To arrive there, we need to transition from Earth-reliant to Earth-independent mission architecture. Agencies like the National Aeronautics and Space Administration and European Space Agencyhave developed exceptional life support systems for Earth-reliant human missions into space. Carefully planned medicine, food, and environmental control re-supply shuttles working in concert with on-board environmental control and life support systems maintain a habitable environment for astronauts in the International Space Station. However, as space missions become longer and they probe deeper into the solar system – to the Moon, to Mars, and beyond – frequent re-supplies for life support systems will become increasingly burdensome. Current exploration medical capabilities are particularly vulnerable to a lower rate of resupply and longer missions. The list of necessary supplies to address persistent exposures of space travel adds up quickly, including: countermeasures for increased radiation, bone loss, kidney stones, vision impairment, and adverse behavioral conditions to name a few. The list of supplies begins to look unmanageable when you add in intermittent, or even unanticipated, exposures such as microbial infection, and spaceflight induced genome instability and metabolic changes. As mission duration increases,flood tray the risk of a low probability medical condition is amplified. When an astronaut is on Mars and the closest hospital or medical re-supply is at least 200 days of interplanetary travel away, it is critical that astronauts are medically self-sufficient.

Furthermore, the recent literature highlights systemic vulnerabilities in space-flown pharmaceutical life support in the biased and under reported historical data of in-flight pharmaceutical use and efficacy, limited fidelity of current ground-analog models, and the in flight instability of drug formulations. Of the small molecule solid formulations tested thus far, three-quarters will have degraded by the end of the proposed first Mars mission duration. There has been no spaceflight testing of biologics, a critical category of pharmaceuticals known to be less stable than small molecule drugs. These issues highlight the need to develop platform technologies for the on-demand production of medicines.The medical systems of future space exploration will need to be reconfigured to guarantee astronaut health. The contemporary standard is the NASA-provided ISS crew health care system consisting of three sub-systems:the countermeasures system composed of exercise hardware and monitoring devices,the environmental health system composed of hardware for environmental monitoring, and the health maintenance system composed of a medical kit for supporting routine minor medical needs for up to 180 days. Earth-reliant medical systems like CHeCS will need to be augmented with medical foundries for self-sufficiency in Earth-independent space mission architectures. A space medical foundry will expand mission capabilities to include high-value medical product manufacturing, of which pharmaceuticals will be a critical product class. This is particularly important for extended duration exploration, and settlement, of extraterrestrial bodies such as the Moon and Mars. A space foundry, of which a medical foundry is a subset, must be capable of utilizing a limited set of inputs to generate a wide spectrum of outputs and must be able to do so in a simple, closed loop. Recent literature has detailed a compelling narrative for the use of biotechnology to answer these challenges.

The Center for Utilization of Biological Engineering in Spaceis a multi-university effort to realize the inherent mass, power, and volume advantages of space biotechnology and advance the practicality of a nearly closed loop, photo autotrophic factory for production of food, pharmaceuticals, and materials on a Mars mission. An alternative method for pharmaceutical production is chemical synthesis. In producing small molecule pharmaceuticals, chemical synthesis is often advantageous on Earth. However, as stereochemical complexity and size of the target pharmaceutical increases, chemical synthesis often becomes dramatically less feasible and attractive. For perspective, there are examples of chemical synthesis used commercially to produce pharmaceuticals as large as peptides, but antibodies, an example class of life-saving pharmaceuticals produced only in biological systems , are two orders of magnitude larger than that. Chemical synthesis of pharmaceuticals can also be contrasted with biological production as having highly reaction-specific inputs and complex synthesis steps, often requiring the use of organic solvents and generating substantial waste by-products, all of which are undesirable attributes for space applications. Chemical synthesis may be necessary for a robust medical foundry for space, indeed it will likely be required to synthesize nucleic acids to mobilize biological production in space, but it will not be sufficient to produce all countermeasures. Space biotechnology has primarily focused on microbes, fungi, and plants. From this perspective, we review the potential utility of plants as a molecular medical foundry for the production of pharmaceuticals in deep space and contrast this with the capabilities of alternative biological organisms.Plants are an established facet of space mission architecture, with research dating back to the 1950s. Most recently, a study on red romaine lettuce grown in the International Space Station using the Vegetable Production System has reported that leafy vegetable crops can be grown and consumed safely in the ISS as a dietary supplement.

Resource flexibility is essential in the confined environments of a space mission, and researchers have shown that plants serve as versatile assets in a space mission life support system. Up to this point, studies have focused on the value of plants to harness solar energy and provide nutrients, and for water treatment, air treatment, and behavioral health. Accordingly, research into advancing the capabilities of plants for space has primarily focused on those key areas. What has not been captured in published research is the potential of plants to provide astronauts with pharmaceuticals and other high value products, which is formally known as molecular pharming.Humans have looked to plants as a source of healing for thousands of years. To date, there are over 120 commercially available drugs consisting of distinct chemical substances that have been derived from plants. This list includes widely used medications such as aspirin, the most commonly used drug in the world, paclitaxel, which is used to treat various forms of cancer, and artemisinin, an antimalarial compound. The breadth of therapeutically-relevant molecules that we can now produce in a plant to support human life has exploded with recombinant DNA technology. Plants have been used to produce a wide variety of complex products for supporting human life – ranging from products as diverse as diagnostic reagents and therapeutic proteins, to bio-materials and bio-fuels. Pioneering work in the past twenty years on plant based production systems has positioned molecular pharming competitively for commercial applications of these diverse products on Earth. Continuing those advances, we focus on producing pharmaceuticals as a high-priority application of molecular pharming to mitigate human health risks in extended deep space exploration. The first commercial therapeutic protein to be produced recombinantly in plant cells was approved for enzyme replacement therapy in 2012. While this product is produced in plant cell culture, it has established a regulatory pathway for addressing concerns with plant-based production in general. There is currently a wide range of whole plant produced pharmaceuticals in commercial pipelines. Perhaps most notably, Medicago’s clinical programconsists of an influenza vaccine in Phase 3 trialsand several other vaccine candidates in earlier stages. Molecular pharming has also found commercial success in other application areas. For example, in diagnostic reagents, with avidin produced in maize, veterinary medicine, with canine interferon-alpha produced in strawberry, nutraceuticals, with human growth factors produced in barley, and commodity chemicals, with cell culture media components produced in rice.Molecular pharming with whole plants can be performed by using one of two strategies: transient production using gene delivery systems to introduce genes for the plant to temporarily transcribe and translate ondemand, or transgenic production using plants with recombinant genes inserted into the genome for stable translation . Either strategy can be executed to produce recombinant products using a simple process flow. Transient production is a strategy that can provide on-demand transformation of food into a medical, or some other high-value product, resource. This enables a rapid response in which initiation of production is linked to the exceeding of some risk threshold, be it triggered by the emergence of a diagnosed disease state or an increased probability of occurrence. This allows stockpiles to be minimized for low frequency disease states, and perhaps, most importantly, builds capability to respond to unanticipated disease states. Key parameters of transient production to meet these capabilities are the production lead time ,ebb and flow tray the specific productivity , and the manufacturing resources . There are a variety of established transient production systems that employ both biotic and abiotic methods as shown in Figure 3. Table 1 summarizes key process differences in these transient production systems. Selecting the most effective transient production system depends on the disease state and the exploration mission architecture .

Pharmaceutical production capability is hardwired into the genome of the plant through either nuclear or plastid engineering. No additional manufacturing resources beyond those used for plants as a traditional bio-regenerative life support object are needed, except an induction agent for inducible promoter-controlled transgenics. This allows for the simple and sustained production of pre-determined molecular target for which a consistent demand is anticipated. Transgenic plants for medical countermeasure production will most likely be distinct resources from food crops unless strategies such as inducible promoters or tissue-specific expression are employed. Combined, transient and transgenic production systems have the potential to cover the breadth of pharmaceutical production needs for deep space missions. Anticipated human health-impacting exposures in deep space missions include intermittent and persistent modes, within which both acute and chronic disease states are possible. Chronic disease states needing a constant supply of medical countermeasures are most likely best addressed by using the simpler manufacturing of transgenic production. Transient production is also a viable strategy for meeting the medical needs of chronic disease states; it often yields higher specific productivity of a product per biomass basis. However, the higher resource demand of production and concerns of long-term pharmaceutical stability raise potential disadvantages in transient production for chronic disease states, such as micro-gravity-induced osteopenia. For acute disease states above a certain risk level, defined by both likelihood of occurrence and severity of mission impact, it may be valuable to generate transgenic plants to produce countermeasures. On the other hand, transient production may be a more cost-effective strategy for reducing mission risk associated with lower risk, and unanticipated, disease states. Here we reiterate that providing medical countermeasures for unanticipated disease states should not be underestimated. The delineation of best use cases for transgenic and transient production system selection depends on mission architecture and the specific resource availability. The decision tree shown in Figure 4 provides a foundational logic framework for evaluating and selecting an appropriate molecular pharming production system on a situational basis.Consider a deep space exploration mission in which plants are grown for their previously established utilities and a crew of six astronauts subsists on a diet supplemented with a single serving, 100 g fresh weight , of lettuce or potato per crew member per day. The primary purpose for growing this single serving of plant-based food per day on an extended space mission is to meet the Food and Nutrition Board of the Institute of Medicine’s Recommended Dietary Allowance of nutrients. The current stated shelf life of prepackaged space food is only 18 months, and the degradation of key nutrients such as thiamineis well documented. Just as when sailors suffered the effects of missing vitamin C on longsea voyages, it will be critical to avoid vitamin deficiencies as we explore deep space. Figure 5 shows the macro-nutrient and labile vitamin contributions of the daily single serving of lettuce or potato as a percentage of recommended dietary allowance. A supplement selected from a variety of food crops would be most effective to meet the RDA, as well as to minimize menu fatigue. Growing a daily single serving supplement of plant based food is estimated to occupy 4.6 and 5.7 m2 of cultivation area for lettuce and potato, respectively. This considers the plant inventory needed for sustained production of a single serving per day. The actual cultivation footprint is expected to be significantly smaller than the cultivation area, as hydroponic cultivation is typically conducted with multi-layered growth stages. The plant cultivation calculations were performed according to values listed in NASA’s Baseline Values and Assumptions Document.