Short-term space travel induces many of the same molecular and physiological changes as long-term space missions, most of which reverse within a few months after returning to Earth. But these changes, which persist for longer and differ between crew members, could reveal new targets for aerospace medicine and guide new missions, according to results from a large international study by researchers at Weill Cornell Medicine, SpaceX, and other organizations.
Christopher Mason, World Quant Professor of Genomic Sciences and Computational Biomedicine at Weill Cornell Medical College, led the Space Omics and Medical Atlas (SOMA) project with Afshin Beheshti of the Broad Institute and NASA. The project involved more than 100 researchers from institutions in more than 24 countries. The collaborators increased the amount of human spaceflight data by 10-fold, including analysis of changes in gene expression, gene regulation, protein production, metabolism, and the human microbiome. The results were published in Nature magazine on June 11 as a collection of 40 articles and summarized in a summary article.
The SOMA team, including co-corresponding author Cem Meydan, an assistant professor of computational biology research at Cornell Medical School, is compiling more than 75 billion gene sequences into an interactive atlas that other researchers can access, and Cornell Medical School will host a repository of about 3,000 biological samples from the study. Mason's team has already begun collecting samples from other missions and is forging several new international collaborations to harmonize spaceflight research efforts.
“This is the largest trove of data ever made public about astronauts and astrobiology,” said Mason, who is also professor of physiology and biophysics, professor of neuroscience at the Feil Family Brain and Mind Institute, member of the Sandra and Edward Meyer Cancer Center, and director of the World Quantitative Forecasting Initiative. “We hope that sharing the data will accelerate discoveries about the health effects of spaceflight and lead to fundamental discoveries about the health of humanity as a whole.”
Commercial Astronaut
The Inspiration 4 mission launched on September 16, 2021, with the first civilian four-person crew flying into low Earth orbit for three days, providing an unprecedented opportunity for science. Prior to the mission, most data on the health effects of space travel had been collected by government-sponsored space agencies from hand-picked, highly trained astronauts, but it was unclear whether the data collected from astronauts could be broadly applied to the general public. The Inspiration 4 mission provided an opportunity to find out.
Mason served as principal investigator for the clinical profile, multi-omics and biobanking studies of the Inspiration 4 mission crew. The crew collected biological samples before, during and after the flight, giving researchers full access to study and share the data. They also conducted a series of experiments during the flight, including the first-ever direct RNA sequencing and skin biopsies of astronauts. Dr. David Leiden, Dr. Richard Grunstein and Dr. Ari Melnick of Cornell University's Weill Medical College, and Eugene de Vlaminck, associate professor in the Meinig School of Biomedical Engineering at Cornell University's College of Engineering, also contributed to the project.
The new data was compared to data collected on previous flights, specifically the NASA Twins Study, for which Mason was principal investigator. The study analyzed data from astronaut Scott Kelly during his year-long mission aboard the International Space Station from 2015-2016, as well as data from his subsequent missions, and found that longer spaceflights lead to greater changes in gene expression in the blood, particularly in the immune and DNA repair systems. Ji-eun Park's new data shows that these differences also manifest in the skin.
Data from Inspiration 4 showed that many of the same changes occurred in the short-term astronauts. For example, Mason and Susan Bailey published a study showing that telomeres, the ends of chromosomes, began to lengthen during the three-day Inspiration 4 mission. And the astronauts saw similar immune system changes after returning to gravity, as evidenced by a surge in anti-inflammatory proteins called cytokines.
Changes in the immune system
The surge in cytokines after re-entry was one of several immune system changes documented by researchers at Weill Cornell Medicine. Through single-cell genetic sequencing led by Mason lab researchers Jangkun Kim and Braden Tierney, the scientists identified immune cells called CD16 monocytes as the cells most responsive to the stresses of spaceflight. These first-response immune cells experience dramatic shifts in gene expression and changes to the chromatin that controls gene expression.
“The immune system is ready to fight, but we don't yet know what we're fighting,” said Mason, who noted that astronauts' exposure to low-dose radiation could be triggering this immune response, and not just changes to telomeres.
While parts of the immune system thrive, others languish. For example, travelers experience reduced expression of genes that code for immune system proteins called human leukocyte antigens, which help the body identify viruses and other invaders. This finding may explain why about half of space travelers and astronauts experienced reactivation of old viral infections, such as herpes simplex virus 1, a mostly benign virus that causes cold sores.
Another study led by graduate student Nadia Hoelbi in Mason's lab and postdoctoral researcher Irina Mattei in Leiden's lab found evidence of brain proteins in the blood of the Inspiration 4 astronauts, as well as the blood of six Japanese astronauts and Scott Kelly. The findings suggest some disruption to the blood-brain barrier, which protects the brain from invading immune cells. Samples from a mouse study by Xiao (Vivian) Mao at Loma Linda University confirmed that spaceflight disrupted the function of the blood-brain barrier.
“It's not something to be concerned about, but it is surprising and something to keep an eye on for future missions,” Mason said.
The Inspiration 4 crew experienced many of the same changes as long-term astronauts, but recovered quickly after the flight. Mason noted that within six months, the crew's biology had returned to pre-flight status for more than 95% of their proteins, chromatin state, and genes, including changes in RNA measured by researchers Kirill Grigorev and Theodore Nelson in Mason's lab.
The “Second Space Age” and Aerospace Medical Biobanks
This finding offers great potential for future research. Although the data from astronauts was small, the SOMA researchers, using data from Ming Yu of the University of Maryland, found some differences between men and women. For example, female astronauts returned to their pre-flight state more quickly after returning to Earth, but some cytokines remained higher longer in women than in men, a finding also seen in 64 other astronauts. Individual physiological responses to space travel also differed, as did genes related to drug processing (known as pharmacogenomics).
“Medications and other countermeasures may need to be customized for each crew member based on their individual response to spaceflight,” said Elia Overbay, lead and co-corresponding author of the SOMA study summary, who was a research scientist in Mason's lab at the time of the study and is now starting her own biospace engineering lab at UT-Austin.
Overbay said making the atlas and biobank available to more scientists could accelerate the pace of discoveries about the effects of spaceflight and its links to aging, chronic disease and immune system disorders. She noted that space travel mimics some of the effects of aging, such as bone and muscle loss, and could provide a way to test drugs to counter these changes.
“By opening up the data to the entire scientific community, we will be better able to uncover links between space-related changes and overall human health,” she said.
Overbay also suggested that increased commercial spaceflight and crew numbers could result in larger data sets and greater power to detect smaller differences.
“We are entering a new space era,” Mason said, “with more data and more space launches than ever before, and we're going to need every bit of biomedical data we can to enable precision medicine for future astronauts and prepare for longer missions to the Moon and Mars.”
Participating organizations include the Japan Aerospace Exploration Agency (JAXA), the European Space Agency, the National Aeronautics and Space Administration (NASA), and SpaceX, a company that provides commercial space flight missions.
Research reported in this article was supported in part by NASA, the National Cancer Institute, part of the National Institutes of Health, and the National Institute of Mental Health, and also by Sovaris Aerospace and WorldQuant.
Dr. Mason is an unpaid member of the board of directors of BioAstra, holds stock in Cosmica Inc., is a paid consultant to Thorne Research, and has served as a speaker for WorldQuant LLC.
Bridget Kuhn is a freelance writer at Weill Cornell Medicine.
