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
Predicting whether someone will get Alzheimer’s disease (AD) late in life, and how to use that information for prevention, has been an intense focus of biomedical research. The goal of this work is to learn not only about the genes involved in AD, but how they work together and with other complex biological, environmental, and lifestyle factors to drive this devastating neurological disease.
It’s good news to be able to report that an international team of researchers, partly funded by NIH, has made more progress in explaining the genetic component of AD. Their analysis, involving data from more than 35,000 individuals with late-onset AD, has identified variants in five new genes that put people at greater risk of AD . It also points to molecular pathways involved in AD as possible avenues for prevention, and offers further confirmation of 20 other genes that had been implicated previously in AD.
The results of this largest-ever genomic study of AD suggests key roles for genes involved in the processing of beta-amyloid peptides, which form plaques in the brain recognized as an important early indicator of AD. They also offer the first evidence for a genetic link to proteins that bind tau, the protein responsible for telltale tangles in the AD brain that track closely with a person’s cognitive decline.
The new findings are the latest from the International Genomics of Alzheimer’s Project (IGAP) consortium, led by a large, collaborative team including Brian Kunkle and Margaret Pericak-Vance, University of Miami Miller School of Medicine, Miami, FL. The effort, spanning four consortia focused on AD in the United States and Europe, was launched in 2011 with the aim of discovering and mapping all the genes that contribute to AD.
An earlier IGAP study including about 25,500 people with late-onset AD identified 20 common gene variants that influence a person’s risk for developing AD late in life . While that was terrific progress to be sure, the analysis also showed that those gene variants could explain only a third of the genetic component of AD. It was clear more genes with ties to AD were yet to be found.
So, in the study reported in Nature Genetics, the researchers expanded the search. While so-called genome-wide association studies (GWAS) are generally useful in identifying gene variants that turn up often in association with particular diseases or other traits, the ones that arise more rarely require much larger sample sizes to find.
To increase their odds of finding additional variants, the researchers analyzed genomic data for more than 94,000 individuals, including more than 35,000 with a diagnosis of late-onset AD and another 60,000 older people without AD. Their search led them to variants in five additional genes, named IQCK, ACE, ADAM10, ADAMTS1, and WWOX, associated with late-onset AD that hadn’t turned up in the previous study.
Further analysis of those genes supports a view of AD in which groups of genes work together to influence risk and disease progression. In addition to some genes influencing the processing of beta-amyloid peptides and accumulation of tau proteins, others appear to contribute to AD via certain aspects of the immune system and lipid metabolism.
Each of these newly discovered variants contributes only a small amount of increased risk, and therefore probably have limited value in predicting an average person’s risk of developing AD later in life. But they are invaluable when it comes to advancing our understanding of AD’s biological underpinnings and pointing the way to potentially new treatment approaches. For instance, these new data highlight intriguing similarities between early-onset and late-onset AD, suggesting that treatments developed for people with the early-onset form also might prove beneficial for people with the more common late-onset disease.
It’s worth noting that the new findings continue to suggest that the search is not yet over—many more as-yet undiscovered rare variants likely play a role in AD. The search for answers to AD and so many other complex health conditions—assisted through collaborative data sharing efforts such as this one—continues at an accelerating pace.
 Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, et. al. Nat Genet. 2019 Mar;51(3):414-430.
 Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, et al. Nat Genet. 2013 Dec;45(12):1452-8.
Alzheimer’s Disease Genetics Fact Sheet (National Institute on Aging/NIH)
Margaret Pericak-Vance (University of Miami Health System, FL)
NIH Support: National Institute on Aging; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Disease; National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
In seeking the biological answer to the question of what it means to be human, the brain’s cerebral cortex is a good place to start. This densely folded, outer layer of grey matter, which is vastly larger in Homo sapiens than in other primates, plays an essential role in human consciousness, language, and reasoning.
Now, an NIH-funded team has pinpointed a key set of genes—found only in humans—that may help explain why our species possesses such a large cerebral cortex. Experimental evidence shows these genes prolong the development of stem cells that generate neurons in the cerebral cortex, which in turn enables the human brain to produce more mature cortical neurons and, thus, build a bigger cerebral cortex than our fellow primates.
That sounds like a great advantage for humans! But there’s a downside. Researchers found the same genomic changes that facilitated the expansion of the human cortex may also render our species more susceptible to certain rare neurodevelopmental disorders.
Posted on by Dr. Francis Collins
Many people probably think of mice as unwanted household pests. But over more than a century, mice have proven to be incredibly valuable in medical research. One of many examples is how studies in mice are now helping researchers understand how mammalian genomes work, including the human genome. Scientists have spent decades inactivating, or “knocking out,” individual genes in laboratory mice to learn which tissues or organs are affected when a specific gene is out of order, providing valuable clues about its function.
More than a decade ago, NIH initiated a project called KOMP—the Knockout Mouse Project . The goal was to use homologous recombination (exchange of similar or identical DNA) in embryonic stem cells from a standard mouse strain to knock out all of the mouse protein-coding genes. That work has led to wide availability of such cell lines to investigators with interest in specific genes, saving time and money. But it’s one thing to have a cell line with the gene knocked out, it’s even more interesting (and challenging) to determine the phenotype, or observable characteristics, of each knockout. To speed up that process in a scientifically rigorous and systematic manner, NIH and other research funding agencies teamed to launch an international research consortium to turn those embryonic stem cells into mice, and ultimately to catalogue the functions of the roughly 20,000 genes that mice and humans share. The consortium has just released an analysis of the phenotypes of the first 1,751 new lines of unique “knockout mice” with much more to come in the months ahead. This initial work confirms that about a third of all protein-coding genes are essential for live birth, helping to fill in a major gap in our understanding of the genome.
Posted on by Dr. Francis Collins
The human genome contains more than 20,000 protein-coding genes, which carry the instructions for proteins essential to the structure and function of our cells, tissues and organs. Some of these genes are very similar to each other because, as the genomes of humans and other mammals evolve, glitches in DNA replication sometimes result in extra copies of a gene being made. Those duplicates can be passed along to subsequent generations and, on very rare occasions, usually at a much later point in time, acquire additional modifications that may enable them to serve new biological functions. By starting with a protein shape that has already been fine-tuned for one function, evolution can produce a new function more rapidly than starting from scratch.
Pretty cool! But it leads to a question that’s long perplexed evolutionary biologists: Why don’t duplicate genes vanish from the gene pool almost as soon as they appear? After all, instantly doubling the amount of protein produced in an organism is usually a recipe for disaster—just think what might happen to a human baby born with twice as much insulin or clotting factor as normal. At the very least, duplicate genes should be unnecessary and therefore vulnerable to being degraded into functionless pseudogenes as new mutations arise over time
An NIH-supported team offers a possible answer to this question in a study published in the journal Science. Based on their analysis of duplicate gene pairs in the human and mouse genomes, the researchers suggest that extra genes persist in the genome because of rapid changes in gene activity. Instead of the original gene producing 100 percent of a protein in the body, the gene duo quickly divvies up the job . For instance, the original gene might produce roughly 50 percent and its duplicate the other 50 percent. Most importantly, organisms find the right balance and the duplicate genes can easily survive to be passed along to their offspring, providing fodder for continued evolution.