Studies in Free Fall

ON THE FLOOR OF PAOLA DIVIETI PAJEVIC’S OFFICE at Massachusetts General Hospital sits a large silvery suitcase that holds precious cargo: a set of minimalist equipment and electronics for conducting a cell biology experiment in space. Sometime in 2014, this payload will journey more than 200 miles above the earth to the International Space Station, or ISS. Inside the case, cells will grow on scaffolds in several cylinders called bioreactors.

But Divieti Pajevic’s research doesn’t focus on space. The biologist wants to unravel the mechanisms through which bone cells called osteocytes sense and respond to mechanical forces. It’s clear that mechanical stimulation causes bones to grow, and that lack of it leads to bone loss—and weightlessness in space takes away most stimulation, leaving astronauts’ bones at risk. But how do physical forces actually change cells’ biochemistry? The answers, derived partly from this experiment, might help create better therapies for osteoporosis, a condition of naturally occurring bone loss afflicting millions.

Divieti Pajevic’s work is supported by a program recently launched by the National Institutes of Health that gives biomedical researchers access to the ISS to study important questions that can be answered only in space. She wants to discover how cells behave when they’re in free fall, with all mechanical forces removed. That’s what happens to astronauts in orbit who experience weightlessness—known as microgravity (there’s a small amount of gravity in an orbiting spacecraft).

When her osteocytes return from space, Divieti Pajevic will analyze the activity of their genes, with particular focus on a gene called sclerostin, which interferes with bone formation. In the meantime, in her earthbound lab, other bioreactors are rotating at a speed designed to mimic microgravity, but because the cells still experience some forces, it’s not clear whether the bioreactor precisely captures what happens in space. Hence the experiment in real weightlessness. “For us it would be a proof of principle that we really are simulating microgravity,” she says.

Before space travel, it was difficult to study or even imagine life without gravity. It keeps us firmly planted on the ground, gives our movements something to resist and creates an orientation of up and down. As humans began spending extended periods in space, however, it became clear that weightlessness interferes with the health of bones, muscles, the cardiovascular and immune systems, and our sense of balance.

Beginning in 2000, the ISS complex, as long as a football field and containing the equivalent of a large house in habitable space, has hosted more than 200 crew members who have spent weeks or months in weightlessness. Studying their health has provided insights into the effects of microgravity, and the ISS now functions as a national laboratory. Some research has focused on keeping astronauts healthy, but other work, including Divieti Pajevic’s new study, has intriguing connections to health problems on earth—not only osteoporosis but also paralysis, balance disorders, immune deficiencies and aging.

THE MOST OBVIOUS EFFECT OF MICROGRAVITY IS SENSORY. Vision tells us where up and down are, our sense of touch registers contact with the ground, and our proprioception—an internal sense of the body’s position—provides feedback about our own movements. These signals are coordinated so seamlessly that we have little awareness of them. But in weightlessness, that system is disrupted.

Motion sickness, among the first health problems most astronauts experience, is thought to stem from conflicting sensory signals. The brain, ever adaptable, helps most people acclimate within a few days, says Scott Wood, a scientist for NASA’s Human Health and Performance Directorate. But they must find new ways of moving. On earth, we work to maintain a stable center of gravity; in space, people have to learn to initiate movement by pushing off objects.

Reconditioning experts help crew members returning from space to get back in sync with when they are moving relative to gravity again. Simply tilting the head back or stooping to pick up an object can be difficult during the first few hours. Astronauts participate in postflight reconditioning that starts with movements and balancing postures that are extremely simple and works toward others progressively more complex.

According to Wood, similar types of exercises also help rehabilitate nonastronauts who have balance disorders because of disease, surgery or normal aging. In each case, he says, “the goal is to learn what your senses will tell you during different motions so that you can improve coordination.”

Without gravity, fluids shift to the chest and head. Richard Hughson, a scientist at the University of Waterloo’s Research Institute for Aging in Ontario, has studied the impact that months on the ISS have on blood vessels in the brain. He found small differences in how astronauts’ blood vessels respond to changes in blood pressure and carbon dioxide levels—differences that might impair how the brain’s blood vessels respond to the challenge of gravity back on earth. Now Hughson is leading a study to determine whether being in space stiffens blood vessels, “something you normally see in aging,” he says.

Beyond the perceptible effects of weightlessness, more insidious changes occur. Astronauts risk decreased fitness, loss of bone density and atrophied muscles. Bone density measurements taken before and after stays on Russia’s Mir space station—occupied from the mid-1980s to the mid-1990s—showed astronauts losing 1.5% of bone mass from the hip each month they were in space.

Many earthbound conditions and processes, including aging, osteoporosis, paralysis and debilitation from stroke, can have similar effects—as can lack of exercise. “The sedentary lifestyle is so much like being inactive in space,” says Hughson, who notes that astronauts who don’t put intense effort into counteracting their weightlessness “show signs of accelerated aging.”

Yet while improving fitness in normal gravity may be straightforward, weightlessness poses special problems. “When you lift weights on the ground you also lift your body mass, but in space that’s not the case,” says Scott M. Smith, who leads NASA’s Nutritional Biochemistry Laboratory and has been involved in efforts to use diet and exercise to counteract the effects of microgravity. “You have to add that extra weight back in.”

A machine introduced in 2008, the Advanced Resistive Exercise Device (ARED), allows astronauts on the ISS to perform squats and dead lifts with as much as 600 pounds of resistance, to make up for gravity“s normal loads. A study Smith led, published last September in The Journal of Bone and Mineral Research, evaluated crew members who had used ARED and found that their bone density had largely been preserved. “Bone metabolism is always a balance between bone breakdown and bone formation,” Smith says. “During space flight, breakdown goes up and formation doesn’t change.” He believes the intensified exercise stimulated astronauts’ bones to rebuild fast enough to keep up with the accelerated breakdown.

But some problems remain. When Thomas Lang, professor in residence of radiology and biomedical imaging at the University of California, San Francisco School of Medicine, and colleagues evaluated astronauts a year after their flights, they found that while typical density measurements indicated that they’d recovered everything lost during microgravity, computed tomography showed that their bones were actually becoming bigger, not denser. Lang says this may be how bones recover from a loss in density. A similar phenomenon is seen in aging, when bones respond to density loss by growing larger.

BECAUSE PERFORMING CLINICAL STUDIES IN SPACE IS DIFFICULT  and the sample size is necessarily small, almost all space medicine research begins on the ground. In human studies, the most important model has been to put people to bed. When the body is kept parallel to the ground, it no longer must hold itself up against gravity. Studies have examined volunteers who have spent weeks or months in bed. Heavy resistance exercise helps protect bone in a manner very similar to the recent findings from space flight. Documenting these effects in space, as done recently, is always the critical test.

Researchers also use animals to model microgravity—for example, by suspending mice by their tails to take weight off their hind limbs. Mary Bouxsein, a researcher in the Orthopedic Biomechanics Laboratory at Beth Israel Deaconess Medical Center in Boston, has developed a model in which mice can move freely but are outfitted with small jackets attached to springs. “We can dial in the amount of loading they get by adjusting the spring,” Bouxsein says, which lets the researchers mimic different levels of gravity. “Even a small reduction in mechanical loading seems to harm bone and muscle,” says Bouxsein.

Bouxsein’s lab has tested an experimental osteoporosis therapy developed by Amgen and UCB to see how it performs in weightlessness. During the summer of 2011, her team, collaborating with researchers at the universities of Colorado and North Carolina, sent mice on NASA’s final shuttle mission. Some animals, which spent 13 days in microgravity, received the drug, an antibody to sclerostin now in human clinical trials. The drug not only prevented bone loss but also spurred new bone formation, suggesting that it can work even without normal loading on bones. Studies like this benefit not only the astronaut population but also clinical situations such as spinal cord injury, stroke and bed rest.

Exercise also helps astronauts prevent muscles from wasting away. Scott Trappe, director of the Human Performance Laboratory at Ball State University, says volunteers who have stayed in bed for 90 days “lose as much muscle as with 55 years of aging—almost 30% of muscle mass.”

Trappe has been working with NASA to determine how much of an astronaut’s exercise regimen should focus on muscles. “You don’t have to do very much as long as it’s good quality,” he says. Astronauts aboard the ISS now do intense weight lifting three times a week. Meanwhile, what he has learned in space and on the ground is showing how intense exercise can prevent muscle loss and frailty in aging—the other focus of his research.

The first direct evidence of another effect of space flight—on the immune system—came 40 years ago, when immune cells in astronauts returning from Skylab were found to have impaired responses. Millie Hughes-Fulford, director of the Hughes-Fulford Laboratory at the University of California Medical School and VA Medical Center in San Francisco, believes that determining the cause of this immunosuppression might help keep people healthy on long space flights and give insights into treating immune deficiencies on earth.

Hughes-Fulford, a former astronaut who flew on the space shuttle in 1991, believes weightlessness interferes with a cell’s cytoskeleton, which not only gives the cell its shape but also influences its biochemistry. In addition, cytoskeletal changes occur in older people, who often experience impaired immunity. “I think there might be a common cause,” Hughes-Fulford says, with microgravity mimicking some effects of aging. Supported by a grant from the NIH and NASA, she will send T cells to the ISS to study microgravity’s effects on levels of microRNAs, which help regulate cell function. The goal is to identify the cellular origins of altered immune responses in space; that, in turn, could suggest targets for therapies that boost immunity.

But there’s another side of compromised immunity in space: In weightlessness, pathogens tend to become more dangerous. Cheryl Nickerson, a microbiologist at Arizona State University, and her collaborators have shown that Salmonella bacteria cultured in microgravity are more virulent. That finding suggests that pathogens could pose particular risks on long space flights, such as a journey to Mars. But when bacteria ramp up their virulence, the immune system may mount a more forceful response, and it might be possible to exploit that tendency to help ward off disease. Nickerson collaborated with Roy Curtiss III, a colleague at Arizona State who has created a genetically altered strain of Salmonella for a vaccine carrying a protective antigen against Streptococcus pneumonia. In summer 2011, they sent the vaccine to space to see whether microgravity can enhance its ability to promote a protective immune response.

Nickerson’s research highlights the sensitivity of microbes to mechanical forces. “The human body is basically a vessel of fluid moving dynamically at different forces,” she says. Working with mathematicians and engineers, Nickerson and her teams found that the forces that Salmonella experienced in a bioreactor were similar to the environment they would face in parts of a host’s digestive system. She believes such conditions switch on a genetic program that may help bacteria invade their hosts. Working in space, she says, may reveal entire classes of microbial genes and proteins that researchers haven’t been able to identify under normal conditions. “The environment of microgravity has a strong similarity to conditions that normal cells encounter here on earth,” she says.

But the future of space research is uncertain. Getting to the ISS has become trickier since 2011, when NASA’s shuttle program ended. The agency is working with private companies such as SpaceX and Orbital Sciences Corp. to plan flights to the ISS. Meanwhile, researchers are able to use Russian Soyuz spacecraft to get there, and Divieti Pajevic and Hughes-Fulford are slated to put experiments aboard SpaceX’s Dragon capsule.

The results of those ventures will help determine the future of research in space. The usefulness of that work is “the ability to take a system that has been in constant gravity and remove a variable,” says Hughes-Fulford. Taking away gravity offers a powerful way to unravel how many systems really work.