Space flight is one of the most extreme conditions encountered by humans. Advances in Omics methodologies (genomics, transcriptomics, proteomics, and metabolomics) have revealed that unique differences exist between individuals. These differences can be amplified in extreme conditions, such as space flight. A better understanding of individual differences may allow us to develop personalized countermeasure packages that optimize the safety and performance of each astronaut. In this review, we explore the role of “Omics” in advancing our ability to: (1) more thoroughly describe the biological response of humans in space; (2) describe molecular attributes of individual astronauts that alter the risk profile prior to entering the space environment; (3) deploy Omics techniques in the development of personalized countermeasures; and (4) develop a comprehensive Omics-based assessment and countermeasure platform that will guide human space flight in the future. In this review, we advance the concept of personalized medicine in human space flight, with the goal of enhancing astronaut safety and performance. Because the field is vast, we explore selected examples where biochemical individuality might significantly impact countermeasure development. These include gene and small molecule variants associated with: (1) metabolism of therapeutic drugs used in space; (2) one carbon metabolism and DNA stability; (3) iron metabolism, oxidative stress and damage, and DNA stability; and (4) essential input (Mg and Zn) effects on DNA repair. From these examples, we advance the case that widespread Omics profiling should serve as the foundation for aerospace medicine and research, explore methodological considerations to advance the field, and suggest why personalized medicine may become the standard of care for humans in space.

The environment of space provides many challenges to the human physiology and therefore to extended habitation and exploration

Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus that causes varicella upon primary infection, establishes latency in multiple ganglionic neurons, and can reactivate to cause zoster. Live attenuated VZV vaccines are available; however, they can also establish latent infections and reactivate. Studies of VZV latency have been limited to the analyses of human ganglia removed at autopsy, as the virus is strictly a human pathogen. Recently, terminally differentiated human neurons have received much attention as a means to study the interaction between VZV and human neurons; however, the short life-span of these cells in culture has limited their application. Herein, we describe the construction of a model of normal human neural progenitor cells (NHNP) in tissue-like assemblies (TLAs), which can be successfully maintained for at least 180 days in three-dimensional (3D) culture, and exhibit an expression profile similar to that of human trigeminal ganglia. Infection of NHNP TLAs with cell-free VZV resulted in a persistent infection that was maintained for three months, during which the virus genome remained stable. Immediate-early, early and late VZV genes were transcribed, and low-levels of infectious VZV were recurrently detected in the culture supernatant. Our data suggest that NHNP TLAs are an effective system to investigate long-term interactions of VZV with complex assemblies of human neuronal cells. Varicella-zoster virus (VZV), the alphaherpesvirus that typically causes childhood chickenpox and shingles in adults, becomes latent in neurons, thus remaining in the body for a lifetime. Unfortunately, few models are available to study the establishment of VZV latency since the virus infects only humans and establishes persistent infections and latency only in neurons, a slowly proliferating, short-lived cell in culture. We have successfully maintained normal human neural progenitor cells (NHNP) in tissue-like assemblies (TLAs) in 3-dimensional (3D) cultures for up to 6 months. The 3D NHNP TLAs show some characteristics as those found in the human trigeminal ganglia, the site of VZV latency. NHNP TLAs infected with VZV remain viable for 3 months during which time VZV DNA replicates and remains genetically stable, virus genes are transcribed, and infectious VZV is sporadically released. The ability to maintain VZV infected NHNP cells in culture for extended times provides the unique opportunity to study the molecular interactions between this important human pathogen and neuronal tissue to an extent previously unattainable.

The next major steps in human spaceflight include flyby, orbital, and landing missions to the Moon, Mars, and near earth asteroids. The first crewed deep space mission is expected to launch in 2022, which affords less than 7 years to address the complex question of whether and how to apply artificial gravity to counter the effects of prolonged weightlessness. Various phenotypic changes are demonstrated during artificial gravity experiments. However, the molecular dynamics (genotype and molecular phenotypes) that underlie these morphological, physiological, and behavioral phenotypes are far more complex than previously understood. Thus, targeted molecular assessment of subjects under various G conditions can be expected to miss important patterns of molecular variance that inform the more general phenotypes typically being measured. Use of omics methods can help detect changes across broad molecular networks, as various G-loading paradigms are applied. This will be useful in detecting off-target, or unanticipated effects of the different gravity paradigms applied to humans or animals. Insights gained from these approaches may eventually be used to inform countermeasure development or refine the deployment of existing countermeasures. This convergence of the omics and artificial gravity research communities may be critical if we are to develop the proper artificial gravity solutions under the severely compressed timelines currently established. Thus, the omics community may offer a unique ability to accelerate discovery, provide new insights, and benefit deep space missions in ways that have not been previously considered.

Spaceflight occasionally requires multiple extravehicular activities (EVA) that potentially subject astronauts to repeated changes in ambient oxygen superimposed on those of space radiation exposure. We thus developed a novel in vitro model system to test lung cell damage following repeated exposure to radiation and hyperoxia. Non-tumorigenic murine alveolar type II epithelial cells (C10) were exposed to >95% O₂ for 8 h only (O₂), 0.25 Gy ionizing γ-radiation (IR) only, or a double-hit combination of both challenges (O₂ + IR) followed by 16 h of normoxia (ambient air containing 21% O₂ and 5% CO₂) (1 cycle = 24 h, 2 cycles = 48 h). Cell survival, DNA damage, apoptosis, and indicators of oxidative stress were evaluated after 1 and 2 cycles of exposure. We observed a significant (p < 0.05) decrease in cell survival across all challenge conditions along with an increase in DNA damage, determined by Comet analysis and H2AX phosphorylation, and apoptosis, determined by Annexin-V staining, relative to cells unexposed to hyperoxia or radiation. DNA damage (GADD45α and cleaved-PARP), apoptotic (cleaved caspase-3 and BAX), and antioxidant (HO-1 and Nqo1) proteins were increased following radiation and hyperoxia exposure after 1 and 2 cycles of exposure. Importantly, exposure to combination challenge O₂ + IR exacerbated cell death and DNA damage compared to individual exposures O₂ or IR alone. Additionally levels of cell cycle proteins phospho-p53 and p21 were significantly increased, while levels of CDK1 and Cyclin B1 were decreased at both time points for all exposure groups. Similarly, proteins involved in cell cycle arrest was more profoundly changed with the combination challenges as compared to each stressor alone. These results correlate with a significant 4- to 6-fold increase in the ratio of cells in G2/G1 after 2 cycles of exposure to hyperoxic conditions. We have characterized a novel in vitro model of double-hit, low-level radiation and hyperoxia exposure that leads to oxidative lung cell injury, DNA damage, apoptosis, and cell cycle arrest.