Man’s fascination with space predates the first space shuttle launch or human footprints on the moon. Yet, sustaining human life in space requires creating a conducive environment and equipping the body with vital resources—such as pharmaceutical drugs—to help withstand the consequences of unique extraterrestrial stressors not experienced on Earth.
The specific spaceflight properties human visitors encounter demand special strategies to resist environmental side effects and treat emergent situations and chronic illnesses. Treatment modalities used on Earth do not always extrapolate to the universe. Spaceflight alters drug integrity and how the human body reacts to it—even in the case of precision medicine. Based on a growing body of data, some experts believe that pharmacogenomics-guided spaceflight is the foundation of precision medicine, a feature that they believe will enable long-term human habitation on the Moon.
Professor
Weill Cornell Medicine in New York
“There are many genes that are related to pharmacogenomics that change during spaceflight, and so this is an area of medical research that will be key for upcoming long-duration missions,” said Christopher Mason, PhD, a professor of genomics and computational biomedicine at Weill Cornell Medicine in New York.
Mason’s research is important as advancements in aerospace pharmacogenomics have largely stalled today, plagued by hurdles to space-flown pharmaceutical data such as limited access, data privacy concerns, interoperability, and reproducibility. The aerospace community has responded by enhancing interdisciplinary collaboration to produce a digital network of databases maintained by space industry stakeholders. Mason and his colleagues have contributed to these efforts by compiling data from publicly available repositories. His team’s efforts have also helped support their own research interests.
Microgravity places the body under unique stress, causing health challenges
Before uncovering how spaceflight impacts pharmacogenomics, one must first understand how the body responds to spaceflight. The unique stressors the human body encounters in space cause it to respond in some unusual ways. These characteristics make medicine, pharmacogenetics, and even cancer behave differently in the extraterrestrial setting.
Perhaps the most commonly known extraterrestrial side effect is a lower gravitational pull called microgravity. Microgravity describes the extent to which acceleration affects an object in outer space. Because space exerts a significantly lower gravitational pull compared to Earth, microgravity is commonly called “zero gravity” (0g). However, at 1×10-6g, the colloquial phrase is slightly misleading, according to the NASA website.
As for specific effects, previous research conducted in models both in space and on Earth has shown that microgravity alters proliferation, migration, adhesion, survival, and apoptosis in human cells. The altered gravitational environment also affects the cytoskeleton structure, focal adhesion, the extracellular matrix, and growth factors.
On a larger scale, some long-term health issues associated with extended space travel manifest as immune system dysregulation and impaired wound healing. More notably, astronauts who spend months in space wrestle with muscle atrophy, bone loss, and potential cardiovascular problems. To counter these problems, astronauts exercise for up to two hours a day to help strengthen the heart and bones; they also take medications such as alendronate to counter bone density, commonly prescribed to treat Earth-dwelling men with osteoporosis and postmenopausal women who either have osteoporosis or are at risk for it.
How does spaceflight alter pharmacogenetics?
“The most critical genes for spaceflight-guided pharmacogenetics are likely those which most impact processing of drugs for inflammation and immune function as well as those that regulate sleep, since they are very common,” said Mason.
Examples might include genes that metabolize the sleep-fighting drug modafinil, sleep-inducing zolpidem, and muscle relaxant scopolamine—all drugs commonly used during space assignments.
It is also worth noting that spaceflight upregulates GCLC and GGTI, which are genes that stimulate glutathione activity. Known as the “master antioxidant,” glutathione plays several important roles in the liver, like activating various drugs. However, in this case, its upregulation suggests an increased response to oxidative stress.
For these reasons, exploring genetic mutations in the liver’s drug-metabolizing CYP450 enzymes is a natural progression. Not only is drug-related inhibition or induction of CYP450 enzymes responsible for most drug–drug interactions, but inhibiting or inducing of one of these enzymes with one drug can simultaneously inhibit the activity of another drug processed by the same enzyme. In addition, while a previous study has shown that spaceflight-induced proteomic activity downregulates CYP450 activity by 50%, no existing studies have evaluated whether pharmaceutical drugs contribute to decreased CYP450 activity.
recent computer science graduate
Cornell University
Of the 218 unique drugs logged in their database, Mason and colleagues have identified 190 interactions with 772 distinct genes, accounting for a total of 2,318 interactions.
“Searching for mutations in drug metabolizer genes active in the liver is a first step towards personalized pharmacogenetics in space,” said Theodore Maximillian Nelson, recent computer science graduate of Cornell University and lead author of the study with Mason and his colleagues.
They concentrated on spaceflight-induced shifts, which helped them identify a new method of identifying the most impactful changes in absorption, distribution, metabolism, and elimination parameters. Pharmacogenetic activity can influence these properties.
Once ingested, spaceflight alters pharmacokinetic activity in the following ways. Delayed gastric emptying and altered microbial community structure accelerate drug degradation. Meanwhile, several factors decrease drug absorption. These include faster intestinal transit, shift-induced hypoperfusion of the gastrointestinal tract, as well as expression of gastrointestinal transporters and enzymes. Through their investigation, Nelson, Mason, and colleagues found that a certain group of solute transporter genes, namely SLC19A1, SLC23A, and SLC2A2, contribute to gastrointestinal cancer.
Other genes seemed to remain stable.
“CYP1B1, CYP2D6, CYP3A43 were differentially expressed within the selected spaceflight study, suggesting that the remaining CYP450 are less affected,” Nelson said. “Nevertheless, while we do not have available human hepatic transcriptomic data, instead we analyze human cardiomyocyte transcriptomic data.”
Based on this information, Nelson described their findings as “rather preliminary.”
Spaceflight alters post-absorption drug metabolism of both orally ingested and injected drugs in many ways. The characteristics vary as much as the individual responses.
For example, spaceflight shifts fluid dynamics. This environment drives fluid toward the head, which increases urination and natriuresis, or sodium excretion through the kidneys, while hindering lymph flow and lymphatic drainage. Astronauts may find themselves less thirsty than usual despite losing more fluid through their lungs and skin in space than on Earth.
Space-bound individuals will also experience a redistribution of fluid from plasma to extracellular volume and subsequently, from extracellular volume to intracellular volume. In addition, unlike on Earth, microgravity decreases volume and drug distribution while increasing plasma concentration. Additional extraterrestrial changes that affect drug behavior are altered binding expression, plasma concentration, and hepatic blood flow.
Space laboratory research could give rise to a new class of cancer therapeutics
Although not directly correlated with pharmacogenomics, another group of researchers at biotechnology startup MicroQuin have uncovered an element of microgravity that could very well lead to breakthrough cancer treatment. The Cambridge, Massachusetts–based firm made an important discovery while growing 3D prostate and breast cancer cell cultures at the International Space Station (ISS) National Laboratory orbing 250 miles above Earth.
MicroQuin found that targeting a specific protein called TMBIM6 that regulates the intracellular environment and defines cell structure can kill cancer cells. MicroQuin researchers developed a small molecule therapeutic that binds to TMBIM6, disrupting the intracellular environment in the process. When the small molecule complexes with TMBIM6 and prevents it from functioning, cancer cells die. In addition, not only is this novel treatment only activated in cancer cells, but researchers found it to work in all kinds of cancer, with potential uses in traumatic brain injury, neurodegenerative diseases, and viral infection.
“Discoveries in space aren’t just achievements on a space station,” said Amelia Smith, ISS National Lab science communications manager in a recent press release. “They are breakthroughs that could lead to a world where families like mine are filled with hope instead of fear in the face of cancer and other devastating diseases.”
MicroQuin could not be reached for comment.
Can artificial intelligence help predict drug responses in space?
Despite having compiled the largest catalog of spaceflight medicine within the current scientific literature, Nelson and his colleagues’ database, combined with pre-existing repositories, is not large enough to train a predictive artificial intelligence (AI) model for drug response at present. However, two other databases have amassed volumes nearly large enough to clear the AI threshold. Space Omics and Medical Atlas (SOMA) is a collaborative project uniting the efforts of more than 25 institutions around the world and collating integrated data and sample repositories for cellular, multi-omic, and clinical research profiles. Nelson and Mason compared their findings to these databases.
“We did not find evidence of astronaut-specific pharmacogenetic profiles being utilized to predict responses, which is becoming more common on Earth in drug prescription,” Nelson said.
Current research highlights the need for greater investigation into other “omics”
Spaceflight-induced immunosuppression has prompted scientists to investigate potential pharmacological treatments, including novel drug therapies. These explorations have increased the risk of polypharmacy but have borne no relationship to genotype profiles. Interestingly enough, the breadth of impact spans beyond drug-metabolizing genes to encompass any known space-induced, drug-gene interactions. In addition, various factors such as epigenetic markers, genotype, transcriptomic upregulation or downregulation, post-translational tagging, and post-transcriptional modification may be involved.
Nelson and his colleagues believe that space genes serve as the primary drivers of individualized transcriptomic responses. The extraterrestrial frontier can expand research to advance research and medicine, especially in the case of proteins.
“For protein crystallization, these space flight studies can allow for the formation and study of proteins in a manner which could not be possible on earth,” Nelson said. “There are research and development case examples where drug manufacturing has been performed in space with greater efficacy because the microgravity environment is more permissive to the formation of complex 3D structure for processes such as biofilm formation and protein crystallization.
“A comprehensive investigation of spaceflight-related pharmacogenetics with pharmacokinetics and biological settings could elucidate novel mechanisms of action for drugs.”
Nelson, Mason, and colleagues cite double reporting as a study limitation. They also noted that labeling their current research as “pharmacogenomics” may be somewhat of a misnomer, as their research focused heavily on transcriptomics. However, Mason and Nelson envision spaceflight pharmacogenomics as amassing a breadth that incorporates every viable mechanism affecting drug behavior that could one day be quantified through high-throughput analysis.
Frieda Wiley, PharmD, is an award-winning medical writer, best-selling author, speaker, and pharmacist who has written for O, The Oprah Magazine, the National Institutes of Health, American History, Pfizer, Merck, AstraZeneca, and many more notable organizations.
