The Twins Study provides the first integrated biomolecular view into how the human body responds to the spaceflight environment, and serves as a genomic stepping stone to better understand how to maintain crew health during human expeditions to the Moon and Mars.

Retired NASA astronauts Scott Kelly and his identical twin brother Mark, participated in the investigation, conducted by NASA’s Human Research Program. Mark provided a baseline for observation on Earth, and Scott provided a comparable test case during the 340 days he spent in space aboard the International Space Station for Expeditions 43, 44, 45 and 46. Scott Kelly became the first American astronaut to spend nearly a year in space.

“The Twins Study has been an important step toward understanding epigenetics and gene expression in human spaceflight,” said J.D. Polk, chief Health and Medical Officer at NASA Headquarters. “Thanks to the twin brothers and a cadre of investigators who worked tirelessly together, the valuable data gathered from the Twins Study has helped inform the need for personalized medicine and its role in keeping astronauts healthy during deep space exploration, as NASA goes forward to the Moon and journeys onward to Mars.”

Key results from the NASA Twins Study include findings related to gene expression changes, immune system response, and telomere dynamics. Other changes noted in the integrated paper include broken chromosomes rearranging themselves in chromosomal inversions, and a change in cognitive function. Many of the findings are consistent with data collected in previous studies, and other research in progress.

The telomeres in Scott’s white blood cells, which are biomarkers of aging at the end of chromosomes, were unexpectedly longer in space then shorter after his return to Earth with average telomere length returning to normal six months later. In contrast, his brother’s telomeres remained stable throughout the entire period. Because telomeres are important for cellular genomic stability, additional studies on telomere dynamics are planned for future one-year missions to see whether results are repeatable for long-duration missions.

A second key finding is that Scott’s immune system responded appropriately in space. For example, the flu vaccine administered in space worked exactly as it does on Earth. A fully functioning immune system during long-duration space missions is critical to protecting astronaut health from opportunistic microbes in the spacecraft environment.

A third significant finding is the variability in gene expression, which reflects how a body reacts to its environment and will help inform how gene expression is related to health risks associated with spaceflight. While in space, researchers observed changes in the expression of Scott’s genes, with the majority returning to normal after six months on Earth. However, a small percentage of genes related to the immune system and DNA repair did not return to baseline after his return to Earth. Further, the results identified key genes to target for use in monitoring the health of future astronauts and potentially developing personalized countermeasures.

“A number of physiological and cellular changes take place during spaceflight,” said Jennifer Fogarty, chief scientist of the Human Research Program at NASA’s Johnson Space Center in Houston. “We have only scratched the surface of knowledge about the body in space. The Twins Study gave us the first integrated molecular view into genetic changes, and demonstrated how a human body adapts and remains robust and resilient even after spending nearly a year aboard the International Space Station. The data captured from integrated investigations like the NASA Twins Study will be explored for years to come.”

Part of the record-setting one-year mission, the NASA Twins Study incorporated 10 investigations to advance NASA’s mission and benefit all of humanity. Scott participated in a number of biomedical studies, including research into how the human body adjusts to known hazards, such as weightlessness and space radiation. Meanwhile, Mark participated in parallel studies on Earth to help scientists compare the effects of space on a body down to the cellular level. The findings represent 27 months of data collection.

The Twins Study helped establish a framework of collaborative research that serves as a model for future biomedical research. Principal investigators at NASA and at research universities across the nation initiated an unprecedented sharing of data and discovery. Supported by 84 researchers at 12 locations across eight states, the data from this complex study was channeled into one inclusive study, providing the most comprehensive and integrated molecular view to date of how a human responds to the spaceflight environment. While significant, it is difficult to draw conclusions for all humans or future astronauts from a single test subject in the spaceflight environment.

“To our knowledge, this team of teams has conducted a study unprecedented in its scope across levels of human biology: from molecular analyses of human cells and the microbiome to human physiology to cognition,” said Craig Kundrot, director, Space Life and Physical Sciences Research and Application Division at NASA Headquarters. “This paper is the first report of this highly integrated study that began five years ago when the investigators first gathered. We look forward to the publication of additional analyses and follow-up studies with future crew members as we continue to improve our ability to live and work in space and venture forward to the Moon and on to Mars.”

The unique aspects of the Twins Study created the opportunity for innovative genomics research, propelling NASA into an area of space travel research involving a field of study known as “omics,” which integrates multiple biological disciplines. Long-term effects of research, such as the ongoing telomeres investigation, will continue to be studied.

NASA has a rigorous training process to prepare astronauts for their missions, including a thoroughly planned lifestyle and work regime while in space, and an excellent rehabilitation and reconditioning program when they return to Earth. Thanks to these measures and the astronauts who tenaciously accomplish them, the human body remains robust and resilient even after spending a year in space.

For more information about the NASA Twins Study, visit: https://www.nasa.gov/twins-study

In 2015, Palmyra experienced its warmest water in recorded history, prompting a widespread bleaching event that affected over 90 percent of the corals surrounding the island. Researchers found that despite the widespread bleaching, most of the corals recovered, with less than 10 percent dying.

The conclusions are based on comprehensive monitoring of the reefs and is providing for more precise observations of how reefs are changing over time. The researchers used a long-term data set of thousands of pictures of the same reef area collected over eight years. These images were stitched together using custom software to create 3D photo mosaics of the ecosystem — a virtual representation of the corals. The technology was developed by the 100 Island Challenge team, a collaborative group of marine ecologists and engineers using the latest technology to monitor coral reefs around the world.

“This imaging provides a way of getting back into the environment in a virtual world,” said Mike Fox, lead author and postdoc at Woods Hole Oceanographic Institution, who completed the research as a Ph.D. student at Scripps. “It allows us to bring the reef back into the lab.”

The researchers combined this imaging technology with a new custom visualization software, VisCore, that allows users to re-examine the thousands of photographs that comprise the mosaics. VisCore took more than 15,000 images for every 10 square-meter area of coral reef and then processed the data to turn the images into a 3D map that users can dive into in virtual reality.

The 100 Island Challenge literally unlocked another dimension to Viscore by bringing a highly interdisciplinary research team together, to create the data, algorithms and tools that are now allowing scientists to virtually explore reefs in the lab; to time-travel virtually from year to year; to track the growth and decline of individual colonies; and to study spatial and temporal relationships across the reef.

The project was made possible by bringing together researchers from Scripps and the Jacobs School of Engineering at UC San Diego with a deep commitment to the project, said Falko Kuester, a professor of computer science and structural engineering at UC San Diego.

“We want to give coral reefs a voice, to tell their stories and engage stakeholders to safeguard them,” he said.

Hundreds of videos the researchers generated are available on YouTube for public viewing.

“The program gave us the unique opportunity to virtually re-visit each of our dives and to examine the reef with a new focus,” said Fox. “When we ‘dove’ back into the images, we realized that the bleaching was even worse than we remembered when we were actually diving on the reef collecting the data.”

Along with documenting the bleaching, the researchers were able to closely monitor coral recovery. Looking at photomosaics of the reef after the bleaching event, Fox and team documented growth in an important reef-building species, crustose coralline algae. This alga helps hold reefs together and can encourage the settlement of juvenile corals.

In areas where coral did die and was covered with reef-smothering algae, researchers saw that in about a year this algae was replaced by the pink crustose coralline. This is partly due to the health of the larger ecosystem, as Palmyra has robust populations of herbivorous fish that can control destructive algae growth.

Tracking these recovery processes at specific coral colonies over time gives researchers a deeper understanding of how individual corals — and the larger reef they are a part of — are coping with environmental stresses in the era of human-influenced climate change.

Traditionally, changes in coral reefs were measured with transect sampling, in which divers record observations along one specific line across the reef.

“It’s like trying to measure national population growth by going to one random U.S. city and asking people if they had a child,” said Stuart Sandin, a Scripps researcher who co-authored the paper and is co-founder of the 100 Island Challenge. “You’re not going to show the larger picture.”

With the reef mosaics and the pinpoint accuracy of VisCore, coral scientists can look at demographic cues in a vast area. The colony-specific nature of the data gives more precision, and like tracking population growth in a country, can show regional and national trends.

“Using a combination of novel technology and more traditional approaches, our team was able to show that the reefs of Palmyra did not suffer the same fate as many other reefs during the recent global bleaching event,” said Jen Smith, a Scripps researcher and senior author on the paper, and co-founder of the 100 Island Challenge. “Despite extreme heating, corals were able to recover without experiencing widespread mortality. These findings certainly provide an important counterpoint to the general decline in reef health being reported globally.”

This research was funded by generous donations from the Scripps Family Foundation, the Bohn Family, the Wilson family, Marcia Grand and several other anonymous donors to the Smith and Sandin labs between 2009-2018.

However, when the NLRP3 inflammasome gets stuck in the “on” position, it can contribute to a number of chronic inflammatory conditions, including gout, osteoarthritis, fatty liver disease and Alzheimer’s and Parkinson’s diseases. In a new mouse study, researchers at University of California San Diego School of Medicine discovered a unique approach that might help treat some chronic inflammatory diseases: force cells to eliminate damaged mitochondria before they activate the NLRP3 inflammasome.

The study, published April 11, 2019 by Cell Metabolism, was led by senior author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine, and first author Elsa Sanchez-Lopez, PhD, a senior postdoctoral researcher in Karin’s lab.

In a 2018 study published in Nature, Karin’s team had shown that damaged mitochondria activate the NLRP3 inflammasome. The researchers also found that the NLRP3 inflammasome is de-activated when mitochondria are removed by the cell’s internal waste recycling process, called mitophagy.

“After that, we wondered if we could reduce harmful excess inflammation by intentionally inducing mitophagy, which would eliminate damaged mitochondria and should in turn pre-emptively inhibit NLRP3 inflammasome activation,” Karin said. “But at the time we didn’t have a good way to induce mitophagy.”

More recently, Sanchez-Lopez was studying how macrophages regulate their uptake of choline, a nutrient critical for metabolism, when she discovered something that can initiate mitophagy: an inhibitor of the enzyme choline kinase (ChoK). With ChoK inhibited, choline is no longer incorporated into mitochondrial membranes. As a result, the cells perceive the mitochondria as damaged, and cleared them away by mitophagy.

“Most importantly, by getting rid of damaged mitochondria with ChoK inhibitors, we were finally able to inhibit NLRP3 inflammasome activation,” Karin said.

To test their new ability to control NLRP3 inflammasome in a living system, the researchers turned to mice. They discovered that treatment with ChoK inhibitors prevented acute inflammation caused by uric acid (accumulation of which triggers gout flares) and a bacterial toxin.

By several measures, ChoK inhibitor treatment also reversed chronic inflammation associated with a genetic disease called Muckle-Well Syndrome, which is caused by mutations in NLRP3 genes. One such measure is spleen size — the larger the spleen, the more inflammation. The spleens of Muckle-Well Syndrome mice are on average twice as large as normal mice, but their spleen sizes normalized after ChoK inhibitor treatment.

NLRP3 inflammasome promotes inflammation because it triggers the release of two very potent pro-inflammatory molecules called cytokines: interleukin (IL)-1β and IL-18. According to Karin, there are existing drugs that can block IL-1β, but not IL-18. ChoK inhibitors, his team found, can reduce both cytokines.

“There are several diseases, including lupus and osteoarthritis, whose treatment will likely require dual inhibition of both IL-1β and IL-18,” Karin said.

Co-authors of this study include Zhenyu Zhong, Alexandra Stubelius, Laela M. Booshehri, Laura Antonucci, Ru Liu-Bryan, Robert Terkeltaub, Anne N. Murphy, Hal M. Hoffman, Monica Guma, UC San Diego; Shannon R. Sweeney, Alessia Lodi and Stefano Tiziani, University of Texas at Austin; and Juan Carlos Lacal, Hospital Universitario Fuenlabrada, Madrid, Spain.

This research was funded, in part, by the National Institutes of Health (grants R01AI43477 and R37AI043477, P42ES010337, P50AR060772, 1I01BX002234, R01DK113592, R01AR073324 and R03AR068094), Rotary Coins for Alzheimer’s Research (CART), Leukemia & Lymphoma Society (award 7005-14), VA Research Service Merit Review Awards (I01BX001660), CymaBay Therapeutics, ISCIII/MICINN (Sara Borrell fellowship), Cancer Research Institute Irvington Fellowship, Prevent Cancer Foundation Board of Directors Research Fund, American Association for the Study of Liver Diseases Pinnacle Research Award, International Cancer Research Fellowship (iCARE) and AIRC co-founded by the European Union.

Disclosure: The University of California San Diego is in the process of applying for a patent covering the use of CTL1 and/or choline kinase genetic/chemical inhibitors to treat NLRP3 inflammasome-associated diseases listing, Michael Karin and Elsa Sanchez-Lopez as inventors.