The Need for Biological Countermeasures to Mitigate the Risk of Space Radiation-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Deficiencies.

NASA's currently planned long-duration, deep space exploration missions outside of low Earth orbit (LEO) will result in the exposure of astronauts to relatively high lifetime doses of ionizing radiation (IR), exceeding what humans have previously encountered in space. Of concern to this exposure are the long-term health consequences of radiation carcinogenesis, cardiovascular and degenerative disease, and central nervous system decrements. Existing engineering solutions are insufficient to decrease the lifetime accumulated IR exposure to levels currently allowable by agency standards, therefore appropriate countermeasure and mitigation strategies must be developed to enable long duration missions. Emerging discoveries in the fields of radiation oncology and the mitigation of Acute Radiation Syndrome (ARS) have demonstrated the potential for compound-based/biological radiomodifiers to drastically improve clinical outcomes and represent a promising strategy for space radiation countermeasure development. This review outlines the unique challenges posed by the space radiation environment, defines the limits of terrestrial radiation protection strategies in space, describes a brief overview of current space radiation countermeasure development strategies, highlights potential new approaches for countermeasure identification and development, and speculates on the potential benefits beyond space exploration.

Inter-agency perspective: Translating advances in biomarker discovery and medical countermeasures development between terrestrial and space radiation environments.

Over the past 20+ years, the U.S. Government has made significant strides in establishing research funding and initiating a portfolio consisting of subject matter experts on radiation-induced biological effects in normal tissues. Research supported by the National Cancer Institute (NCI) provided much of the early findings on identifying cellular pathways involved in radiation injuries, due to the need to push the boundaries to kill tumor cells while minimizing damage to intervening normal tissues. By protecting normal tissue surrounding the tumors, physicians can deliver a higher radiation dose to tumors and reduce adverse effects related to the treatment. Initially relying on this critical NCI research, the National Institute of Allergy and Infectious Diseases (NIAID), first tasked with developing radiation medical countermeasures in 2004, has provided bridge funding to move basic research toward advanced development and translation. The goal of the NIAID program is to fund approaches that can one day be employed to protect civilian populations during a radiological or nuclear incident. In addition, with the reality of long-term space flights and the possibility of radiation exposures to both acute, high-intensity, and chronic lower-dose levels, the National Aeronautics and Space Administration (NASA) has identified requirements to discover and develop radioprotectors and mitigators to protect their astronauts during space missions. In sustained partnership with sister agencies, these three organizations must continue to leverage funding and findings in their overlapping research areas to accelerate biomarker identification and product development to help safeguard these different and yet undeniably similar human populations - cancer patients, public citizens, and astronauts.

Interagency approaches to animal models for acute radiation exposure.

Ionizing radiation can cause devastating injuries including hemorrhage, immune suppression, increased susceptibility to infection, and death. Medical countermeasures (MCMs) that address and mitigate radiation-induced injuries are the most important tools for countering the consequences of radiation exposure. Likewise, in matters of public health security, the development and advancement of radiological MCMs are fundamental for establishing an effective response to radiological and nuclear threats. United States Government agencies such as the Biomedical Advanced Research and Development Authority (BARDA), the National Institute of Allergy and Infectious Diseases (NIAID), and the National Aeronautics and Space Administration (NASA) have dedicated significant efforts to advance the development of MCMs to treat radiation injury and facilitate their introduction into the public sphere. Due to the severe nature of radiation injuries, clinical trials are unethical. Therefore, nonclinical models that accurately replicate clinical manifestations of ionizing radiation injury observed in humans are essential to MCM advancement. The most frequently used nonclinical models of radiation injury are rodents and non-human primates (NHPs). These species reproduce many aspects of human disease caused by ionizing radiation and have been pivotal for the development and licensure of radiological MCMs. Despite these successes, model drawbacks have prompted the exploration and development of additional nonclinical models. Minipigs and rabbits show promise as acceptable models of radiation injury and demonstrate the potential to contribute significantly to MCM advancement. This collection of research showcases the capabilities of minipigs and rabbits in mirroring clinically relevant aspects of radiation-induced disease and documents the potential value these models may hold for radiological and nuclear MCM research. Together, these government-funded studies represent advances in radiological MCM development that can facilitate the emergence of cutting-edge technologies.

Medical countermeasures for radiation induced health effects: report of an Interagency Panel Session held at the NASA Human Research Program Investigator's Workshop, 26 January 2017.

An Interagency Panel Session organized by the NASA Human Research Program (HRP) Space Radiation Program Element (SRPE) was held during the NASA HRP Investigator's Workshop (IWS) in Galveston, Texas on 26 January 2017 to identify complementary research areas that will advance the testing and development of medical countermeasures (MCMs) in support of radioprotection and radiation mitigation on the ground and in space. There were several areas of common interest identified among the various participating agencies. This report provides a summary of the topics discussed by each agency along with potential areas of intersection for mutual collaboration opportunities. Common goals included repurposing of pharmaceuticals, nutraceuticals for use as radioprotectors and/or mitigators, low-dose/chronic exposure paradigms, late effects post-radiation exposure, mixed-field exposures of gamma-neutron, performance decrements, and methods to determine individual exposure levels.

Spaceflight medical countermeasures: a strategic approach for mitigating effects from solar particle events.

NASA was recently charged with returning humans to the lunar surface within the next five years. This will require preparation for spaceflight missions of longer distance and duration than ever performed in the past. Protecting the crew and mission from the hazards associated with spaceflight will be a priority. One of the primary hazards to address is the challenging radiation environment. Space is unforgiving when it comes to radiation. There is galactic cosmic radiation (GCR) that is pervasive in space and the possibility of solar particle events (SPE) that release high energy particles from the sun that can result in high doses of radiation to the crew if unprotected. NASA has been preparing and evaluating several means of ensuring that crew health is not compromised during these missions. Physical shielding, space weather monitoring, and more recently storm shelters are all possible means of protecting crew during a SPE. Medical countermeasures have not been necessary for operations in low Earth orbit; however, future human exploration missions should consider including therapies onboard to address radiation-induced health effects. While the likelihood of experiencing a significant SPE is very low, serious adverse health effects or even death could occur if no medical countermeasures were available. Having a Food and Drug Administration (FDA) approved medical countermeasure on board that could mitigate acute radiation-induced hematopoietic syndrome due to a SPE could provide life saving measures for the crew. This paper discusses the mitigation strategies that can be implemented for Artemis missions and identifies numerous areas of research for future improvements.

Challenges in Clinical Management of Radiation-Induced Illnesses During Exploration Spaceflight.

INTRODUCTION: Analysis of historical solar particle events (SPEs) provides context for some understanding of acute radiation exposure risk to astronauts who will travel outside of low-Earth orbit. Predicted levels of radiation exposures to exploration crewmembers could produce some health impacts, including nausea, emesis, and fatigue, though more severe clinical manifestations are unlikely. Using current models of anticipated physiological sequelae, we evaluated the clinical challenges of managing radiation-related clinical concerns during exploration spaceflight.METHODS: A literature review was conducted to identify terrestrial management standards for radiation-induced illnesses, focusing on prodromal symptom treatment. Terrestrial management was compared to current spaceflight medical capabilities to identify gaps and highlight challenges involved in expanding capabilities for future exploration spaceflight.RESULTS: Current spaceflight medical resources, such as those found on the International Space Station, may be sufficient to manage some aspects of radiation-induced illness, although effective treatment of all potential manifestations would require substantial expansion of capabilities. Terrestrial adjunctive therapies or more experimental treatments are unavailable in current spaceflight medical capabilities but may have a role in future management of acute radiation exposure.DISCUSSION: Expanded medical capabilities for managing radiation-induced illnesses could be included onboard future exploration vehicles. However, this would require substantial research, time, and funding to reach flight readiness, and vehicle limitations may restrict such capabilities for exploration missions. The benefits of including expanded capabilities should be weighed against the likelihood of significant radiation exposure and extensive mission design constraints.Blue RS, Chancellor JC, Suresh R, Carnell LS, Reyes DP, Nowadly CD, Antonsen EL. Challenges in clinical management of radiation-induced illnesses during exploration spaceflight. Aerosp Med Hum Perform. 2019; 90(11):966-977.

Microgravity induces proteomics changes involved in endoplasmic reticulum stress and mitochondrial protection.

On Earth, biological systems have evolved in response to environmental stressors, interactions dictated by physical forces that include gravity. The absence of gravity is an extreme stressor and the impact of its absence on biological systems is ill-defined. Astronauts who have spent extended time under conditions of minimal gravity (microgravity) experience an array of biological alterations, including perturbations in cardiovascular function. We hypothesized that physiological perturbations in cardiac function in microgravity may be a consequence of alterations in molecular and organellar dynamics within the cellular milieu of cardiomyocytes. We used a combination of mass spectrometry-based approaches to compare the relative abundance and turnover rates of 848 and 196 proteins, respectively, in rat neonatal cardiomyocytes exposed to simulated microgravity or normal gravity. Gene functional enrichment analysis of these data suggested that the protein content and function of the mitochondria, ribosomes, and endoplasmic reticulum were differentially modulated in microgravity. We confirmed experimentally that in microgravity protein synthesis was decreased while apoptosis, cell viability, and protein degradation were largely unaffected. These data support our conclusion that in microgravity cardiomyocytes attempt to maintain mitochondrial homeostasis at the expense of protein synthesis. The overall response to this stress may culminate in cardiac muscle atrophy.