during the yearlong study, mice in previous studies ate the exact same diet. Still, the space mice experienced shifts in their gut microbiomes compared to the control mice on Earth.

Turek believes microgravity is most likely responsible for the change: “We think that microgravity has an effect on the bacteria.

“That’s what we want to determine going forward.”

Examining Genetic changes during and after prolonged spaceflight

Scientists from Johns Hopkins, Stanford University and other institutions found no long-lasting, major differences between the epigenomes of space-bound Scott and his Earth-bound twin, Mark.

Andrew Feinberg and Lindsay Rizzardi test procedures for purifying blood samples on NASA’s microgravity plane called the ‘Vomit Comet.’ (John Hopkins)

Andrew Feinberg, M.D., describes his team’s work in this larger project: “This is the dawn of human genomics in space.

“We developed the methods for doing these types of human genomic studies, and we should be doing more research to draw conclusions about what happens to humans in space.”

Feinberg and former postdoctoral student Lindsay Rizzardi, now a senior scientist at the HudsonAlpha Institute for Biotechnology, focused on epigenetic changes to Scott and Mark’s genomes.

Epigenetic changes involve chemical “tweaks” to DNA that can influence gene activity. These changes don’t affect the underlying genetic code itself. They do affect when and how a gene is read, or expressed, for its protein-encoding instructions. When epigenetic changes occur at the wrong time or place, the process can turn genes on or off at the wrong time and place, too.

The pair examined two types of white blood cells (CD4+ and CD8+) isolated from Mark and Scott’s blood, focusing on epigenetic marks consisting of methylation — a process in which chemical modifications called methyl groups are added onto the DNA.

The team found there was a less than 5% difference in overall methylation between the twins during the mission. The largest difference occurred nine months into the mission when 79% of Scott’s DNA was methylated, compared with 83% of Mark’s.

The locations of methylation changes in the genome were different for each twin. For example, the scientists found methylation changes near genes involved in immune system responses in Scott during his time in space, but not in Mark. This correlated with data from other researchers involved in the current study who found increases in certain biochemical markers associated with inflammation in Scott but not Mark.

Feinberg says this study lays the groundwork to make predictions about an astronaut’s gene-related and physiological function during a long-term mission:

“If we know what to expect, we can anticipate health problems astronauts may encounter and ensure that medicines and other remedies are at hand during a mission.”

Examining changes in telomeres due to long term space flight

Colorado State University Professor Susan Bailey, studies telomeres — the protective “caps” on the ends of chromosomes, almost analogous to the plastic tips on the end of shoelaces which prevent them from fraying. She and her team found that Scott’s telomeres in his white blood cells got much longer while in space.

: Colorado State University Professor Susan Bailey studies the effects of space on the human body

(Jason Russell/ Colorado State University)

Upon his return to Earth, Bailey and her team discovered that Scott’s telomeres returned to their previous length rather rapidly. In fact, he now has more short telomeres than he did previous to embarking on his 342-day-mission.

Having shorter telomeres puts a person at higher risk for accelerated ageing, says Bailey. This also increases the risk for diseases that come along with ageing, including cardiovascular disease and some cancers.

Colorado State University Professor Susan Bailey studies telomeres — the protective ‘caps’ on the ends of chromosomes. Telomeres typically shorten as a person ages ( John Eisele/Colorado State University)

The study has implications, not just for space travel, but for understanding how ageing works here on Earth. Bailey explains: “We all worry about getting older, and everyone wants to avoid cardiovascular disease and cancer. If we can figure out what’s going on, what’s causing these changes in telomere length, perhaps we could slow it down.

“That’s something that would be of benefit to everybody.”

These findings ran counter to what Bailey thought might occur. As she explains: “We were surprised, that was the first reaction.

“But that’s what science is all about, right?”

Bailey will continue her telomere research with NASA through a new project designed to answer questions about astronaut health and performance on long missions as they journey to the Moon and Mars.

In this integrated One-Year Mission Project, she’ll study 10 astronauts on one-year missions, 10 on six-month missions, and 10 on trips from two to three months at a time. Health data will be compared with people on the ground who are in isolation for those same periods of time.

She concludes: “We’re trying to determine if it is indeed something specific about space flight that is causing the changes we’ve seen.”

How did prolonged spaceflight effect mitochondria — the cell’s energy source?

Kumar Sharma, M.D., and Manjula Darshi, Ph.D., from UT Health San Antonio’s Center for Renal Precision Medicine, who study diabetic and other forms of kidney disease, focus their research on mitochondria — cellular powerhouses that supply the body with energy, and on metabolites — small molecules involved in the energy-production process.

The team identified several metabolite alterations associated with mitochondria which also occur in diabetic kidney disease and contribute to mitochondrial dysfunction.

Analysis showed that a metabolite called lactate was increased in Scott Kelly during his spaceflight and reverted to normal levels when he returned back to earth. Darshi says: “That was very exciting for us because lactate is directly connected to mitochondrial function.”

Sharma continues: “Elevated lactate could potentially mean your mitochondria are not functioning normally.”

Sharma explains that the researchers don’t yet know the reason for the increase in lactate in Scott, because levels can change with increased exercise, low oxygen, stress and inflammation.

Changes in gene expression were more extreme during the second six months

Dr Chris Mason (Weill Cornell Medicine)

Dr Christopher Mason and his team looked for changes in gene activity, such as those involved in bone formation and DNA repair.

Mason says: “In the last six months of the mission, there were six times more changes in gene expression than in the first half of the mission.” While many of the changes reversed after Scott returned to Earth, a few remained, including cognitive deficits, DNA damage and some changes in T-cell activation.

Mason continues: “We don’t know yet if these changes are good or bad.

“This could just be how the body responds, but the genes are perturbed, so we want to see why and track them to see for how long.”

The study may also help patients on Earth — particularly those with cancer who often undergo dramatic genetic changes and endure radiation exposure. Studying both a healthy human on Earth in great detail as well as a person exposed to tremendous stressors in space can give scientists new insights into what is a normal response to stress and how much the body can adapt.

This may help scientists distinguish the body’s normal stress response from pathological changes associated with cancer, infection, or other stressors.

Sources

NASA teleconference (09/04/19)

“The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight,” by F.E. Garrett-Bakelman; C. Meydan; E. Afshinnekoo; D. Bezdan; A.M.K. Choi; J.A. Gandara; G.S. Grills; M. MacKay; A.M. Melnick; K. Nakahira; C.K. Sheridan; C.E. Mason at Weill Cornell Medicine in New York, NY; F.E. Garrett-Bakelman at University of Virginia School of Medicine in Charlottesville, VA; M. Darshi; K. Sharma at University of Texas Health in San Antonio, TX; S.J. Green; G.E. Chlipala; M.G. Maienschein-Cline at University of Illinois at Chicago in Chicago, IL; R.C. Gur; J. Nasrini; D.F. Dinges; T.M. Moore; M. Basner at University of Pennsylvania Perelman School of Medicine in Philadelphia, PA; L. Ling; T. Mishra; B.D. Piening; S. Ahadi; A. Ambati; S. Chen; K. Contrepois; R.P. Hillary; B. Lee-McMullen; V. Rao; D.N. Salins; A.E. Urban; J. Zhang; E. Mignot; M.P. Snyder at Stanford University School of Medicine in Palo Alto, CA; B.R. Macias; M. Arya; D.J. Ebert; K.A. George; S.S. Laurie; R. Pietrzyk; S.M.C. Lee at KBRwyle in Houston, TX; M.J. McKenna; L. Taylor; S.M. Bailey at Colorado State University in Fort Collins, CO; C. Meydan; E. Afshinnekoo; D. Bezdan; C.E. Mason at The Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine in New York, NY; L.F. Rizzardi; C.M. Callahan; J.I. Feinberg; J. Goutsias; G. Jenkinson; R. Tryggvadottir; A.P. Feinberg at Johns Hopkins University in Baltimore, MD; J.H. Siamwala; A.R. Hargens; V.Y.H. Hook; H.H. Patel; R. Saito; J.M. Schilling; D.D. Sears; B. Van Espen; M.G. Ziegler; B.K. Rana at University of California, San Diego in La Jolla, CA; M.H. Vitaterna; P. Jiang; F.W. Turek at Northwestern University in Evanston, IL; M. Afkarian at University of California, Davis in Davis, CA; M. Covington; B.E. Crucian; M.B. Stenger; J.B. Charles; S.M. Smith at National Aeronautics and Space Administration (NASA) in Houston, TX; I. De Vivo at Harvard T.H. Chan School of Public Health in Boston, MA; M. Heer at University of Bonn in Bonn, Germany; A.N. Hoofnagle; T. Vaisar at University of Washington in Seattle, WA; A. Keshavarzian at Rush University Medical Center in Chicago, IL; S.B. Lumpkins at MEI Technologies in Houston, TX; S.R. Zwart at University of Texas Medical Branch in Galveston, TX; C.E. Kundrot at NASA Headquarters in Washington, DC; G.B.I. Scott at Baylor College of Medicine in Houston, TX; C.E. Mason at The Feil Family Brain and Mind Research Institute in New York, NY; C.E. Mason at The WorldQuant Initiative for Quantitative Prediction in New York, NY; B.D. Piening at Providence Portland Medical Center in Portland, OR; L.F. Rizzardi; J.B. Charles; C.E. Kundrot; G.B.I. Scott; S.M. Bailey; M. Basner; A.P. Feinberg; S.M.C. Lee; C.E. Mason; E. Mignot; B.K. Rana; S.M. Smith; M.P. Snyder; F.W. Turek at HudsonAlpha Institute for Biotechnology in Huntsville, AL; J.H. Siamwala at Brown University in Providence, RI; G.S. Grills at Augusta University in Augusta, GA; M. Heer at IUBH International University of Applied Sciences in Bad Reichenhall, Germany; G. Jenkinson at Mayo Clinic in Rochester, MN; R. Saito at Keio University in Tokyo, Japan, 2019, Science.

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