genes
On-the-Spot Gene Readouts Offer Clues to How Cells Work
Posted on by Dr. Francis Collins
Just as two companies can merge to expand their capabilities, two technologies can become more powerful when integrated into one. That’s why researchers recently merged two breakthrough technologies into one super powerful new method called ExSeq. The two-in-one technology enables researchers for the first time to study an intact tissue sample and track genetic activity on the spot within a cell’s tiniest recesses, or microenvironments—areas that have been largely out of reach until now.
ExSeq, which is described in a paper in the journal Science [1], will unleash many new experimental applications. Beyond enabling more precise analysis of the basic building blocks of life, these applications include analyzing tumor biopsies more comprehensively and even unlocking mysteries of how the brain works. The latter use is on display in this colorful cross-section of a mouse’s hippocampus, a region of the brain involved in the memory of facts and events.
Here you can see in precise and unprecedented detail the areas where genes are activated (magenta) in the brain’s neurons (green). In this particular example, the genes are working within subregions of the hippocampus called the CA1 and dentate gyrus regions (white, bottom and top left).
ExSeq is a joint effort from NIH grantees Ed Boyden, Massachusetts Institute of Technology (MIT), Cambridge, and George Church, Harvard Medical School, Boston. The new method combines a technology called tissue expansion with an in situ sequencing approach.
Tissue expansion swells the contents of tissue sections up to 100 times their normal size but retains their same physical structure [2]. It’s sort of like increasing the font size and line spacing on a hard-to-read document. It makes cellular details that were outside the resolution range of the light microscope suddenly accessible.
With the information inside cells now easier to see, the next step involves a technique called FISSEQ (fluorescent in situ sequencing), which generates readouts of thousands of mRNA molecules in cells [3]. FISSEQ works by detecting individual RNA molecules where they are inside cells and amplifying them into “nanoballs,” or rolled-up copies of themselves. Each nanoball can be read using standard sequencing methods and a fluorescence microscope.
Using the combined ExSeq approach, the team can analyze precisely where gene activity changes within tiny cellular microenvironments. Or, it can compile a more-comprehensive readout of gene activity within cells by analyzing as many gene readouts as detectable. When used in the hippocampus, this untargeted, “agnostic” approach led to some surprises—revealing unusual forms of RNA and, by association, genes for proteins not previously linked with communication between neurons.
Like many technology developments, the scientists envision that ExSeq can be used in many ways, including for more precise analysis of tumor biopsies. To illustrate this point, the researchers analyzed breast cancer metastases, which are cells from breast tumors that have spread to other areas in the body. Metastases contain many different cell types, including cancer cells and immune cells.
Using ExSeq, Boyden and Church learned that these distinct cell types can behave differently depending on where they are inside a tumor. They discovered, for example, that immune B cells near tumor cells expressed certain inflammatory genes at a higher level than immune B cells that were further away. Precise information about a tumor’s composition and activity may lead to development of more targeted approaches to attack it.
Many discoveries come on the heels of transformative new technologies. ExSeq shines a much brighter light on the world of the very small. And that should help us better understand how different parts of cells work together, as well as how cells work with each other in the brain, in cancer, and throughout the body.
References:
[1] Expansion sequencing: Spatially precise in situ transcriptomics in intact biological systems. Alon S, Goodwin DR, Sinha A, Wassie AT, et al. Science. 2021 Jan 29;37:eaax2656.
[2] Expansion microscopy. Chen F, Tillberg PW, Boyden ES. Science. 2015;347:543-548.
[3]. Highly multiplexed subcellular RNA sequencing in situ. Lee JH, Daugharthy ER, Scheiman J, Kalhor R, et al. Science. 2014;343:1360-1363.
Links:
Ribonucleic Acid (RNA) (National Human Genome Research Institute/NIH)
Synthetic Neurobiology Group (Massachusetts Institute of Technology, Cambridge)
George Church (Harvard Medical School, Boston)
NIH Support: National Human Genome Research Institute; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke
The People’s Picks for Best Posts
Posted on by Dr. Francis Collins
It’s 2021—Happy New Year! Time sure flies in the blogosphere. It seems like just yesterday that I started the NIH Director’s Blog to highlight recent advances in biology and medicine, many supported by NIH. Yet it turns out that more than eight years have passed since this blog got rolling and we are fast approaching my 1,000th post!
I’m pleased that millions of you have clicked on these posts to check out some very cool science and learn more about NIH and its mission. Thanks to the wonders of social media software, we’ve been able to tally up those views to determine each year’s most-popular post. So, I thought it would be fun to ring in the New Year by looking back at a few of your favorites, sort of a geeky version of a top 10 countdown or the People’s Choice Awards. It was interesting to see what topics generated the greatest interest. Spoiler alert: diet and exercise seemed to matter a lot! So, without further ado, I present the winners:
2013: Fighting Obesity: New Hopes from Brown Fat. Brown fat, one of several types of fat made by our bodies, was long thought to produce body heat rather than store energy. But Shingo Kajimura and his team at the University of California, San Francisco, showed in a study published in the journal Nature, that brown fat does more than that. They discovered a gene that acts as a molecular switch to produce brown fat, then linked mutations in this gene to obesity in humans.
What was also nice about this blog post is that it appeared just after Kajimura had started his own lab. In fact, this was one of the lab’s first publications. One of my goals when starting the blog was to feature young researchers, and this work certainly deserved the attention it got from blog readers. Since highlighting this work, research on brown fat has continued to progress, with new evidence in humans suggesting that brown fat is an effective target to improve glucose homeostasis.
2014: In Memory of Sam Berns. I wrote this blog post as a tribute to someone who will always be very near and dear to me. Sam Berns was born with Hutchinson-Gilford progeria syndrome, one of the rarest of rare diseases. After receiving the sad news that this brave young man had passed away, I wrote: “Sam may have only lived 17 years, but in his short life he taught the rest of us a lot about how to live.”
Affecting approximately 400 people worldwide, progeria causes premature aging. Without treatment, children with progeria, who have completely normal intellectual development, die of atherosclerotic cardiovascular disease, on average in their early teens.
From interactions with Sam and his parents in the early 2000s, I started to study progeria in my NIH lab, eventually identifying the gene responsible for the disorder. My group and others have learned a lot since then. So, it was heartening last November when the Food and Drug Administration approved the first treatment for progeria. It’s an oral medication called Zokinvy (lonafarnib) that helps prevent the buildup of defective protein that has deadly consequences. In clinical trials, the drug increased the average survival time of those with progeria by more than two years. It’s a good beginning, but we have much more work to do in the memory of Sam and to help others with progeria. Watch for more about new developments in applying gene editing to progeria in the next few days.
2015: Cytotoxic T Cells on Patrol. Readers absolutely loved this post. When the American Society of Cell Biology held its first annual video competition, called CellDance, my blog featured some of the winners. Among them was this captivating video from Alex Ritter, then working with cell biologist Jennifer Lippincott-Schwartz of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The video stars a roving, specialized component of our immune system called cytotoxic T cells. Their job is to seek out and destroy any foreign or detrimental cells. Here, these T cells literally convince a problem cell to commit suicide, a process that takes about 10 minutes from detection to death.
These cytotoxic T cells are critical players in cancer immunotherapy, in which a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. Cancer immunotherapy remains a promising area of research that continues to progress, with a lot of attention now being focused on developing immunotherapies for common, solid tumors like breast cancer. Ritter is currently completing a postdoctoral fellowship in the laboratory of Ira Mellman, Genentech, South San Francisco. His focus has shifted to how cancer cells protect themselves from T cells. And video buffs—get this—Ritter says he’s now created even cooler videos that than the one in this post.
2016: Exercise Releases Brain-Healthy Protein. The research literature is pretty clear: exercise is good for the brain. In this very popular post, researchers led by Hyo Youl Moon and Henriette van Praag of NIH’s National Institute on Aging identified a protein secreted by skeletal muscle cells to help explore the muscle-brain connection. In a study in Cell Metabolism, Moon and his team showed that this protein called cathepsin B makes its way into the brain and after a good workout influences the development of new neural connections. This post is also memorable to me for the photo collage that accompanied the original post. Why? If you look closely at the bottom right, you’ll see me exercising—part of my regular morning routine!
2017: Muscle Enzyme Explains Weight Gain in Middle Age. The struggle to maintain a healthy weight is a lifelong challenge for many of us. While several risk factors for weight gain, such as counting calories, are within our control, there’s a major one that isn’t: age. Jay Chung, a researcher with NIH’s National Heart, Lung, and Blood Institute, and his team discovered that the normal aging process causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies showed it also slows down metabolism, making it more difficult to burn fat.
Since publishing this paper in Cell Metabolism, Chung has been busy trying to understand how aging increases the activity of DNA-PK and its ability to suppress renewal of the cell’s energy-producing mitochondria. Without renewal of damaged mitochondria, excess oxidants accumulate in cells that then activate DNA-PK, which contributed to the damage in the first place. Chung calls it a “vicious cycle” of aging and one that we’ll be learning more about in the future.
2018: Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic? This impressive bit of microbial detective work had blog readers clicking and commenting for several weeks. So, it’s no surprise that it was the runaway People’s Choice of 2018.
Clostridium difficile (C. diff) is a common bacterium that lives harmlessly in the gut of most people. But taking antibiotics can upset the normal balance of healthy gut microbes, allowing C. diff. to multiply and produce toxins that cause inflammation and diarrhea.
In the 2000s, C. diff. infections became far more serious and common in American hospitals, and Robert Britton, a researcher at Baylor College of Medicine, Houston, wanted to know why. He and his team discovered that two subtypes of C. diff have adapted to feed on the sugar trehalose, which was approved as a food additive in the United States during the early 2000s. The team’s findings, published in the journal Nature, suggested that hospitals and nursing homes battling C. diff. outbreaks may want to take a closer look at the effect of trehalose in the diet of their patients.
2019: Study Finds No Benefit for Dietary Supplements. This post that was another one that sparked a firestorm of comments from readers. A team of NIH-supported researchers, led by Fang Fang Zhang, Tufts University, Boston, found that people who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to amounts that are available from food consumption. The researchers based their conclusion on an analysis of the well-known National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010 survey data. The team, which reported its data in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess.
2020: Genes, Blood Type Tied to Risk of Severe COVID-19. Typically, my blog focuses on research involving many different diseases. That changed in 2020 due to the emergence of a formidable public health challenge: the coronavirus disease 2019 (COVID-19) pandemic. Since last March, the blog has featured 85 posts on COVID-19, covering all aspects of the research response and attracting more visitors than ever. And which post got the most views? It was one that highlighted a study, published last June in the New England Journal of Medicine, that suggested the clues to people’s variable responses to COVID-19 may be found in our genes and our blood types.
The researchers found that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death. The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system.
In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.
That’s it for the blog’s year-by-year Top Hits. But wait! I’d also like to give shout outs to the People’s Choice winners in two other important categories—history and cool science images.
Top History Post: HeLa Cells: A New Chapter in An Enduring Story. Published in August 2013, this post remains one of the blog’s greatest hits with readers. The post highlights science’s use of cancer cells taken in the 1950s from a young Black woman named Henrietta Lacks. These “HeLa” cells had an amazing property not seen before: they could be grown continuously in laboratory conditions. The “new chapter” featured in this post is an agreement with the Lacks family that gives researchers access to the HeLa genome data, while still protecting the family’s privacy and recognizing their enormous contribution to medical research. And the acknowledgments rightfully keep coming from those who know this remarkable story, which has been chronicled in both book and film. Recently, the U.S. Senate and House of Representatives passed the Henrietta Lacks Enhancing Cancer Research Act to honor her extraordinary life and examine access to government-funded cancer clinical trials for traditionally underrepresented groups.
Top Snapshots of Life: A Close-up of COVID-19 in Lung Cells. My blog posts come in several categories. One that you may have noticed is “Snapshots of Life,” which provides a showcase for cool images that appear in scientific journals and often dominate Science as Art contests. My blog has published dozens of these eye-catching images, representing a broad spectrum of the biomedical sciences. But the blog People’s Choice goes to a very recent addition that reveals exactly what happens to cells in the human airway when they are infected with the coronavirus responsible for COVID-19. This vivid image, published in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. This image squeezed in just ahead of another highly popular post from Steve Ramirez, Boston University, in 2019 that showed “What a Memory Looks Like.”
As we look ahead to 2021, I want to thank each of my blog’s readers for your views and comments over the last eight years. I love to hear from you, so keep on clicking! I’m confident that 2021 will generate a lot more amazing and bloggable science, including even more progress toward ending the COVID-19 pandemic that made our past year so very challenging.
Genes, Blood Type Tied to Risk of Severe COVID-19
Posted on by Dr. Francis Collins
Credit: National Institute of Allergy and Infectious Diseases, NIH
Many people who contract COVID-19 have only a mild illness, or sometimes no symptoms at all. But others develop respiratory failure that requires oxygen support or even a ventilator to help them recover [1]. It’s clear that this happens more often in men than in women, as well as in people who are older or who have chronic health conditions. But why does respiratory failure also sometimes occur in people who are young and seemingly healthy?
A new study suggests that part of the answer to this question may be found in the genes that each one of us carries [2]. While more research is needed to pinpoint the precise underlying genes and mechanisms responsible, a recent genome-wide association (GWAS) study, just published in the New England Journal of Medicine, finds that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death.
The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system. In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.
These new findings—the first to identify statistically significant susceptibility genes for the severity of COVID-19—come from a large research effort led by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway. Their study included 1,980 people undergoing treatment for severe COVID-19 and respiratory failure at seven medical centers in Italy and Spain.
In search of gene variants that might play a role in the severe illness, the team analyzed patient genome data for more than 8.5 million so-called single-nucleotide polymorphisms, or SNPs. The vast majority of these single “letter” nucleotide substitutions found all across the genome are of no health significance, but they can help to pinpoint the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19-related respiratory failure. To find them, the researchers compared SNPs in people with severe COVID-19 to those in more than 1,200 healthy blood donors from the same population groups.
The analysis identified two places that turned up significantly more often in the individuals with severe COVID-19 than in the healthy folks. One of them is found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. For instance, this portion of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the surface receptor that allows the novel coronavirus that causes COVID-19, SARS-CoV-2, to bind to and infect human cells. It also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.
The other association signal popped up on chromosome 9, right over the area of the genome that determines blood type. Whether you are classified as an A, B, AB, or O blood type, depends on how your genes instruct your blood cells to produce (or not produce) a certain set of proteins. The researchers did find evidence suggesting a relationship between blood type and COVID-19 risk. They noted that this area also includes a genetic variant associated with increased levels of interleukin-6, which plays a role in inflammation and may have implications for COVID-19 as well.
These findings, completed in two months under very difficult clinical conditions, clearly warrant further study to understand the implications more fully. Indeed, Franke, Karlsen, and many of their colleagues are part of the COVID-19 Host Genetics Initiative, an ongoing international collaborative effort to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. Some NIH research groups are taking part in the initiative, and they recently launched a study to look for informative gene variants in 5,000 COVID-19 patients in the United States and Canada.
The hope is that these and other findings yet to come will point the way to a more thorough understanding of the biology of COVID-19. They also suggest that a genetic test and a person’s blood type might provide useful tools for identifying those who may be at greater risk of serious illness.
References:
[1] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Wu Z, McGoogan JM, et. al. 2020 Feb 24. [published online ahead of print]
[2] Genomewide association study of severe Covid-19 with respiratory failure. Ellinghaus D, Degenhardt F, et. a. NEJM. June 17, 2020.
Links:
The COVID-19 Host Genetics Initiative
Andre Franke (Christian-Albrechts-University of Kiel, Germany)
Tom Karlsen (Oslo University Hospital Rikshospitalet, Norway)
Largest-Ever Genetic Study of Autism Yields New Insights
Posted on by Dr. Francis Collins
Anyone who’s spent time with people affected by autism spectrum disorder (ASD) can tell you that it’s a very complex puzzle. The wide variability seen among individuals with this group of developmental brain disorders, which can disrupt communication, behavior control, and social skills, has also posed a huge challenge for researchers trying to identify underlying genetic and environmental factors. So, it’s no surprise that there’s been considerable interest in the recent findings of the largest-ever genetic study of ASD.
In a landmark study that analyzed the DNA of more than 35,000 people from around the world, the NIH-funded international Autism Sequencing Consortium (ASC) identified variants in 102 genes associated with increased risk of developing ASD, up from 65 identified previously. Of the 102 genes, 60 had not been previously linked to ASD and 53 appeared to be primarily connected to ASD as opposed to other types of intellectual disability or developmental delay. It is expected that this newfound genetic knowledge will serve to improve understanding of the complex biological mechanisms involved in ASD, ultimately paving the way for new approaches to diagnosis and treatment.
The study reported in the journal Cell was led by Joseph Buxbaum, Icahn School of Medicine at Mount Sinai, New York; Stephan Sanders, University of California, San Francisco; Kathryn Roeder, Carnegie Mellon University, Pittsburgh, PA; and Mark Daly, Massachusetts General Hospital, Boston, MA and the Broad Institute of MIT and Harvard, Cambridge, MA. These researchers and their teams faced what might seem like a rather daunting task.
While common genetic variants collectively are known to contribute substantially to ASD, rare variants have been recognized individually as more major contributors to a person’s risk of developing ASD. The challenge was how to find such rare variants—whether inherited or newly arising.
To do so, the researchers needed to analyze a enormous amount of DNA data. Fortunately, they and their ASC colleagues already had assembled a vast trove of data. Over the last decade, the ASC had collected DNA samples with full consent from thousands of people with and without ASD, including unaffected siblings and parents. All were aggregated with other studies, and, at the time of this investigation, they had gathered 35,584 unique samples. Those included more than 21,000 family-based samples and almost 12,000 samples from people diagnosed with ASD.
In search of rare genetic alterations, they sequenced whole exomes, the approximately 1.5 percent of the genome that codes for proteins. Their search produced a list of 102 ASD-associated genes, including 30 that had never been implicated in any developmental brain disorder previously.
But that was just the beginning. Next, the ASC team dug deeper into this list. The researchers knew from previous work that up to half of people with ASD also have an intellectual disability or developmental delay. Many of the associated genes overlap, meaning they play roles in both outcomes. So, in one set of analyses, the team compared the list to the results of another genetic study of people diagnosed with developmental delays, including problems with learning or gross motor skills such as delayed walking.
The detailed comparison allowed them to discern genes that are more associated with features of ASD, as opposed to those that are more specific to these developmental delays. It turns out that 49 of the 102 autism-associated genes were altered more often in people with developmental delay than in those diagnosed with ASD. The other 53 were altered more often in ASD, suggesting that they may be more closely linked to this condition’s unique features.
Further study also showed that people who carried alterations in genes found predominantly in ASD also had better intellectual function. They also were more likely to have learned to walk without a developmental delay.
The 102 new genes fell primarily into one of two categories. Many play a role in the brain’s neural connections. The rest are involved primarily in switching other genes on and off in brain development. Interestingly, they are expressed both in excitatory neurons, which are active in sending signals in the brain, and in inhibitory neurons that squelch such activity. Many of these genes are also commonly expressed in the brain’s cerebral cortex, the outermost part of the brain that is responsible for many complex behaviors.
Overall, these findings underscore that ASD truly does exist on a spectrum. Indeed, there are many molecular paths to this disorder. The ASC researchers continue to collect samples, so we can expect this list of 102 genes will continue to expand in the future.
With these gene discoveries in hand, the researchers will now also turn their attention to unravelling additional details about how these genes function in the brain. The hope is that this growing list of genes will converge on a smaller number of important molecular pathways, pointing the way to new and more precise ways of treating ASD in all its complexity.
Reference:
[1] Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, Peng M, Collins R, Grove J, Klei L, Stevens C, Reichert J, Mulhern MS, Artomov M, Gerges S, Sheppard B, Xu X, Bhaduri A, Norman U, Brand H, Schwartz G, Nguyen R, Guerrero EE, Dias C; Autism Sequencing Consortium; iPSYCH-Broad Consortium, Betancur C, Cook EH, Gallagher L, Gill M, Sutcliffe JS, Thurm A, Zwick ME, Børglum AD, State MW, Cicek AE, Talkowski ME, Cutler DJ, Devlin B, Sanders SJ, Roeder K, Daly MJ, Buxbaum JD.Cell. 2020 Jan 23. {Epub ahead of print]
Links:
Autism Spectrum Disorder (NIH/National Institute of Mental Health)
Joseph Buxbaum (Icahn School of Medicine at Mount Sinai, New York)
Sanders Lab (University of California, San Francisco)
Kathryn Roeder (Carnegie Mellon University, Pittsburgh, PA)
Mark Daly (Broad Institute of MIT and Harvard, Cambridge, MA)
Autism Sequencing Consortium (Emory University, Atlanta)
NIH Support: National Institute Mental Health; National Human Genome Research Institute
NASA Twins Study Reveals Health Effects of Space Flight
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.
Reference:
[1] 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).
Links:
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
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