Manjula Darshi, Ph.D.
Kumar Sharma, M.D., and Manjula Darshi, Ph.D., from UT Health San Antonio’s Center for Renal Precision Medicine, together with Brinda Rana, Ph.D., from the University of California, San Diego, led one of the teams of investigators involved in a unique study to answer these questions. The study is examining the effects of a year’s spaceflight on NASA astronaut Scott Kelly in comparison to his identical twin and fellow astronaut, Mark Kelly, who remained on Earth.
Results of the NASA Twins Study were published in the prestigious journal Science on April 12. The study is an integrated multiomics, molecular, physiological and behavioral analysis of the changes that occurred during a yearlong spaceflight.
Changes likely within range for humans under stress
Samples were collected and analyzed before, during and after the space mission, over a period of 27 months. Even though Scott Kelly’s DNA was not altered, researchers noted changes in gene expression, which is the body’s response to the environment. NASA said the changes were likely within the range for humans under stress, such as intense exercise.
“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,” a NASA release stated.
About 7 percent of gene expression changes persisted after six months on Earth, NASA reported. Targeted countermeasures will need to be developed as space travel to Mars and beyond is anticipated to increase in the 2020s and 2030s, NASA said.
Metabolite alterations and link to mitochondria
Dr. Sharma and Dr. Darshi, who study diabetic and other forms of kidney disease, focus their research on mitochondria, which are cellular powerhouses that supply the body with energy, and on metabolites, which are small molecules involved in the energy-production process.
The Center for Renal Precision Medicine has previously identified several metabolites associated with mitochondria that are altered in diabetic kidney disease and contribute to mitochondrial dysfunction. “We were surprised to see there was a similar pattern of metabolite alterations in Scott Kelly, who went up into space,” Dr. Sharma said.
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. “That was very exciting for us because lactate is directly connected to mitochondrial function,” Dr. Darshi said.
Conversion to an alternative, and perhaps not so desirable, fuel-generating process
When mitochondria cannot produce sufficient energy required for normal cellular functions, cells switch to an alternate fuel-generating process called glycolysis, where glucose is metabolized through a series of enzymes and generates lactate. “Thus, elevated lactate could potentially mean your mitochondria are not functioning normally,” Dr. Sharma said. “As part of this study, other groups have evaluated mitochondrial function and mitochondrial gene expression, and the data supported our findings.”
The researchers don’t yet know the reason for the increase in lactate in Scott Kelly, because levels can change with increased exercise, low oxygen, stress and inflammation, Dr. Sharma said. Follow-up studies with mouse models that traveled to space will add more to this exciting story.
The NASA Twins Study utilized the expertise of teams from top universities in multiple disciplines, including genomics, proteomics and metabolomics. “We were the targeted metabolomics site and also coordinated the proteomics study with our collaborator,” Dr. Sharma said.
Spaceflight connected to oxygen deprivation stress, increased inflammation and nutrient shifts
The result was a rich picture of the health of the astronaut in space compared to his identical twin, the ground control. By measuring large numbers of metabolites, cytokines (molecules secreted by certain cells of the immune system) and proteins, researchers learned that spaceflight is associated with oxygen deprivation stress, increased inflammation and dramatic nutrient shifts that affect gene expression, NASA reported.
“This is exactly what precision medicine is about,” Dr. Sharma said. “At an individual level, what can we measure and learn in a specific context? In this case, it happened to be a spaceflight. But it could be somebody taking medication for diabetes or starting an exercise regimen or beginning a new dietary plan.”
Customizing the individual’s prescription based on their “omics” is the desired goal, he said.
The logistics of obtaining samples
The San Antonio team was first asked to figure out how they would obtain blood and urine samples from space. “This was quite an adventure in itself,” Dr. Sharma said. “Collection is different in space. Freezing the samples is challenging. We ended up helping to develop a method where samples had to be collected at zero gravity, be sent from the spaceship, land in a location in Asia and be brought to our lab.”
Institutions from coast to coast were involved in the overall study. “It’s a great way to do team science,” Dr. Sharma said. “This is the way team science will be able to address both simple and complicated questions, and could arrive at comprehensive answers a lot faster than individual teams have been able to do in the past.”
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The Center for Renal Precision Medicine at UT Health San Antonio is supported by grants from NASA, the National Institutes of Health (NIH) Kidney Precision Medicine Program, an NIH R24 grant (with the University of Michigan), several U.S. Department of Veterans Affairs grants, the NIH Small Business Innovation Research program and JDRF (the Juvenile Diabetes Research Foundation). Visit the Center for Renal Precision Medicine at https://wp.uthscsa.edu/nephrology/ and https://wp.uthscsa.edu/crpm/.
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