Posted on by Dr. Francis Collins
Most children infected with SARS-CoV-2, the virus that causes COVID-19, develop only a mild illness. But, days or weeks later, a small percentage of kids go on to develop a puzzling syndrome known as multisystem inflammatory syndrome in children (MIS-C). This severe inflammation of organs and tissues can affect the heart, lungs, kidneys, brain, skin, and eyes.
Thankfully, most kids with MIS-C respond to treatment and make rapid recoveries. But, tragically, MIS-C can sometimes be fatal.
With COVID-19 cases in children having increased by 21 percent in the United States since early August , NIH and others are continuing to work hard on getting a handle on this poorly understood complication. Many think that MIS-C isn’t a direct result of the virus, but seems more likely to be due to an intense autoimmune response. Indeed, a recent study in Nature Medicine  offers some of the first evidence that MIS-C is connected to specific changes in the immune system that, for reasons that remain mysterious, sometimes follow COVID-19.
These findings come from Shane Tibby, a researcher at Evelina London Children’s Hospital, London. United Kingdom; Manu Shankar-Hari, a scientist at Guy’s and St Thomas’ NHS Foundation Trust, London; and colleagues. The researchers enlisted 25 children, ages 7 to 14, who developed MIS-C in connection with COVID-19. In search of clues, they examined blood samples collected from the children during different stages of their care, starting when they were most ill through recovery and follow-up. They then compared the samples to those of healthy children of the same ages.
What they found was a complex array of immune disruptions. The children had increased levels of various inflammatory molecules known as cytokines, alongside raised levels of other markers suggesting tissue damage—such as troponin, which indicates heart muscle injury.
The neutrophils, monocytes, and other white blood cells that rapidly respond to infections were activated as expected. But the levels of certain white blood cells called T lymphocytes were paradoxically reduced. Interestingly, despite the low overall numbers of T lymphocytes, particular subsets of them appeared activated as though fighting an infection. While the children recovered, those differences gradually disappeared as the immune system returned to normal.
It has been noted that MIS-C bears some resemblance to an inflammatory condition known as Kawasaki disease, which also primarily affects children. While there are similarities, this new work shows that MIS-C is a distinct illness associated with COVID-19. In fact, only two children in the study met the full criteria for Kawasaki disease based on the clinical features and symptoms of their illness.
Another recent study from the United Kingdom, reported several new symptoms of MIS-C . They include headaches, tiredness, muscle aches, and sore throat. Researchers also determined that the number of platelets was much lower in the blood of children with MIS-C than in those without the condition. They proposed that evaluating a child’s symptoms along with his or her platelet level could help to diagnose MIS-C.
It will now be important to learn much more about the precise mechanisms underlying these observed changes in the immune system and how best to treat or prevent them. In support of this effort, NIH recently announced $20 million in research funding dedicated to the development of approaches that identify children at high risk for developing MIS-C .
The hope is that this new NIH effort, along with other continued efforts around the world, will elucidate the factors influencing the likelihood that a child with COVID-19 will develop MIS-C. Such insights are essential to allow doctors to intervene as early as possible and improve outcomes for this potentially serious condition.
 Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Carter MJ, Fish M, Jennings A, Doores KJ, Wellman P, Seow J, Acors S, Graham C, Timms E, Kenny J, Neil S, Malim MH, Tibby SM, Shankar-Hari M. Nat Med. 2020 Aug 18.
 Children and COVID-19: State-Level Data Report. American Academy of Pediatrics. August 24, 2020.
 Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. Swann OV, Holden KA, Turtle L, Harrison EW, Docherty AB, Semple MG, et al. Br Med J. 2020 Aug 17.
 NIH-funded project seeks to identify children at risk for MIS-C. NIH. August 7, 2020.
Coronavirus (COVID-19) (NIH)
Kawasaki Disease (Genetic and Rare Disease Information Center/National Center for Advancing Translational Sciences/NIH)
Shane Tibby (Evelina London Children’s Hospital, London)
Manu Shankar-Hari (King’s College, London)
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Drug Abuse; National Institute of Minority Health and Health Disparities; Fogarty International Center
Posted on by Dr. Francis Collins
Sending one identical twin into space while the other stays behind on Earth might sound like the plot of a sci-fi thriller. But it’s actually a setup for some truly fascinating scientific research!
As part of NASA’s landmark Twins Study, Scott Kelly became the first U.S. astronaut to spend nearly a year in “weightless” microgravity conditions aboard the International Space Station. Meanwhile, his identical twin, retired astronaut Mark Kelly, remained earthbound. Researchers put both men—who like all identical twins shared the same genetic makeup at birth—through the same battery of biomedical tests to gauge how the human body responds to life in space. The good news for the future of space travel is that the results indicated that health is “mostly sustained” during a prolonged stay in space.
Reporting in the journal Science, the Twins Study team, which included several NIH-funded researchers, detailed many thousands of differences between the Kelly twins at the molecular, cellular, and physiological levels during the 340-day observation period. However, most of Scott’s measures returned to near pre-flight levels within six months of rejoining Mark on Earth.
Over the past nearly 60 years, 559 people have flown in space. While weightless conditions are known to speed various processes associated with aging, few astronauts have remained in space for more than a few months at a time. With up to three year missions to the moon or Mars planned for the future, researchers want to get a better sense of how the human body will hold up under microgravity conditions for longer periods.
To get a more holistic answer, researchers collected a variety of biological samples from the Kelly twins before, during, and after Scott’s spaceflight. All told, more than 300 samples were collected over the course of 27 months.
Multiple labs around the country used state-of-the art tools to examine those samples in essentially every way they could think of doing. Those analyses offer a remarkably detailed view of changes in an astronaut’s biology and health while in space.
With so much data, there were lots of interesting findings to report, including many changes in the expression of Scott’s genes that weren’t observed in his twin. While most of these changes returned to preflight levels within six months of Scott’s return to Earth, about 7 percent of his genes continued to be expressed at different levels. These included some related to DNA repair and the immune system.
Despite those changes in immunity-related gene expression, his immune system appeared to remain fully functional. His body responded to the flu vaccine administered in space just as would be expected back home on Earth.
Scott also had some measurable changes in telomeres—complexes of specialized DNA sequences, RNA, and protein that protect the tips of our chromosomes. These generally shorten a bit each time cells divide. But during the time in space, the telomeres in Scott’s white blood cells measured out at somewhat greater length.
Potentially, this is because some of his stem cells, which are younger and haven’t gone through as many cell divisions, were being released into the blood. Back on Earth, his telomere lengths returned to an average length within six months of his return. Over the course of the study, the earthbound telomeres of his twin brother Mark remained stable.
Researchers also uncovered small but significant changes to Scott’s gut microbiome, the collection of microbes that play important roles in digestion and the immune system. More specifically, there was a shift in the ratio of two major groups of bacteria. Once back on Earth, his microbiome quickly shifted back to its original preflight state.
The data also provided some metabolic evidence suggesting that Scott’s mitochondria, the cellular powerhouses that supply the body with energy, weren’t functioning at full capacity in space. While further study is needed, the NIH-funded team led by Kumar Sharma, University of Texas Health Science Center, San Antonio, suggests that changes in the mitochondria might underlie changes often seen in space to the human cardiovascular system, kidneys, and eyes.
Of course, such a small, two-person study makes it hard to draw any general conclusions about human health in space. But the comparisons certainly help to point us in the right direction. They provide a framework for understanding how the human body responds on a molecular and cellular level to microgravity over time. They also may hold important lessons for understanding human health and precision medicine down here on Earth.
I look forward to future space missions and their contributions to biomedical research. I’m also happy to report, it will be a short wait.
Last year, I highlighted the Tissue Chips in Space Initiative. It’s a unique collaboration between NIH and NASA in which dozens of human tissue chips—tiny, 3D devices bioengineered to model different tissues and organs—will be sent to the International Space Station to study the accelerated aging that occurs in space.
The first tissue chips were sent to the International Space Station last December. And I’m pleased to report that more were aboard recently when the SpaceX Dragon cargo spacecraft made a resupply run to the International Space Station. On May 8, astronauts there successfully completed offloading miniaturized tissue chips of the lungs, bone marrow, and kidneys, enabling more truly unique science in low gravity that couldn’t be performed down here on Earth.
 The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Garrett-Bakelman FE, Darshi M, Green SJ, Gur RC, Lin L, Macias BR, et. al. Science. 2019 Apr 12;364(6436).
Twins Study (NASA)
Launches and Landings (NASA. Washington, D.C.)
Kumar Sharma (University of Texas Health Science Center, San Antonio)
Tissue Chips in Space (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases
Posted on by Dr. Francis Collins
About a year ago, Tom Glover began sifting through a stack of applications from prospective students hoping to be admitted into the Master’s Degree Program in Human Genetics at the University of Michigan, Ann Arbor. Glover, the program’s director, got about halfway through the stack when he noticed applications from two physicians in West Africa: Charlotte Osafo from Ghana, and Yemi Raji from Nigeria. Both were kidney specialists in their 40s, and neither had formal training in genomics or molecular biology, which are normally requirements for entry into the program.
Glover’s first instinct was to disregard the applications. But he noticed the doctors were affiliated with the Human Heredity and Health in Africa (H3Africa) Initiative, which is co-supported by the Wellcome Trust and the National Institutes of Health Common Fund, and aims in part to build the expertise to carry out genomics research across the continent of Africa. (I am proud to have had a personal hand in the initial steps that led to the founding of H3Africa.) Glover held onto the two applications and, after much internal discussion, Osafo and Raji were admitted to the Master’s Program. But there were important stipulations: they had to arrive early to undergo “boot camp” in genomics and molecular biology and also extend their coursework over an extra term.