The need for a systems biology approach to develop personalized medicine programs for astronauts derives from two key convergent influences. First, there are vast molecular networks that interact dynamically to influence astronaut susceptibility to any specific environment or condition to which he or she is exposed. Second, there are a series of mission stressors that impact heavily upon the individual susceptibility of each astronaut. Whether one thrives within the space environment may be heavily dependent upon individual susceptibility, space environmental exposures, and whether the countermeasures deployed for an individual astronaut are sufficient to overcome these susceptibilities. By illustration, one can use DNA stability to explore these convergent influences.
Convergent effects of essential input deficits on DNA in space flight
DNA stability and DNA damage are among the key safety considerations in human space flight. Thus, we will use DNA stability here to establish a further premise that concomitant genetic variants and essential input deficits can aggregate to raise the risk of developing unstable DNA. On one hand, we have summarized data showing that one carbon deficits can lead to uracil accumulation in the nucleus, which may be followed by single- and double-strand DNA breaks. This alone represents a novel, but modifiable risk to DNA damage in space.
A further influence described herein is that of iron excess, which is associated with a common single nucleotide polymorphism (HFE). As noted previously, elevated iron can lead to the oxidation of DNA and RNA, adding yet another potential convergent variable to the space flight equation. A separate influence described herein is that of Mg, which is central to the activity of a wide range of DNA repair enzymes (base excision repair, MMR, etc.). As noted above, insufficient Mg has been associated with inefficient DNA repair, representing another novel, but modifiable risk to DNA instability in space.
One can quickly see the risk of a single gene variant or essential input deficit on DNA stability. The aggregation of two or more variants or essential input deficits represents an additional risk, which has not been properly characterized in astronauts. Under the limited scenario just described, one can envision a condition where altered one carbon metabolism (due to genetic variant and/or micronutrient deficit) leads to unstable DNA and DNA strand breaks, while a convergent deficit (Mg) leads to a reduced efficiency to repair such damage.
The phenomenon of two or more essential input deficits is plausible, given that one carbon deficits, declining Mg status, and altered iron metabolism have already been shown to exist within the flying astronaut population. But it also illustrates a greater premise asserted within this review. That is, there is a need to more broadly profile genotype, essential inputs, and metabolic networks in all astronauts, so as to begin to identify “off-target” influences that may bear upon individual susceptibility to the space environmental condition. This necessarily leads us to Omics approaches, which allow us to address the requisite complexity encountered in such analyses.
Translational Omics strategy for space
The purpose of applying broad analytics and personalized medicine in human space flight participants is not to reduce participation or to find biomarkers that will limit the ability of astronauts to participate in missions. The focus of personalized medicine in human space flight is to develop countermeasures that are individualized to each space participant. The goal of this individualized approach is aimed at improving all aspects of mission performance, as well as limiting adverse sequelae of prolonged space flight. The emergent participation of space tourists will add yet another layer of complexity that can be addressed by personalization.
In this review, we primarily highlighted four areas of biological variance that are fundamental to a personalized medicine paradigm in human space flight. These include: (1) gene and small molecule variants associated with metabolism of therapeutic drugs used in space; (2) gene and small molecule variants associated with one carbon metabolism; (3) gene and small molecule variants associated with iron metabolism and oxidative stress; and (4) Mg as an essential input with effects on DNA stability and energy.
We have drawn attention to these areas for the purpose of simplicity. In practice, the same premise described in this review can be applied across a wide range of molecular processes. We suggest here that the more broadly we understand this variability of molecular networks in each astronaut, the better we will be able to develop countermeasures that optimize astronaut safety and performance.
This variability can be assessed by the application of Omics approaches to space medicine research (Table ). For example, one can use Omics to better characterize the molecular events associated with the variable oxygen conditions that will be encountered in the space suit EVA condition compared with the space habitat environment noted previously (Figure ). This can be done by using genomics (SNP profiling) to examine how genotype may be linked to tolerance in the two conditions. Transcriptomics, proteomics, and metabolomics can be used to further characterize the changing molecular dynamics that might be associated with the varying PAO2/PaO2/CO2 conditions.
Proposed use of Omics in human space research
Patterns derived from these research-based Omics methods, can then be used to identify novel and relevant biomarkers, which may subsequently be used to develop personalized countermeasures applied to the individual astronaut entering such variable oxygen conditions (Table )
Proposed use of targeted Omics as a basis for personalized countermeasure development
Introducing Omics into space biomedicine research adds a layer of complexity that will initially offer challenges in technology and methodology. But the ability to identify novel patterns, novel solutions, and predictive capability is expected to ultimately reduce complexity, by refining our engineering designs and human countermeasure approaches.
Omics technology approaches to human space flight countermeasures
Earth-based human space flight research will benefit from the same range of technologies applied in all domains of systems biology. This includes, but is not limited to, LC–MS, GC–MS, NMR, ELISA, electrophoresis, PCR, gene arrays, protein arrays, flow cytometry, microscopy, and many others. These technologies will support assessment of genome, transcriptome, proteome, and metabolome in: (1) Earth-based space analogue research, (2) short-duration flight research where specimens are retained for ground analysis, (3) in-habitat research (such as the ISS) where retained specimens are returned to Earth for analysis, and (4) post-mission research.
These technologies can serve the purposes of human space flight research today, as well as providing the kind of analytics from which personalized countermeasures can be developed. However, real time Omics assessment during space flight and habitation presents a unique set of challenges, due to vehicle size, instrument weight, fluid handling characteristics in microgravity, and power constraints.
None of the current analytical technologies or methods is presently used by any space program to survey the changing molecular dynamics of astronauts in space. Instead, samples (blood, urine, or saliva) are frozen at −80 °C in the ISS (MELFI Rack freezers) and usually (every 90–180 days, notwithstanding schedule changes) transported to Earth for retrospective analyses, using some of the aforementioned technologies. Transport volumes are low, since the returning vehicles, such as the SpaceX Dragon and Soyuz vehicles, have limited cargo capacity, when compared with the retired Space Shuttle. Thus, multiple trips are required to transport MELFI freezer volumes to the ground.
This impacts research, as well as real-time assessment of markers relevant to astronaut health and safety. To further complicate the situation, exploration class missions beyond LEO to Moon and Mars will be constrained by cost and use smaller vehicle volumes than the ~400 m3
of habitable volume of the ISS (Wikipedia ISS and assembly pages; NASA Facts and Figs 2012
). The smaller vehicles present two significant challenges to biochemical analyses. First, the vehicles will be roughly < 50 m3
in total volume, significantly limiting the potential size of the analytical equipment. Second, this reduced volume eliminates the ability to use the size- and power-hungry electrical systems, like the ISS MELFI freezers. This reduces the ability to store large amounts of samples for later analyses upon return to Earth.
Future in-flight and in-habitat analytical systems will require compact analytical solutions to transmit data to Earth, allowing for monitoring and intervention. The most likely and reasonable approaches to real time monitoring in these exploration vehicles will be, at least initially, proteomics-based, compact (small foot print) analytical equipment capable of operating at low power. It will also require reagents that, for the most part, show a tolerance to the environmental conditions in space, in particular radiation. Most of the current systems are fluid- and antibody-based, and the cartridges require refrigeration.
As with freezers, refrigerators for space vehicles (e.g. Merlin) provide ~20 l of storage in ~2 ft3 of volume at a maximum cold point of −20 °C (NASA Fact Sheet). Both of these requirements are unsuitable for exploration missions for the reasons outlined above. To combat the inherent fragility of antibodies in hostile conditions, new, more adaptable molecules are being used with considerable success.
We and our colleagues are pursuing X-Aptamer technology for the purpose of assessing a targeted proteome and metabolome on missions to the Moon and Mars. This will afford the ability to make real-time assessment of astronaut health during missions BLEO. X-Aptamers are small DNA fragments (oligonucleotides) resistant to denaturation. Like antibodies, they are made to specific protein epitopes, thus allowing a direct rather than indirect measure of the biomarker. Real-time evaluation affords protection of volatile analytes that might otherwise be degraded. X-Aptamers are coupled with a variety of chromophores, and have proven to be more tolerant to hostile environmental conditions and also to have sensitivity comparable to or greater than antibodies (Durland et al. 1991
; He et al. 2012
; Hecht et al. 2010
With these attributes, aptamer reagents may be stored for years, rather than weeks, without refrigeration and yet assure reliability when needed. X-Aptamers can be designed to detect specific proteins as standard antibodies traditionally do. These can be measured during long-duration missions and results transmitted electronically to Earth for medical evaluation. Similar technologies will have to be developed with careful attention to parameters of instrument volume, reagent volume, reagent stability to radiation and temperature, and reliability in microgravity.
In general, the Omics technologies available today are fully ready to support development of personalized medicine in human space flight. Understanding the real-time molecular dynamics in long-duration missions will, however, require significant advances in the field, with regard to the space flight hardware. There is little doubt that these advances would also confer considerable value to the evolution of Earth-based technology and medicine.
Systematic application of personalized medicine
The application of personalized medicine in human space flight seems inevitable given the vast pool of knowledge emerging from the field of systems biology and our growing understanding of individual susceptibility. Working from this assumption, it is imperative that a road map be developed that accounts for the present state of knowledge, as well as for the evolution of the field going forward. We suggest that a road map be developed with the goal of advancing Omics-based assessment and individualized countermeasures, as the foundation of medicine of the twenty first century for human space flight. This medicine would be personalized, preventive, predictive, and participatory.
The new paradigm will necessarily involve Earth-based mission-preparatory countermeasures, in-flight space-based countermeasures, habitation space-based countermeasures, and recovery-based countermeasures on return to Earth.
This would, at minimum, include: (1) establish the criteria for “best evidence” that can be used to develop individualized countermeasures today; (2) establish the criteria for best evidence that prioritizes research, clinical assessment, and individualized countermeasures to be developed in the near term; (3) establish a deliberate discovery path that seeks to develop sophisticated and more complex models for long-term deployment of personalized medicine as the standard in human space flight.
In summary, this review is not intended to proffer any policy statement or position, but rather to explore a series of core concepts from which personalized approaches to enhance astronaut performance, endurance, and safety can be developed. This new approach will require both scientific and technology advances, coupled with novel implementation strategies compelled by the rigors of extended duration missions and habitation in the final frontier. These methods applied to the complexity of space flight are also expected to become valuable tools, as we advance the personalized medicine paradigm in Earth-based medicine.