The preceding chapters present recommendations for research and research priorities in a wide range of disciplinary and interdisciplinary fields relevant to space biology and medicine. This chapter considers the question of overall priorities for research supported by the National Aeronautics and Space Administration (NASA) in the next decade, taking into account budgetary realities and the need for clearly focused programs.

The highest priority for NASA support should be given to research meeting the following criteria:

1. Research aimed at understanding and ameliorating problems that may limit astronauts' ability to survive and/or function during prolonged spaceflight. Such studies include basic as well as applied research and ground-based investigations as well as flight experiments. NASA programs should focus on aspects of research in which NASA has unique capabilities or that are underemphasized by other agencies; and
2. Fundamental biological processes in which gravity is known to play a direct role. As above, programmatic focus should emphasize NASA's capabilities and take into account the funding patterns of other agencies.

A lower priority should be assigned to areas of basic and applied research that are relevant to fields of high priority to NASA but are extensively funded by other agencies, and in which NASA has no obvious unique capability or special niche.

In the near term, until the research facilities of the International Space Station come online or an additional Spacelab mission is provided, NASA-supported research will necessarily be largely directed toward ground-based investigations designed to answer fundamental questions and frame critical hypotheses that can later be tested in space. Indeed, as the preceding chapters have emphasized, understanding the basic mechanisms underlying biological and behavioral responses to spaceflight is essential

for designing effective countermeasures and protecting astronaut health and safety both in space and upon return to Earth. For these reasons, the following recommendations for high-priority areas of research over the entire life sciences program place greater emphasis on ground-based studies.

The committee considers the following areas of research to be the most important for ensuring astronaut health, safety, and performance during and after long-duration spaceflight. The specific order of research priorities among these areas is likely to shift depending on the nature of the planned missions; for this reason the topics are not presented in an order of priority.

Bone and muscle deterioration is one of the best-documented deleterious effects caused by spaceflight in humans and animals. The reduction in bone mass has been shown to exceed 1 percent per month in weight-bearing bones, even when an in-flight exercise regime was followed, making this one of the major barriers to long-term human space exploration. Dramatic losses in strength and changes in functional properties of weight-bearing muscles have also been observed even after short-duration flights. Exercise has been only partially successful in preventing bone loss and muscle weakness. Development of effective countermeasures requires advances in several areas of basic research.

• Research should emphasize studies that provide mechanistic insights into the development of effective countermeasures for preventing bone and muscle deterioration during and after spaceflight.
• Ground-based model systems, such as hindlimb unloading in rodents, should be used to investigate the mechanisms of changes that reproduce in-flight and postflight effects.
• A database on the course of microgravity-related bone loss and its reversibility in humans should be established in preflight, in-flight, and postflight recording of bone mineral density.
• Hormone profiles should be obtained on humans before, during, and after spaceflight.
• The relationship between exercise activity levels and protein energy balance in-flight should be investigated.

Over the past 10 years, extensive experimental research has been conducted on humans to better understand how the space environment affects the control of posture and movement in astronauts. Because of this, considerable information is now available regarding spatial orientation, postural control, the vestibular ocular reflex (VOR), and space motion sickness in microgravity. In future work, it will be important to extend these findings from human studies to mechanistic studies in suitable animal models. This should provide a better understanding of the basic mechanisms operating at the cellular and molecular levels in the control of posture and movement in microgravity.

We know that compensatory mechanisms function effectively in the vestibulomotor pathways on Earth and that compensatory mechanisms also occur in space.

• Experiments to determine the basis for the compensation on Earth and in space, and to evaluate whether the mechanisms are the same, should receive the highest priority, since these compensatory mechanisms operate in astronauts entering and returning from space and may have a profound effect on their performance in space and their postflight recovery on Earth.
• In-flight recordings of signal processing following otolith afferent stimulation should be made by a trained physiologist serving as a payload specialist, to determine how exposure to microgravity affects central and peripheral vestibular function and development.
• From ground-based experiments, we know that the vestibulo-oculomotor system is capable of learning new motor patterns in response to sensory perturbations; therefore, future investigation should focus on determining whether and how these mechanisms are affected by exposure to microgravity.

Significant progress in cardiovascular research occurred during the 1990s on a series of Spacelab missions, but orthostatic hypotension, present since the earliest human spaceflights, still affects a high percentage of astronauts returning from flights of relatively short duration. It is an even greater problem for shuttle pilots, who must perform complex reentry maneuvers in an upright, seated position. The incidence and magnitude of orthostatic hypotension will increase with longer-duration flights planned for the space station and both lunar or Mars missions. The problem remains despite the use of extensive antiorthostatic countermeasures by both U.S. and Russian space programs. The committee recommends several areas of research.

• Current knowledge of the magnitude, time course, and mechanisms of cardiovascular adjustments should be extended to include long-duration exposure to microgravity.
• The specific mechanisms underlying inadequate total peripheral resistance observed during postflight orthostatic stress should be determined.
• Current antiorthostatic countermeasures should be reevaluated to refine those that offer protection and eliminate those that do not. Studies should avoid confounding effects of multiple, simultaneous interventions unless data support these combinations. Priority should be given to interventions that may provide simultaneous bone and/or muscle protection.
• Appropriate methods for referencing intrathoracic vascular pressures to systemic pressures in microgravity should be identified and validated, given the observed changes in cardiac and pulmonary volume and compliance.

The biological effects of exposure to radiation in space pose potentially serious health effects for crew members that must be controlled or mitigated before initiation of long-term missions beyond low Earth orbit. High priority is given to the following.

• Determine the carcinogenic risks following irradiation by protons and high-atomic-number, high-energy (HZE) particles.

• Determine if exposure to heavy ions at the level that would occur during deep-space missions of long duration poses a risk to the integrity and function of the central nervous system.
• Determine how the selection and design of the space vehicle affect the radiation environment in which the crew has to exist.
• Determine whether combined effects of radiation and stress on the immune system in spaceflight could produce additive or synergistic effects on host defenses.

The immune system has close interactions with the neuroendocrine system. Results of these studies indicate a close association between alterations in status of the immune system and the state of the neuroendocrine system of the host.

Interactions between the hypothalamic-pituitary-adrenal (HPA) axis and the immune system during spaceflight should be analyzed to determine the role that the host response to stressors plays in alterations in host defenses.

Aspects of living and working in space that have been well-tolerated by astronauts during short-duration missions are likely to have significant impacts on health, well-being, and performance during long-duration missions. Mechanisms of response to physiological and psychosocial stressors encountered in spaceflight must be better understood in order to ensure crew safety, health, and productivity during prolonged residence in space. These mechanisms require an interdisciplinary approach since many of the physiological changes (e.g., endocrine, immune, cardiovascular, neurovestibular) likely to occur during prolonged exposure to microgravity will have important implications for behavior and performance. Likewise, many of the characteristics of the psychosocial environment of long-duration missions—such as interpersonal conflicts, restrictions on privacy and territoriality, social monotony, and prolonged isolation from family and friends—have important implications for these physiological systems by virtue of their influences on the HPA axis.

Research is recommended in two areas, both of which will require the development of noninvasive techniques for the ongoing assessment of behavior and performance.

1. Research should be conducted on the neurobiological (circadian, endocrine) and psychosocial (individual, group, organizational) mechanisms underlying the effects of physical (microgravity, hazards) and psychosocial (isolation, confinement) environmental stressors on cognitive, affective, and psychophysiological measures of behavior and performance. Such research should be interdisciplinary and conducted in ground-based analogue settings as well as in-flight.
2. The efficacy of existing countermeasures (screening and selection, training, monitoring, support) should be determined.
3. • Studies of the use of psychophysiological measures in the implementation of these countermeasures

• and the effects of microgravity on the kinetics and efficacy of psychopharmacological medications should be interdisciplinary in nature.
• In those instances where existing countermeasures are found to be ineffective, new countermeasures should be developed that effectively contribute to optimal levels of crew performance, individual well-being, and mission success.

Multicellular plants respond to changes in the direction of the gravitational vector by altering the direction of growth of roots and stems. The gravitropic response requires (1) perception of the gravitational vector by gravisensing cells, (2) intracellular transduction of this information, (3) translocation of the resulting signal to the sites of reaction (i.e., sites of differential growth), and (4) reaction to the signal by the responding cells (i.e., initiation of differential growth). In some systems, the gravity-perceiving cell is also the site of reaction (e.g., in the Chara rhizoid).

• Studies of graviperception should concentrate on three problems:
1. The identity of the cells that perceive gravity in multicellular plants;
2. The intracellular mechanisms by which the direction of the gravity vector is perceived; and
3. The threshold value for graviperception—this will require a spaceflight experiment.
• Studies of gravitropic transduction should focus on the nature of the cellular asymmetry that is set up in a cell that perceives the direction of the gravity vector.
• Studies on the translocation step should concentrate on the nature and mechanism of the translocation of the signals that pass from the site of perception to the site of reaction.
• Studies on the reaction step should focus on the mechanism(s) by which gravitropic signals cause unequal rates of cell elongation, and on the possible effects of gravity on the sensitivity of these cells to the signals.

Work on space research is concerned with whether those parts of the vestibular system that are gravity sensitive (otolith organs) can develop and function adequately in microgravity. In addition, it is important to determine whether gravity influences the sensory systems that depend for their development and function on vestibular input. This includes the other sensory systems that interact directly with the vestibular system, the multiple brain regions containing neural space maps, and finally those areas in the brain capable of responding to alterations in their activity by neuroplastic changes.

• Space-based experiments are needed to test the role of gravity on the embryonic development and maintenance of the vertebrate vestibular system. Prior to this, ground-based studies are needed to identify the critical periods in vestibular neuron develpment. In both Earth and space-based studies, it

• is important to characterize vestibular development at several different times to determine the sequence of intermediate events leading up to the final outcome. In space studies, controls for the effects of nongravitational stresses, including loud noise and vibration, must be performed on the ground so that the space experiments are designed to isolate the effects of microgravity from the effects due to other stresses.
• Pre- and postflight functional magnetic resonance imaging (fMRI) studies should be conducted with astronauts to determine the effects of microgravity on neural space maps.

To determine whether there are developmental processes that are critically dependent upon gravity, organisms should be grown through at least two full generations in space.

• Key model animals should be grown through two life cycles; highest priority should be given to vertebrate models (e.g., fish, birds, and small mammals such as mice or rats). If significant developmental effects are detected, control experiments must be performed (including the use of a space-based 1-g centrifuge) to determine whether gravity or some other element of the space environment induces these developmental abnormalities.
• An analogous experiment should be carried out with the model plant Arabidopsis thaliana to confirm results obtained on Mir with a preliminary experiment using Brassica rapa. The ideal experiment will require the development of a suitable plant growth unit and of Arabidopsis plants containing stress-indicator genes and/or mutations conferring insensitivity to environmental stresses.