September 2015 – A Lab Aloft (International Space Station Research)

Twins Double the Data for Space Station Research – Part Two

In today’s A Lab Aloft, Graham Scott, Ph.D., completes his two-part series looking at the National Space Biomedical Research Institute’s (NSBRI’s) and NASA’s Twins Study that is conducting biomedical research on a pair of identical twin brothers, who are both astronauts.

As you may recall from part one of this blog, personalized medicine involves the application of many sophisticated molecular and bioinformatics techniques. At a high level, it means that when you visit your doctor(s), they examine you and determine the best drug or therapeutic intervention based on your individual health and biomolecular profile, rather than what usually works for the general population. This approach views you as distinct from any other patient, and as such you receive care based on your unique genome. By obtaining and analyzing your genome, doctors can detect and characterize your individual genetic variants – and prescribe precision or personalized treatments accordingly.

This strategy of using genetic profiling to inform individualized treatments has become quite mainstream in the best cancer hospitals and leading medical schools. NASA and the National Space Biomedical Research Institute (NSBRI) have the long-term goal of employing this personalized approach to mitigate the significant health risks that astronauts will face during deep space exploration missions. The Twins Study that involves the identical twin Kelly brothers, who happen to also be astronauts, is a pilot demonstration project that will collect and analyze integrated omics data – thereby laying the foundations for such a personalized or precision medicine approach.

Personalized medicine also applies to enabling future space exploration missions, such as an expedition to Mars, by making such a multi-year journey much safer. The crew will need to be highly self-sufficient or “autonomous” during that multi-year journey to and from the red planet. This includes sending each astronaut with the right drugs to effectively treat them as an individual, should they become ill. We want to also ensure that each crew member has tailored countermeasures available to them, to help them sleep or relax. Personalized medicine is a cutting edge methodology to make space exploration as safe as possible for astronauts. It’s a strategy that allows us to harness the full arsenal of health advances that we’re seeing in our leading medical institutions and universities today.

NASA’s & NSBRI’s initiative may motivate the next generation of scientists, physicians, engineers and astronauts as they watch how omics studies are implemented as a precursor to deploying personalized medicine in space. In addition, these types of studies will help educate as well as address some of the ethical and philosophical questions that arise with genetics-based care.

We are carefully considering ethical considerations surrounding integrated omics studies. Astronauts are high profile public figures, but a person’s genome is unique and extremely private. In the hands of an expert, a person’s genome can infer a person’s susceptibility to developing certain diseases over the course of their lifetime. As you can imagine, this is not the kind of information an individual wants to publically disclose. Genetic information can also lead to inferences regarding the current or future health status of other close family members. In this way the findings and implications of an integrated omics study, such as the Twins Study, are not limited to the individual(s) being studied. Add to these considerations an astronaut’s fear of being grounded and prevented from participation in future space exploration missions, due to medical findings, and it is evident that a number of sensitive topics arise with integrated omics studies that must be thoughtfully addressed.

NASA astronaut Scott Kelly handling the Rodent Research Facility aboard the International Space Station. (NASA)

NASA is examining how to handle omics data and privacy concerns from the perspective of medical ethics. The Twins Study helps the agency begin to grapple with these potentially difficult and complex issues, including how to archive this type of genetic information, “mine” it responsibly, and develop and implement policies. To protect against the misuse of personal genetic information, NASA has put a strict information barrier in place between the research team and the flight surgeons whom are tasked with providing medical treatment to astronauts. This type of impermeable confidential barrier protects research subjects, and is a practice that may help mainstream terrestrial medicine evolve in regards to how sensitive genetic information should be treated.

These considerations are very important, because many people worry about how their own genetic information could potentially impact their lives, jobs, ability to procure life insurance, and their families. NASA and NSBRI are thinking through all of these concerns as they relate to the astronauts, providing a benchmark for the medical, research, and legal communities to consider.

We are not all going to travel to Mars, of course, but in the near future we are all likely to experience or observe the application of individualized medicine here on Earth. The use of omics data will help doctors here on Earth customize treatments and optimize care to the general public. The Twins Study is breaking new ground in this area of personalized medicine, and how we apply the concept in space can provide an informative example for leading institutions as they continue to transition into an individualized care approach.

Graham Scott, Ph.D., is the Chief Scientist and Institute Associate Director at the National Space Biomedical Research Institute (NSBRI), NASA’s biomedical research institute that was established in 1997 to work in partnership with the agency’s Human Research Program. A New Zealander by birth, Scott served as a Royal New Zealand Air Force pilot before obtaining a Ph.D. in astrochemistry. He came to the U.S. in 1997 where he worked for Nobel Laureate Robert F. Curl, Jr, Ph.D., at Rice University. Scott then went on to work on the Human Genome Project at Baylor College of Medicine, followed by a decade of leading R&D and marketing teams in corporate America, before being recruited back to Baylor to undertake his current leadership role with NSBRI.

Twins Double the Data for Space Station Research – Part One

In today’s A Lab Aloft, Graham Scott, Ph.D., kicks off a two-part series looking at the National Space Biomedical Research Institute’s (NSBRI’s) and NASA’s Twins Study that is conducting biomedical research on a pair of identical twin brothers, who are both astronauts.

Medical care and biomedical research are rapidly becoming personal—as underscored by President Obama’s recently announced Precision Medicine Initiative that considers patient’s individual variations in genes, environment and lifestyle as inputs to disease prevention and treatment. The President’s Precision Medicine Initiative has the goal of generating the scientific evidence needed to propel precision medicine into clinical practice. Individualized healthcare unleashes powerful 21^st century molecular diagnostics that offer exciting new treatment options for patients and their families. Molecular diagnostics analyze biological markers such as genes, proteins and metabolites present in a person’s tissues, cells and biofluids (such as blood or urine), by applying techniques developed by molecular biologists to medical testing.

In an effort to address the age-old question of “nature versus nurture,” the NASA and the National Space Biomedical Research Institute (NSBRI) funded Twins Study is conducting biomedical research on the Kelly brothers—identical twin astronauts. This first of its kind integrated “astro-omics” study will lay the foundations for the eventual development of precision medicine-based countermeasures for astronauts that may contribute to future missions to Mars. Spaceflight challenges humans in new, unexpected and extreme ways, and people on and off the ground will undoubtedly benefit from the knowledge obtained as a result of this unique investigation.

The origins of this research are also personal. The twins themselves, Mark and Scott Kelly, raised the idea that they be studied before, during, and after Scott’s current one year mission aboard the International Space Station. Scott is one of two selected crew members who will spend a full 12 months on orbit, rather than the usual six months. Meanwhile his brother Mark, a retired astronaut, remains firmly on the ground.

During a news conference on Jan. 19, 2015 at Johnson Space Center in Houston Texas, Expedition 45/46 Commander, astronaut Scott Kelly—along with his brother, former astronaut Mark Kelly—spoke about Scott Kelly's impending one-year mission aboard the International Space Station (ISS). (NASA/Robert Markowitz) — During a news conference on Jan. 19, 2015 at Johnson Space Center in Houston Texas, Expedition 45/46 Commander, astronaut Scott Kelly—along with his brother, former astronaut Mark Kelly—spoke about Scott Kelly’s impending one-year mission aboard the International Space Station (ISS). (NASA/Robert Markowitz)

The Twins Study dovetails seamlessly with the one-year mission, creating an opportunity to take a detailed look at Scott’s DNA, his complement of proteins, the ensemble of bacteria living in his gut, and the milieu of metabolites found in his bloodstream. We call this type of research—where we simultaneously look at many different biomolecular levels—an integrated omics study.

The term “omics” is relatively new. In 2003 the first “finished” human genome, which detailed the genetic make-up or blueprint of a person, became broadly available to the scientific community. This led to an observation of how genes are copied or “transcribed” ahead of ultimately being synthesized into proteins, which we refer to as the transcriptome. This work was quickly followed by efforts to study the proteome, cataloging the thousands of proteins that are circulating at any given time in our blood or performing signaling within our cells. More recently we have characterized the microbiome, which refers to the community of microorganisms living within our gut and on our skin. We also are studying the epigenome, which involves investigating reversible chemical changes that occur dynamically within our DNA and the histone proteins that “package” our DNA as a result of environmental stressors. The number of “omes” that we can examine seems to continually increase and the term “omics” is an umbrella term to cover these areas of molecular research as a newly emerged category of biomedical study.

The opportunity to observe Scott (in space) and Mark (on the ground) at a fundamental biomolecular level is unique because they are identical twin brother astronauts. Around the turn of the 21^st century we would have stated that they were genetically the same. Actually, it turns out that identical twins are not 100 percent identical. To a first order of approximation their DNA sequence is matched, but there are actually some small underlying genetic differences. Moreover, the biomolecules that are generated or “expressed” at the RNA, protein, and metabolite levels are quite different. This is due to the responses of each twin to the environment that they encounter at any given moment, as well as the experiences that have accumulated throughout their lifetimes.

We plan to look at both Mark and Scott’s molecular profiles at a fine, granular-level to see what is occurring with their genomes, transcriptomes, proteomes, metabolomes, etc. in space, relative to on the ground. Mark provides about as ideal of a control subject as one could imagine, because he is so close genetically to Scott. Starting in late 2014 we have been collecting biofluids and obtaining baseline measurements from Scott and Mark for the study. We will continue to collect samples from both twins following Scott’s return to Earth in early 2016.

What we may see with Scott, based on experiments previously performed using animal research models, are different RNA expression levels for certain genes, relative to what we typically observe on the ground. We can also perform a comparison of Scott’s RNA expression profile to that of his brother, Mark. For instance, during his mission Scott will experience approximately 20 times higher levels of radiation than Mark. This is because the combined effect of our planet’s protective atmosphere and strong magnetic field protects Earth-bound humans.

The impact that space radiation has on a person’s DNA is one of the things we’re interested in learning more about. We will study how rapidly the ends of the chromosomes or “telomeres” shorten in response to the effects of radiation and other stressors that are inherent to the space environment. This research on telomeres will provide follow-up data to the chromosomal damage published in 2008 by Dr. Francis Cucinotta and colleagues in Radiation Research.

A better understanding of the impact of space radiation at the molecular level may ultimately benefit cancer patients who undergo proton radiation as part of their treatment regimen. Up until the 21^st century, cancer patients received radiation treatments that were quite different from what astronauts are bombarded with in space. Now many leading cancer hospitals are using proton therapy and some are even beginning to employ carbon ions to fight cancer. This “particle therapy” is similar to the heavy particle component of space radiation, though with varied rates and doses.

This higher radiation exposure Scott will experience in space may reveal biomolecular impacts in ways that could lead to new findings. The twins close genetics make them ideal study subjects for attempting to tease out the role of environmental effects in disease development, versus the inherent genetic makeup of a person.

We factored into the studies that Mark was an astronaut up until 2012, meaning he also spent a significant amount of time in space. Mark has spent 54 days in space, while Scott will accumulate 540 days on orbit by the end of his one-year mission—ten times as many days as his brother. Both of the brothers’ biomolecular profiles have almost certainly been impacted by their previous experience in space. Scott will of course encounter a new set of stressors, now that he is once again aboard the ISS.

Astronaut Mark Kelly, STS-124 commander, looking through the Earth observation window in the Japanese Experiment Module of the ISS during his 2008 mission. (NASA)

As with many scientific projects, the Twins Study is likely to raise more questions than answers. That said, we hope to have many tantalizing leads and interesting pieces of data to follow up on with more integrated omics research on larger numbers of astronauts.

To baseline the biomolecular profiles of both Scott and Mark, we obtained and safely stored blood, urine, saliva, and other biofluid samples. We also are performing a longitudinal study on Scott, by collecting samples while he was on Earth prior to launch, then following him throughout his space mission and again periodically for many months after his return. The same goes for Mark; we will perform a similar longitudinal study on him. For both twin astronaut brothers we will track them over time, specifically for several years. In fact we will be looking at Scott’s telomeres, as far out as 720 days after his landing in March 2016.

The results of this study won’t just impact the twins, but actually will have a lot to do with the rest of us living here on Earth. One of the things you may have noticed if you saw the President’s State of the Union speech was that Scott Kelly was in the First Lady‘s boxed seating area. During his speech President Obama specifically mentioned the one year mission and cited the importance of the area of personalized or precision medicine that is rapidly emerging as a powerful new set of techniques within biomedical research and clinical practice.

NASA astronaut Scott Kelly stands as he is recognized by President Barack Obama, while First Lady Michelle Obama (lower left corner) and other guests applaud. The President recognized Kelly during the State of the Union address on Capitol Hill in Washington D.C. on Jan. 20, 2015. (NASA/Bill Ingalls)

In part two of this blog posting, I will share with you the ethics and impacts of personalized medicine in space and on the ground.

Boning Up on Skeletons in Space

In today’s A Lab Aloft, Jean Sibonga, Ph.D., explains what’s next for microgravity bone research aboard the International Space Station. Using what we’ve learned in the last 50 years, investigations in orbit will help scientists pinpoint the impacts of countermeasures and refine treatments.

Boning Up on Skeletons in Space

All research begins with a question. In my case, two of them. My first question came from research I was doing during my postdoctoral study at the Harvard School of Dental Medicine working with oral biologists and orthodontists. Impressed with how an orthodontist can practically move teeth from one end of your mouth to another — I wondered about what told the cells to break down the bone at the front end of the tooth and then to fill in the cavity left by the tooth’s movement. What kind of chemical communication was happening to make this possible?

My second question came years later from former NASA administrator Michael Griffin during a visit to my directorate at Johnson Space Center. Griffin asked: “How can we make those bone cells stop what they are doing up in space?” He was referring to the real concern of accelerated bone loss for humans living in microgravity. He wanted to know if it were possible to stop the cells from breaking down bone.

Both questions about cell communication are fundamental to my research into bone strength and how it changes under certain circumstances, such as with aging or in microgravity. The answers are pivotal for long duration living in space, whether aboard the International Space Station or future missions. We’re trying to understand if space disrupts the communication between cells, whether this miscommunication is responsible for reducing the strength of bone and whether we can prevent this decline in strength by overriding this perturbed cellular communication.

You may have read about the findings from the first 50 years of bone research in space, compiled by my colleague Scott M. Smith, Ph.D., and his team. With Smith’s biochemical data we can get an idea of how cells are responding to the spaceflight environment—which cells are stimulated, which are suppressed or un-responsive. More importantly, we can try to figure out why this is happening—that is, are the signals that turn cells on or off not being produced or not being received? Pharmaceutical companies, for example, are particularly interested in this topic. The answer may help them develop medications for patient use on Earth. So, by refining our understanding of how current countermeasures work in space, at the cellular level, we might advance treatments for future space explorers, as well as Earth dwellers.

My research is an extension of Smith’s results. So far, our research suggests to us that the right combination of nutrition and specific types of exercise—can reduce the loss of bone mass in astronauts. What we still need to understand is whether the bones protected by the combined effects of diet and resistive exercise in space are as strong as they were before spaceflight.

My training in bone research was in histomorphometry; simply, it means that I measured bone tissue. I measured the amount of newly-formed tissue, I counted the number of cells, I calculated the rates of bone formation, I measured cellular activity. So while biochemistry helps researchers surmise why and how changes in a bone’s mass are occurring in microgravity, bone histomorphometry helps us understand the cellular activity that change bone tissue. The result of these changes—by different cells, on different surfaces—can end up reshaping the structure of bone.

Since the bone structure is a contributor to bone strength, I think it’s really important to understand how bone strength changes with spaceflight—not just how bone mass or bone cells change. After all, NASA research tries to solve potential problems in space by asking: Are astronaut’s bones strong enough to do the operations of a mission without fracturing? Will exposure to spaceflight cause fractures to occur earlier in an aging astronaut after he/she returns to Earth?

Research that describes how living in space changes bone cell signaling, bone mineral and bone structure helps us to understand how space may be changing the strength of bone. But, these research tools require looking at bone tissue extracted from animals or in biopsies from test subjects—not a very attractive test to spin-off for an Earth-based doctor.

So, in Earth-based medicine, bone clinicians use an x-ray-based technology to measure the amount of bone minerals in an image of bone, without having to remove any bone tissue from the body. But those measurements are no longer sufficient for understanding whether or not a bone will fracture. A previous flight study used a research technology called QCT to measure bone mineral in different astronauts’ hip bones before and after spaceflight. The study then used a computational tool that engineers developed to test the integrity of complex structures, like bridges or cars. This tool estimates the force of the load that would cause the hip to fracture by applying a “virtual” mechanical load to the computerized model of the hip until the structure “fails.” We are hoping to use these estimates to figure out which tasks performed by an astronaut could lead to a hip fracture.

My background in animal studies tells me that different countermeasures affect different types of bone cells in different locations of the hip. When countermeasures affect the very dense cortical bone shell differently from the spongy, more porous trabecular bone on the inside, then the overall structure of bone changes and the strength of the bone may change as a result. I like to remind people that you can’t “feel” when your bones are weakened. If we could compare hip bone strength with the loads of physical activity, we might be able to detect when an astronaut might overload his or her bones, even after return to Earth.

NASA astronaut Barry "Butch" Wilmore setting up the Rodent Reseach-1 Hardware in the Microgravity Science Glovebox aboard the International Space Station. (NASA) — NASA astronaut Barry “Butch” Wilmore setting up the Rodent Reseach-1 Hardware in the Microgravity Science Glovebox aboard the International Space Station. (NASA)

This is why I proposed a study called Hip QCT, which is building on results of multiple flight studies. It’s like a jigsaw puzzle. With biochemical tests, we can monitor the hormones that induce the production of protein signals, the signals that stimulate cellular activity, and the by-products that reflect the formation and the degradation of bone tissue. I hypothesized that Hip QCT can capture the difference between mechanical countermeasures, such as exercise, and biochemical countermeasures, like nutrition or pharmaceutical agents, because of its ability to detect changes in bone structure. In the end, we want to describe how countermeasures during spaceflight change the strength of the hip by changing the structure of hip bone.

There’s a problem with QCT as a test, however, as there is an issue with greater radiation exposure. One hip scan, for example, amounts to two to six days on the space station, depending on the age and sex of the astronaut. We’re trying to demonstrate the value of collecting QCT data and estimating hip strength. Someday we hope to detect the effects of spaceflight in astronauts on the connectivity of trabecular bone as observed in our mouse studies. We are investigating some emerging technologies which do not require any radiation. With these collective measures, we are hoping to prevent fractures by estimating which physical activities may cause bones to be overloaded during a mission or even after return to Earth.

Micro-computed tomography bone density imaging shows ground mice (G) with highly connected, dense spongy bone structure, flight mice (F) with less connectivity and flight mice treated with a myostatin inhibitor (F+D) on STS-118 that appear to have bone structure unaffected by microgravity. (Bioserve)

Because we have an aggressive schedule for decision-making, NASA puts innovative approaches on a fast track for application. If NASA can clearly demonstrate the benefits of these innovations to protect astronaut health and performance, then the translation of these novel predictive capabilities may enhance the earlier diagnosis of osteoporosis in people here on Earth.

This was really brought home at last year’s meeting of the American Society for Bone and Mineral Research where I hosted a workshop. It was standing room only! Everything we learn about bone loss and rebuilding in space can also provide insights to the numerous scientists studying osteoporosis and its treatment on Earth.

In order to monitor changes in skeletal health that could lead to fracture, we need to leverage new and innovative ways of evaluating changes to bone tissue and the impact on bone strength. There’s a whole new generation of technologies and scientists to look into these questions. I am excited to see what we discover as we work together for better bones!

Jean Sibonga, Ph.D., lead scientist in the discipline of bone research for the Human Research Program at NASA’s Johnson Space Center in Houston, TX (NASA) — Jean Sibonga, Ph.D., lead scientist in the bonediscipline of bone research for the Human Research Program at NASA’s Johnson Space Center in Houston, TX (NASA)

Jean Sibonga, Ph.D. is the lead for bone discipline in the Human Research Program at NASA’s Johnson Space Center in Houston. Sibonga received her B.S. in Chemistry and English from the University of Puget Sound in Tacoma, Washington. She later earned her Ph.D. in Biochemistry from Loma Linda University, California. Sibonga has more than 30 years of research experience in bone cell biology & physiology at such institutions as the Jerry L. Pettis VAMC, Loma Linda, CA; NASA Ames Research Center; Harvard School of Dental Medicine; and the Mayo Clinic, Rochester, MN.