Area Drugs Brings Researchers into the Second Area Age

Imagine this scenario: A researcher prepares for a day in the field. They start their day with a daily preventative medication and then don their protective, pressurized suit. They may wear a dosimeter to monitor their radiation exposure. As they leave the confines of the base with its thick shielding, they look across the dusty, oxidized surface of Mars, their home for the next two years.

A crewed mission to the red planet to study its history and potential for human settlement is increasingly becoming less science fiction and more of a future possibility. The ability to put boots on the ground of Mars can greatly increase scientists’ ability to study the foreign world. In June 2023, a four-person team began a 378 day simulated mission to Mars, where they practiced working with robots and limited resources and maintaining their habitat and hygiene.

A journey to Mars will be preceded by returning to the moon for an extensive period to prepare humans for life further from Earth and develop the technology to succeed in this endeavor; NASA outlined a four-phase plan for a lunar return under the Artemis program that includes the development of long-term colonies that researchers would inhabit akin to the current international space station (ISS). These lunar bases will allow researchers to study the moon’s surface more in depth and develop resource extraction technologies.

Additionally, manufacturing in space, in the absence of gravity, offers advantages that cannot be easily met on the Earth’s surface. For example, stem cells produced for regenerative medicine more potently produce immune suppressive cytokines, proteins crystallize more uniformly, and bioinks, semiconductor electronics, and fiber optic glasses form better.^1-5 In addition to advancing technologies to use resources available on the moon, these sectors offer the potential for building a lunar economy.^6,7

Although researchers have been able to study how the human body fares in space, most of this involves exposures in low-Earth orbit, where there is still some protection against the harsh radiation of outer space. Journeying to the moon, or farther to Mars, will involve significantly greater exposures.

“We don’t know how a human being will do in that environment. So we are essentially sending people on a mission to Mars, sending people on a mission to the moon, and don’t really, really know for sure how they’re going to react and also the differences between individuals and how they’re going to react to the space exposure of radiation,” said Dorit Donoviel, a biologist and the executive director of the Translational Research Institute for Space Medicine (TRISH) at the Baylor College of Medicine.

Mitigating the Damaging Effects of Space

Since November 2, 2000, at least one person has lived on the ISS. However, the longest period of time a single person has lived aboard any space station to date has been 438 days—Valery Polyakov holds this record for living on the space shuttle Mir between 1994 and 1995. From these decades of human space-residence, researchers have learned a lot about the effects of space on the human body.

“Every physiological system within the human body is impacted by space,” said Fathi Karouia, a space life scientist at the Blue Marble Space Institute of Science and NASA Ames Research Center. With a fraction of Earth’s gravity, outer space strains the cardiovascular system.^8,9 Muscles and bones lose mass and density.^10,11 Even orbiting Earth, astronauts are exposed to more radiation, which stresses cells and alters DNA expression.^12-15

Astronauts aboard the ISS mitigate some of these effects through exercise and protective shield reinforcement to block harmful solar radiation.^16-18 Only 250 miles above Earth, they are also still protected by the planet’s magnetosphere from galactic cosmic radiation, consisting of heavy, high-energy elemental ions.

It seems like by studying what’s happening in space, maybe we can also leverage whatever we found for us on Earth.

—Fathi Karouia, Blue Marble Space Institute, NASA Ames Research Center

The moon, however, is well beyond this protective field. Although 24 people have traveled to our celestial satellite and orbited it, researchers don’t know what the long-term effects of extended space habitation would be. Understanding these risks and how to mitigate them will be imperative to the future of human space exploration.

On Earth, researchers used particle accelerators to replicate some types of galactic cosmic radiation that astronauts may experience in outer space to glean insights into how these may affect organisms. In mice, these beams increased kidney dysfunction, promoted cancer development, and impaired cognitive functions.^19-23

Shielding against this type of space radiation is difficult because the heavy ions penetrate material further than solar radiation. They can also crash into atoms like lead and cause the emission of dangerous secondary particles. Karouia said that, in this scenario, the best shielding to use is hydrogen-dense materials, like water. Hydrogenated composite carbon fiber and plastic materials have also shown promise.²⁴

However, no barrier is ever perfect, so researchers are also considering pharmaceutical interventions to mitigate the effects of radiation. “There’s a lot of different approaches that one can take,” Donoviel said. Previously, TRISH funded several projects tackling radiation mitigation with nucleotide-based therapeutics and different gene therapy strategies.²⁵ Others have considered various antioxidants and repurposed drugs for radiation protection.^26,27

Although several possible mitigation strategies exist, the reality of a drug for future astronauts will face the most challenging gauntlet. “If you’re giving a drug to a healthy human being to prevent a disease or prevent a problem from radiation, it’s got to be super safe,” Donoviel said. “That raises the bar really high on what you would give as a radiation mitigator.”

These potential interventions not only have to be worth their physical risk, but they will also be exposed to the same radiation challenges as the astronauts themselves, so their stability is paramount. “The other concern that they have is, on a Mars mission, think about how many pills you would have to have for the crew. And so even just the logistics of bringing that much medication, you got to be sure that that stuff is going to work and is worth trading out bringing more food, for example, more fuel, more water, more oxygen, more different types of supplies,” Donoviel explained.

For this reason, another TRISH-funded scientist is exploring the potential of utilizing bacteria as in-resident drug factories. Donoviel said, “What we’re thinking about is actually creating a bespoke cocktail of microbes that will sit in the gut and essentially elute out all the juicy, good nutritional things that we think will help a human protect themselves from some of these assaults from radiation exposure.”

Biological Models Take Humans to Space Without the Risk to the Body

Any mitigation measures will have to endure rigorous testing prior to implementation. However, since animals don’t replicate human biology and researchers don’t know how human cells respond to extended microgravity and space radiation, scientists are developing novel ways to put cell models into space ahead of humans.

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Masafumi Muratani, a molecular biologist at the University of Tsukuba, and his team previously observed evidence of mitochondrial stress after studying cell-free RNA from six astronauts aboard the ISS for 120 days.²⁸ Similar to other studies, they showed an overall trend of increasing cell stress during space exposure that returned to baseline after the astronauts returned to Earth. However, they also saw variability in the extent of these effects between these participants. This got Muratani interested in identifying the genes involved in high and low responders and proposing individualized intervention strategies.

In a 2024 analysis work group symposium, Muratani outlined his team’s plan to leverage induced pluripotent stem cells from people traveling to space to expose these to simulated space environments. “We can potentially assess how an individual astronaut will react in a real space mission before the mission, using the cell model as a surrogate of the reaction of the human,” he said.

Muratani’s goal is to compare the effects and changes seen in the in vitro models to cells exposed as part of an organism to determine if the cell-based models accurately predicted the responses to space. Additionally, with a large enough population of cell-based models, researchers could identify genotypes associated with sensitivities or resistance to different conditions, according to Muratani. These data could then be used to train artificial intelligence models to anticipate an individual’s response to space and propose mitigation strategies.

Muratani believes that these cell-based models can help prepare astronaut teams in advance of space missions further beyond Earth. “It doesn’t mean we are going to use this for the selection of astronauts,” he said, adding that instead, it would provide useful information about what potential risks individuals may have.

In contrast to simulating the space environment beyond Earth, researchers at TRISH are working to put cell models into outer space with the help of organ-on-a-chip technology.²⁹ Advances in automation could even make it possible for these researchers to conduct molecular assays, including testing mitigation candidates, on the models in the real space environment.³⁰

“The crazy idea we were building towards is actually to create a completely non-human tended payload that we will put in deep space with your cells,” Donoviel said. “Then you would basically remote down the data that will be analyzing what’s happening to your organs-on-a-chip longitudinally over time.”

Indeed, researchers like Karouia have been thinking about autonomous science for more than a decade. He and his team built the Gene Expression Measurement Model (GEMM), a miniature, automated instrument for bacterial nucleic acid extraction and measurement.³¹ “The idea there is to have [a] space like similarly to what it is here on Earth, like a laboratory with all those different multiomics-based analytical tools,” he explained.

Not only will automated technologies like GEMM expedite research on the ISS and help TRISH researchers study the effects of space on organ systems, but these types of instruments will be invaluable to space research beyond Earth. “If you’re planning to have a mission which will be going to Mars, it needs to be independent, and therefore you need to rely on in situ capabilities to be able to monitor the environment, to be able to monitor the health of the crew, and to be able to do science,” Karouia said.

Bringing Space Advancements Back to Earth

While all of these teams are helping to bring humanity into the second space age, the technology and knowledge that they create will also be beneficial to life on Earth.

For example, Karouia said that the miniaturization and microfluidic technology that enables instruments like GEMM to function could easily be applied to similar systems that could be used in resource-limited settings on Earth. “People actually underestimate the number of applications that they are using in daily life that actually were initially developed in space,,” he added.

“Learning how different people, and particularly those on the ends, the ones that are super sensitive and super resistant, are repairing quickly in response to a high radiation exposure, is going to give us insights about resisting cancer or resisting other types of stressors in the body, or even if you’re a cancer patient receiving radiation therapy protecting your healthy, normal tissues from the damaging effects of the radiation that’s killing the tumor,” Donoviel said.

The biological effects of space seen in existing astronaut data, such as altered gene expression, oxidative stress, and inflammation, also closely resemble those changes seen in aging and neurodegenerative diseases.³² “It seems like by studying what’s happening in space, maybe we can also leverage whatever we found for us on Earth,” Karouia said.

We can potentially assess how an individual astronaut will react in a real space mission before the mission, using the cell model as a surrogate of the reaction of the human.

—Masafumi Muratani, University of Tsukuba

Other systems that are of immediate concern for agencies like NASA include cognitive and cardiovascular impairments. Since both problems could emerge during a long-term mission to Mars, researchers will be considering interventions and mitigation strategies for these so that astronauts can remain fit for their far away work. “What’s cool about all this is, if we can solve it, we can solve all of this, we can actually really translate to how to make people more resilient here on Earth when they’re exposed to various stressors,” Donoviel said.