The core of the National Aeronautics and Space Administration's (NASA's) life sciences research lies in understanding the effects of the space environment on human physiology and on biology in plants and animals. The strategy for achieving that goal as originally enunciated in the 1987 Goldberg report, A Strategy for Space Biology and Medical Science for the 1980s and 1990s,¹ remains generally valid today. However, during the past decade there has been an explosion of new scientific understanding catalyzed by advances in molecular and cell biology and genetics, a substantially increased amount of information from flight experiments, and the approach of new opportunities for long-term space-based research on the International Space Station. A reevaluation of opportunities and priorities for NASA-supported research in the biological and biomedical sciences is therefore desirable.

The strategy outlined in the Goldberg report had two main purposes: "(1) to identify and describe those areas of fundamental scientific investigation in space biology and medicine that are both exciting and important to pursue and (2) to develop the foundation of knowledge and understanding that will make long-term manned space habitation and/or exploration feasible."² To achieve these purposes, the Goldberg report identified four major goals of space life sciences:

• "1.	To describe and understand human adaptation to the space environment and readaptation upon return to earth.

• "2.	To use the knowledge so obtained to devise procedures that will improve the health, safety, comfort, and performance of the astronauts.

• "3.	To understand the role that gravity plays in the biological processes of both plants and animals.

• "4.	To determine if any biological phenomenon that arises in an individual organism or small group of organisms is better studied in space than on earth."3

These goals remain valid and form the basis of the present report.

Both the Goldberg report and the 1991 follow-up assessment, Assessment of Programs in Space Biology and Medicine 1991,⁴ emphasized basic research and the importance of vigorous ground-based programs aimed at addressing the fundamental mechanisms that underlie observed effects of the space

environment on human physiology and other biological processes. The present report strongly reemphasizes that strategy and calls for an integrated, multidisciplinary approach that encompasses all levels of biological organization—the molecule, the cell, the organ system, and the whole organism—and employs the full range of modern experimental approaches from molecular and cellular biology to organismic physiology.

The sections that follow summarize the Committee on Space Biology and Medicine's priorities for NASA-supported research, its recommendations for high-priority research in individual disciplines, and its recommendations for overall priorities for NASA-sponsored research across disciplinary boundaries. The final section outlines significant concerns in the program and policy arena and offers related recommendations.

Taking into account budgetary realities and the need for clearly focused programs, the highest priority for NASA-supported research in space biology and medicine in the new century should be given to research meeting one of 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.
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.

Because the recommendations for research, and research priorities, in the discipline-specific chapters cover a wide range of fields relevant to space biology and medicine, the committee chose not to reproduce all of those recommendations in full in this executive summary. Instead the committee sought to capture the essence of what is recommended in Chapters 2 through 12, an approach that was best served by condensation, full quotation, or addition of supplemental detail as seemed useful to preserve the intent of the recommendations in their full form and context. The recommendations are numbered only in instances in which the committee considered that there was a clear priority order.

Rapid advancement in the field of cell biology offers novel opportunities for studying the effects of spaceflight, including weightlessness, on cells and tissues. This possibility for progress stems both from developments in technology and advances in basic concepts of cell structure and function at the molecular

level. Reasonable goals for the next period of NASA investigation are to clearly delineate the specific cellular phenomena that are affected by conditions of microgravity, to develop an understanding of the molecular mechanisms by which these changes are induced, and to begin to suggest strategies for countermeasures where indicated. Experience from previous in-flight and ground-based studies has highlighted certain pitfalls that must be avoided in the design and analysis of future experiments. Cellular systems should be emphasized that are known to be affected by gravitational force (e.g., bone, muscle, and vestibular systems in animals; gravitropic systems in plants) or by other aspects of the space environment (e.g., stress-induced phenomena). Consideration should be given to using molecular techniques for the analysis of gene expression and cell architecture and function, and to extending cell culture studies to the analysis of cellular physiology in intact tissues and whole organisms.

The committee makes the following specific recommendations for research in cell biology:

• General mechanisms of mechanoreception and pathways of signal transduction from mechanical stresses are areas of special opportunity and relevance for NASA life sciences. Studies of mechanisms of cellular mechanoreception should include identification of the cellular receptor, investigation of possible changes in membrane and cytoskeletal architecture, and analysis of pathways of response, including signal transduction and resolution in time and space of possible ion transients.
• Studies of cellular responses to environmental stresses encountered in spaceflight (e.g., anoxia, temperature, shock, vibration) should include investigation of the nature of cellular receptors, signal transduction pathways, changes in gene expression, and identification and structure and function analysis of stress proteins that mediate the response.
• The successful conduct of sophisticated cell biological experiments in space will require the development of highly automated and miniaturized instrumentation and advanced methodologies. NASA should work with the scientific community and industry to foster development of advanced instrumentation and methodologies for space-based studies at the cellular level.

The specific physiological systems in humans and animals for which gravity is likely to play a critical role in development and/or maintenance include the vestibular system, the multiple sensory systems that interact with the vestibular system, and the topographic space maps that exist throughout the brain. Major changes in perspective in recent years in the general field of developmental biology could greatly affect our ability to study and understand these systems. In particular, the use of saturation mutagenesis to identify genetic components of development, the recognition that molecular mechanisms are conserved across phylogeny, and the information provided by genome sequencing projects have transformed basic developmental studies since the publication in 1987 of the Goldberg report.⁵ In the present report the committee stresses the importance of two types of studies, those looking at life cycles and those examining development of gravity-sensing systems such as the vestibular system.

• The committee recommends that key model organisms be grown through two complete life cycles in space to determine whether there are any critical events during development that are affected by space conditions. Because no critical effects have been seen in model invertebrates, the highest priority should be given to testing vertebrate models such as fish, birds, and small mammals such as mice or rats. If developmental effects are detected, control experiments must be performed on the

• ground and in space, including the use of a space-based 1-g centrifuge, to identity whether gravity or some other element of the space environment induces the developmental abnormalities.

Analysis of the development of gravity-sensing systems, including the vestibular system and other systems that interact with it in vertebrates, should be carried out to determine the importance of gravity to their normal development and maintenance. The recommended investigations summarized below should be performed first in ground-based studies to identify appropriate experiments to be performed in space.

• Studies should be performed to define the critical periods for development of the vestibular system. Thus, the critical periods for cellular proliferation, migration, and differentiation and programmed cell death should be identified and the effects of microgravity on these processes assessed.

Neurons composing the brainstem, hippocampal, striatal, and sensory and motor cortical space maps should be investigated as part of the following recommended studies:

• The role of otolithic stimulation on the development and maintenance of the different neural space maps should be investigated.
• Studies should be designed to address how neurons of the various sensory and motor systems interact with vestibular neurons in the normal assembly and function of the neural space maps. Factors should be identified that are supplied by and to the sensory neurons that produce the orderly assembly of these maps in precise coordinate registration.
• The influence of microgravity on the development and maintenance of the neural space maps should be studied.

It is important to characterize neuroplasticity using multidisciplinary approaches that combine structural and molecular with functional investigations of identified cell populations. The process should be characterized at several different times following perturbation, in order to determine the sequence of intermediate events leading to the plastic change. Controls for the effects of nongravitational stresses of the types likely to be encountered in space (such as loud noise and vibration) must also be performed on the ground, so that the space-based experiments can be designed to isolate the effects of microgravity from the effects of other stresses. The committee makes the following recommendations for research on neuroplasticity, including one recommendation taken from Chapter 5, "Sensorimotor Integration."

• Studies are needed to determine whether the compensatory mechanisms that normally function in the vestibulomotor pathways are altered by exposure to microgravity. These experiments should be given the highest priority, because 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.
• Experiments are needed to critically test the role of gravity on the development and maintenance of the vestibular system's capability for neuroplasticity.

• Because the vestibulo-oculomotor system is capable of learning new motor patterns in response to sensory perturbations, it is important to determine if and how these mechanisms are affected by exposure to microgravity.
• Functional magnetic resonance imaging (fMRI) should be employed to investigate the following:
• • Changes in sensory and motor cortical maps in human bed-rest studies mimicking different flight durations.
  • The effects of microgravity on cortical maps in the human. Pre-and postflight fMRI studies should be conducted with astronauts.

The study of plants in the space environment has been driven by three main needs: (1) learning how to grow plants successfully in space (space horticulture) either for research or for eventual use in long-term life support systems, (2) determining whether there are any plant developmental or metabolic processes that are critically dependent on gravity, and (3) learning how plants alter their patterns of growth and development to respond to changes in the direction of the gravity vector.

A major goal of the Advanced Life Support (ALS) program is to develop an effective, completely closed plant growth system capable of growing plants for a bioregenerative life support system. Toward this end, the committee makes the following recommendations:

• The ALS program should concentrate its ground-based research on developing a completely enclosed plant growth system. This effort will require close collaboration between engineers and plant environmental scientists.
• The ALS spaceflight program should focus on testing the potentially gravity-sensitive components of the closed plant growth system, such as the nutrient delivery system.

Whether gravity is required for any specific aspect of the development or metabolism of a plant can best be determined by growing a model plant in space through at least two successive generations (seed-to-seed experiment) and examining carefully the development of the resulting plants to ascertain whether any aspect of the development is altered by a lack of gravity. Specifically, the committee recommends the following:

• The seed-to-seed experiment should be the top priority in this area. The promising results obtained with Brassica rapa should be confirmed and extended, using Arabidopsis thaliana plants. This experiment must be conducted on the ISS, because the plants should be grown through at least two generations in space.
• To conduct a meaningful seed-to-seed experiment, NASA needs to develop the following:
• • A superior plant growth unit, with adequate lighting, gas exchange, and water and/or nutrient delivery; and
  • Arabidopsis thaliana plants that are insensitive to expected environmental stresses and that contain indicator genes for all the expected environmental stresses, such as high levels of CO₂, vibration, anaerobiosis, water stress, and temperature stresses.

• In the interim, before the ISS is functional, studies on specific stages of plant development in space should be limited to small plants with short life cycles (e.g., Arabidopsis thaliana or Brassica rapa ). Whenever possible, a 1-g on-board centrifuge should be available.

Plants respond to the specific direction of the gravity vector in several ways. Among these are the direction of growth of stems and roots (gravitropism) and the swimming direction of some unicellular algae (gravitaxis). Among the committee's recommendations regarding this area of research, the following have the highest priority:

• A primary focus of NASA-sponsored research in plant biology should be on the mechanisms of gravitropism. In particular, modern cellular and molecular techniques should be used to determine the following:
• The identity of the cells that actually perceive gravity, and the role of the cytoskeleton in the process;
• The nature of the cellular asymmetry set up in a cell that perceives the direction of the gravity vector;
• The nature and mechanism of the translocation of the signals that pass from the site of perception to the site of reaction; and
• The nature of the response to the signal(s) that leads to alterations in the rate of cell enlargement.
• A secondary focus should be on the mechanisms of graviperception in single cells, including gravitropic responses of mosses and gravitaxic responses of algae.

Sensorimotor integration is an essential element in the control of posture and locomotion, as well as in coordinated body activities such as manipulation of objects and use of tools. The transition from normal gravity to microgravity disrupts postural control and orientation mechanisms. Spatial illusions, and often motion sickness, occur until adaptation to the new force background is achieved. On reentry, severe disturbances of postural, locomotory, and movement control are experienced with reexposure to the normal terrestrial environment. Thresholds for angular and linear accelerations, vestibulo-ocular reflexes, postural mechanisms, vestibulo-spinal reflexes, and gaze control all have been studied extensively in humans, but the development of animal models has lagged. Some of these areas require additional study, and a number of new experimental questions arise, given current knowledge and the need to consider human performance during extended-duration space missions.

Future work should emphasize mechanisms related to the active control of body orientation and movement rather than passive thresholds for the detection of angular or linear acceleration. Briefly summarized, the committee's research recommendations are as follows:

1. It is of critical interest to determine how microgravity and other unusual force environments, including rotating environments, affect the integrative coordination of eye, head, torso, arm, and leg movements.

2. It is important for the success of long-duration space missions to identify the sensory, motor, and cognitive factors that influence adaptation and retention of adaptation to different force environments, including rotating environments.
3. The influence of altered force levels, including microgravity, on spatial coding of position should be explored in parallel experiments with humans and animals.

The severe reentry disturbances of posture and locomotion experienced by astronauts and cosmonauts after even short-duration spaceflight pose potentially dangerous operational problems. These disturbances would be especially critical in long-duration missions that require accurate postural, locomotory, and manipulatory control during transitions in background force level. The committee recommends the following:

• The time course for adaptation of locomotion and posture to variations in background force level should be determined.
• Techniques should be developed to provide ancillary sensory inputs or aids to enhance postural and locomotory control during and after transitions between different force levels.

Considerable progress has been made in understanding how microgravity affects vestibulo-ocular reflexes, pursuit and saccadic eye movements, and control of gaze. The following studies, which can be carried out in parabolic flight, orbital flight, and rotating rooms, are recommended to achieve closure on understanding these critical functions.

• Systematic parametric studies of pursuit, saccadic, and optokinetic eye movements should be carried out as a function of background force level in humans from microgravity to 2 g.
• The coordination of eye-head-torso synergies in different force levels and their adaptation to changes in force level should be assessed, with the goal of developing a comprehensive three-dimensional model of the vestibulo-ocular reflex and cervical control of gaze.

Space motion sickness is an operational problem during the first 72 hours of flight, despite the use of medication, and is a hazard for initial transitions between force environments. The use of virtual environment devices in spaceflight to augment training in long-duration missions and for experimental purposes will likely exacerbate motion sickness. Research is recommended on the following:

• The relationship of motion sickness to altered sensorimotor control of the head and body in microgravity and greater than 1-g force backgrounds generated in parabolic flight and rotating rooms; and
• The relationship of the vestibular system to autonomic function, especially cardiovascular regulation.

One of the best-documented pathophysiological changes associated with microgravity and the spaceflight environment is bone loss, which can exceed 1 percent per month in weight-bearing bones

even when an in-flight exercise regime is followed. Within the discipline of bone physiology, the phenomenon of bone loss in astronauts is clearly the issue of greatest concern to NASA. Both the extent and the reversibility of the bone loss are crucial questions for long-term crewed flights on the space station and for future space exploration and should be addressed by collecting data from each astronaut to build up the necessary database.

The committee recommends that questions about microgravity-induced bone loss in humans be studied as follows:

1. To obtain a detailed description of human bone loss in space, a record of skeletal changes occurring during microgravity and postflight should be generated for each astronaut and correlated with age and gender, muscle changes, hormonal changes during flight, diet, and genetic factors (e.g., susceptibility to osteoporosis) if and when these genetic factors become known.
2. Bone turnover studies should establish if bone loss is due to increased bone destruction (resorption), decreased bone formation, or both.
3. To develop effective countermeasures, different modalities of mechanical stimulation, the use of exercise (e.g., impact loading), and pharmacological means to prevent bone loss should be evaluated.

If applicable to humans, a considerable amount of useful data on bone loss could be generated using animal models. The committee's priority recommendations are summarized as follows:

1. It should be determined if mechanisms of the bone changes produced by microgravity in animal models are similar to those in humans. Rodent models should include mice, given their smaller size and the availability of genetic variants and transgenic animals. Adult animals should be used. In-flight experiments should include animals exposed to centrifugal forces that reproduce 1-g conditions.
2. When an animal model is identified that mimics human bone changes in spaceflight, it should be used in ground-based models of microgravity, such as hindlimb-suspension unloading. If the ground-based model reproduces the changes observed under microgravity conditions, it should be used extensively to address questions of mechanisms.

A better understanding of the deleterious effects on skeletal muscle of spaceflight and reloading upon return to Earth is necessary to maintain performance and prevent injury. Even after missions of a few weeks, the locomotion of astronauts is very unstable immediately after they return to Earth, owing to a combination of orthostatic intolerance, altered otolith-spinal reflexes, reliance on weakened atrophic muscles, and inappropriate motor patterns. The committee's high-priority research recommendations are summarized below:

• Priority should be given to research that focuses on cellular and molecular mechanisms underlying muscle weakness, fatigue, incoordination, and delayed-onset muscle soreness.
• Ground-based models, including bed rest for humans and hindlimb unloading in normal and genetically altered rodents, should be used within and across disciplines to investigate the mechanisms

• underlying in-flight and postflight effects on muscle mass, protein composition, myogenesis, fiber type differentiation, and neuromuscular development.
• The mechanisms should be determined whereby muscle cells sense working length and the mechanical stress of gravity. Signal transduction pathways for growth factors, stretch-activated ion channels, regulators of protein synthesis, and interactions of extracellular matrix and membrane proteins with the cytoskeleton should be investigated.

The cardiovascular and pulmonary systems undergo major changes in microgravity, including reduced blood volume that is redistributed headward, increased heart volume, altered blood pressure and heart rate, and improved gas exchange in the lungs despite the surprising persistence of lung ventilation-perfusion inequalities. Many observational research questions have been answered. Future research should focus more on mechanisms. The committee developed a number of recommendations for specific research studies which are broadly summarized below.

• Reevaluate current antiorthostatic countermeasures, and develop and validate new ones. Priority should be given to interventions that may provide simultaneous bone and/or muscle protection.
• Extend current knowledge regarding the magnitude, time course, and mechanisms of cardiovascular adjustments to include long-duration microgravity.
• Determine the mechanisms underlying inadequate total peripheral resistance observed during postflight orthostatic stress.
• Identify and validate appropriate methods for referencing intrathoracic vascular pressures to systemic pressures in microgravity.

• Characterize gravity-determined topographical differences of blood flow, ventilation, alveolar size, intrapleural pressures, and mechanical stresses in microgravity during rest and exercise.
• Determine the extent to which pulmonary vascular and microvascular pressures and lymphatic flow are altered by microgravity and whether these changes have any impact on either aging or disease processes.
• Examine patterns of aerosol deposition, and determine whether ventilatory and nonventilatory responses to particulate or antigen inhalation are altered by microgravity.
• Identify changes in pulmonary function that occur during extravehicular activity (EVA), and establish resuscitation procedures for crew members in the event of loss of cabin pressure or EVA suit pressure.
• Evaluate respiratory muscle structure and function in microgravity, at rest, and during maximal exercise.

The endocrine, nervous, and immune systems regulate the human response to spaceflight and the readjustment processes that follow landing. The principal spaceflight responses to which there is a

significant endocrine contribution are the fluid shifts, perturbation of circadian rhythms, loss of red blood cell mass, possible alterations in the immune system, losses of bone and muscle, and maintenance of energy balance. With the advent of the space station era, the focus shifts from early responses to spaceflight to the long-term adaptive responses. The three chronic responses that are areas of serious concern are bone loss, muscle atrophy, and possibly the question of maintaining energy balance at an acceptable level. Priority should be given to studies that are designed to do the following:

• Ensure adequate dietary input during spaceflight. Energy intake must meet needs, and physiological measurements must be made on subjects that are in approximate energy balance so that measurements are not confounded by an undernutrition response. The relationship between the amount of exercise and the protein and energy balance in-flight should be investigated.
• Obtain a human hormone profile early and late in-flight and, as a control, preflight measurements on the same individuals over an extended period of time.
• Determine the effects of spaceflight on human circadian rhythms. If significant degradation of performance is found and it can be attributed to the disturbed circadian rhythm, explore the use of countermeasures, including a combination of light and melatonin.

As individuals stay longer in space, the potential effects of spaceflight on immune function become more significant. There is now convincing evidence that immunological parameters are affected by spaceflight, and important questions should be answered regarding both the biological and the medical significance of these effects and their mechanisms. Future immunological studies should concentrate on functional immunological changes that have been shown to be biologically and medically significant.

Rodent studies can be used to help determine the biological and/or biomedical significance of spaceflight-induced changes in immune responses. Both short- and long-term studies should be carried out, with priority given to those briefly summarized below:

1. Resistance to infection should be examined in animals immediately after their return from spaceflight.
2. Acquired immune responses should be examined, including specific humoral and cellular immune responses.

Immunological measurements and testing of humans should be carried out to examine parameters with potential functional consequences. The recommended studies are briefly summarized below:

1. Acquired immune responses should be examined as described above for animals.
2. Innate immune responses should be examined, including natural killer cell and neutrophil function.
3. Epidemiological studies should be conducted, as the population of astronauts and cosmonauts increases, to assess the potential risk of infection and, in particular, of the development of tumors.

Exposure of crew members to radiation in space poses potentially serious health effects that need to be controlled or mitigated before long-term missions beyond low Earth orbit can be initiated. The levels of radiation in interplanetary space are high enough and the missions long enough that adequate shielding is necessary to minimize carcinogenic, cataractogenic, and possible neurologic effects for crew members.

The knowledge needed to design adequate radiation shielding has both physical and biological components: (1) the distribution and energies of radiation particles present behind a given shielding material as a result of the shield being struck by a given type and level of incident radiation and (2) the effects of a given dose on relevant biological systems for different radiation types. Each component involves significant uncertainty that must be reduced to permit the effective design of shielding, given that the level of uncertainty governs the amount of shielding.⁶

The execution of the recommended strategies will require considerably more beam time at a heavyion accelerator than is currently available, and it is recommended that NASA explore various possibilities, including the construction of new facilities, to increase the research time available for experiments with high-atomic-number, high-energy (HZE) particles. Priority should be given to the following studies:

1. Determine the carcinogenic risks following irradiation by protons and HZE particles.
2. Determine how cell killing and induction of chromosomal aberrations vary as a function of the thickness and composition of shielding.
3. Determine whether there are studies that can be conducted to increase the confidence of extrapolation from rodents to humans of radiation-induced genetic alterations that in turn could enhance similar extrapolations for cancer.
4. 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.
5. Determine if better error analyses can be performed of all factors contributing to the estimation of risk by a particular method, and determine the types and magnitude of uncertainty associated with each method.
6. Determine how the selection and design of the space vehicle affect the radiation environment in which the crew has to exist.

Long-duration missions in space are likely to produce significant changes in individual, group, and organizational behavior. Future missions in space will involve longer periods of exposure to features of the physical environment unique to space and features of the psychosocial environment characteristic of isolated and confined environments. Evidence from previous space missions and from analogue studies suggests that behavioral responses to these environmental stressors will be influenced by characteristics of the individuals, groups, and organizations involved in long-duration missions.

The following list broadly summarizes, in order of priority, the recommended research for behavior and performance during long-duration missions in space:

1. Develop noninvasive qualitative and quantitative techniques for the ongoing assessment of preflight, in-flight, and postflight behavior and performance.

2. Investigate the neurobiological and psychosocial mechanisms underlying the effects of physical and psychosocial environmental stressors on cognitive, affective, and psychophysiological measures of behavior and performance. Such research should be conducted both in space and in ground-based analogue environments.
• Research on environmental factors should include an assessment of affective and cognitive responses to microgravity-related changes in perceptual and physiological systems and behavioral responses to perceived physical dangers, restricted privacy and personal space, and physical and social monotony.
• Research on physiological factors should include studies of behavioral correlates of changes in circadian rhythms and sleep patterns; changes in and stability of individual physiological patterns in response to psychosocial and environmental stress and their applicability to measures of in-flight behavior and performance; and the relationship between self-reports and external performance-related and physiological symptoms of stress.
• Research on individual factors should include studies of specific coping strategies and behavioral and physiological indicators of coping-stage transitions during long-duration missions; associations between general and mission-specific personality characteristics and performance criteria of ability, stability, and compatibility; changes in problem-solving ability and other aspects of cognitive performance in-flight; and changes in personality and behavior postflight.
• Research on interpersonal factors should include studies of the influence of crew psychosocial heterogeneity on crew tension, cohesion, and performance during a mission; factors affecting ground-crew interactions; and the influence of different styles of leadership and decision-making procedures on group performance.
• Research on organizational factors should include studies of the effect of differences in the cultures of the participating agencies on individual and group performance and behavior; the association between mission duration and changes in behavior and performance; and the organizational requirements for effective management of long-duration missions as they relate to task scheduling and workload and to the distribution of authority and decision making.

3. Evaluate existing countermeasures and develop new countermeasures that effectively contribute to optimal levels of crew performance, individual well-being, and mission success. These countermeasures include the following:
• Screening and selection procedures that are based on a "select-in" assessment of individual personality characteristics and interpersonally oriented psychological assessments of crew compatibility;
• Training programs that are team oriented and that enable crews to successfully address the social, cultural, and psychological issues likely to occur in-flight;
• Organizational countermeasures for filling unstructured time and reducing boredom and monotony;
• Clinical countermeasures, such as the use of psychoactive medications in microgravity environments and the use of voice analysis for monitoring the interpersonal performance of crews; and
• Design of spacecraft interiors and amenities to maximize control over the physical environment and reduce the impacts of physical monotony on behavior and performance.

This section summarizes the committee's recommendations for the highest-priority research across the entire spectrum of space life sciences. 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 directed primarily toward ground-based investigations designed to answer fundamental questions and frame critical hypotheses that can later be tested in space. Indeed, as this report emphasizes, understanding the basic mechanisms underlying biological and behavioral responses to spaceflight is essential to 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 crosscutting research place emphasis on ground-based studies.

Priority should be given to research aimed at ameliorating problems that may limit astronauts' health, safety, or performance during and after long-duration spaceflight. The committee emphasizes that specific priorities may shift to a significant degree depending on the types of missions to be carried out in the future, particularly as related to long-term human exploration of space. For this reason, the recommended areas of research are not given an order of priority.

Bone loss and muscle deterioration are among the best-documented deleterious effects caused by spaceflight in humans and animals. Exercise has been only partially successful in preventing muscle weakness and bone loss. Development of effective countermeasures requires advances in several areas of 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.
• Hormonal 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.

During the transitions in gravitational force that occur going into and returning from spaceflight, the vestibular system undergoes changes in activity that can result in debilitating symptoms in astronauts.

• The highest priority should be given to studies designed to determine the basis for the adaptive compensatory mechanisms in the vestibular and sensorimotor systems that operate both on the ground and in space.
• In-flight recordings of signal processing following otolith afferent stimulation should be made to determine how exposure to microgravity affects central and peripheral vestibular function and development.

• Motor learning should be investigated in spaceflight and the results compared with findings obtained in ground-based studies of this process.

Orthostatic hypotension, present since the very earliest human spaceflights, still affects a high percentage of astronauts returning from spaceflights even of relatively short duration and is an even greater problem for shuttle pilots, who must perform complex reentry maneuvers in an upright, seated position. The problem remains despite the use of extensive antiorthostatic countermeasures by both U.S. and Russian space programs. Studies should focus on determining physiological mechanisms and developing effective countermeasures.

• 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. 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 in long-term missions beyond low Earth orbit. High priority is given to the following recommended studies:

• 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 interacts closely with the neuroendocrine system. Results indicate a close association between the neuroendocrine status of the host and host defense systems.

• The role that the host response to stressors during spaceflight plays in alterations in host defenses should be determined.

The health, well-being, and performance of astronauts on extended missions may be negatively affected by many stressful aspects of the space environment. Mechanisms of response to physiological and psychosocial stressors encountered in spaceflight must be better understood in order to ensure crew safety, health, and productivity.

• Highest priority should be given to interdisciplinary research on the neurobiological (circadian, endocrine) and psychosocial (individual, group, organizational) mechanisms underlying the effects of physical and psychosocial environmental stressors. Cognitive, affective, and psychophysiological measures of behavior and performance should be examined in ground-based analogue settings as well as in-flight.
• High priority should be given to evaluation of existing countermeasures (screening and selection, training, monitoring, support) and development of effective new countermeasures.

Plants respond to changes in the direction of the gravitational vector by altering the direction of the 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.

• Studies of graviperception should concentrate on three problems:
• The identity of the cells that actually perceive gravity;
• The intracellular mechanisms by which the direction of the gravity vector is perceived; and
• 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.

It is known that in several systems sensory stimulation plays a role in the development of the neural connections necessary for normal processing of sensory information. The potential role of gravity in the normal development of the gravity-sensing vestibular system of animals is therefore an important area for ground- and space-based research.

• Ground-based studies should identify the critical periods in vestibular neuron development before initiation of experiments on the effects of microgravity on vestibular development.
• 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 on gravity, organisms should be grown through at least two full generations in space.

• Key model animals should be grown through two life cycles; the highest priority should be given to vertebrate models. If significant developmental effects are detected, control experiments must be performed 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.

Although NASA has responded effectively to many of the programmatic and policy issues raised in the 1987 and 1991 reports,^{7 8} significant concerns in the program and policy arena remain unresolved. These concerns focus on issues relating to strategic planning and conduct of space-based research; utilization of the International Space Station (ISS) for life sciences research; mechanisms for promoting integrated and interdisciplinary research; collection of and access to human flight data, specifically; publication of and access to space life sciences research in general; and professional education.

Future life sciences flight experiments on the ISS will depend on the availability of advanced instrumentation to carry out the measurements and analyses required by the research questions and approaches described in this report. In addition, facile data and information transfer between space- and ground-based investigators are crucial.

• NASA should work with the broad life sciences community to identify and catalyze the development of advanced instrumentation and methodologies that will be required for sophisticated space-based research in the coming decade.
• NASA should take advantage of advanced instrumentation developed in other countries.
• The capability for direct, real-time communication between space-based experimenters and principal investigators at their home laboratories should be a high-priority objective for the ISS.

Issues relating to the design and use of the ISS are a major concern of the committee. These issues include (1) changes in the design of the ISS, (2) the diversion of funds intended for scientific facilities and equipment into construction budgets, (3) the adequacy of power and transmission of data to and from Earth, (4) the availability of crew time for research, and (5) an extended hiatus in-flight opportunities for life sciences research owing to delays in ISS construction. These issues have alarmed the life sciences communities.

• To better ensure that the ISS will adequately meet the needs of space life sciences researchers, NASA should continue to bring the external user community as well as NASA scientists into the planning and design phases of facility construction.
• NASA should make every effort to mount at least one Spacelab life sciences flight in the period between Neurolab and the completion of ISS facilities.
• NASA should determine whether continuation of shuttle missions for short-term flight experiments after the opening of ISS would be economically and scientifically sound.

The Division of Life Sciences initiated a universal system of peer review in 1994 for all NASA-supported investigators. The new process has the committee's strong support.

• Responsibility for the establishment of peer review panels and for funding decisions should remain a function of the Headquarters Division of Life Sciences.
• NASA should regularly evaluate the composition of scientific review panels to ensure that the feasibility of proposed flight experiments receives appropriate expert evaluation.

• Principal investigators of projected flight experiments should be brought together with NASA managers and design engineers at the beginning of the planning process to function as an integrated team responsible for all phases of the planning, design, and testing. This integration should continue throughout the life of the project.
• NASA should regularly review and evaluate the NASA Specialized Centers of Research and Training (NSCORT) program to determine whether this mechanism provides the best way to foster interdisciplinary research and increase the scientific value of the life sciences research program.
• NASA should regularly review and evaluate the performance of the National Space Biomedical Research Institute and the impact of its funding on the overall life sciences research budget and program.

The disciplinary chapters of this report repeatedly stress the need for improved, systematic collection of data on astronauts preflight, in space, and postflight.

• NASA should initiate an ISS-based program to collect detailed physiological and psychological data on astronauts before, during, and after flight.
• NASA should make every effort to promote mechanisms for making complete data obtained from studies on astronauts accessible to qualified investigators in a timely manner. Consideration should be given to possible modifications of current policies and practices relating to the confidentiality of human subjects that would ethically ensure astronaut cooperation in a more effective manner.

An essential outcome of scientific research is publication—dissemination of results to the scientific community at large. The record of peer-reviewed publication, especially of spaceflight experiments, by funded investigators in NASA's life sciences programs needs to be improved, as does the usefulness of the Spaceline Archive to the scientific community.

• NASA should provide funding for data analysis and publication of flight experiments for a sufficient period to ensure analysis of the data and publication of the results.
• NASA should insist on timely dissemination of the results of space life sciences research in peer-reviewed publications. For investigators with previous NASA support, the publication record should be an important criterion for subsequent funding.
• NASA should take as a high priority the completion of data entry into the Spaceline Archive and should ensure that access to the archive is simple and transparent.

NASA should make every effort to ensure the professional training of graduate students and postdoctoral fellows in space and gravitational biology and medicine.

• NASA should take as high priority the support of a small, highly competitive program of postdoctoral fellowships for training in laboratories of NASA-supported investigators in academic and research institutions external to NASA centers.

1. Space Science Board, National Research Council. 1987. A Strategy for Space Biology and Medical Science for the 1980s and 1990s. National Academy Press, Washington, D.C.

2. Space Science Board, 1987, A Strategy for Space Biology and Medical Science for the 1980s and 1990s, p. xi.

3. Space Science Board, 1987, A Strategy for Space Biology and Medical Science for the 1980s and 1990s, p. 4.

4. Space Studies Board, National Research Council. 1991. Assessment of Programs in Space Biology and Medicine 1991. National Academy Press, Washington, D.C.

5. Space Science Board, National Research Council. 1987. A Strategy for Space Biology and Medical Science for the 1980s and 1990s. National Academy Press, Washington, D.C.

6. Wilson, J.W., Cucinotta, F.A., Shinn, J.L., Kim, M.H., and Badavi,F.F. 1997. Shielding strategies for human space exploration: Introduction. Chapter 1 in Shielding Strategies for Human Space Exploration: A Workshop (John W. Wilson, Jack Miller, and Andrei Konradi, eds.). National Aeronautics and Space Administration.

7. Space Science Board, National Research Council. 1987. A Strategy for Space Biology and Medical Science for the 1980s and 1990s. National Academy Press, Washington, D.C.

8. Space Studies Board, National Research Council. 1991. Assessment of Programs in Space Biology and Medicine 1991. National Academy Press, Washington, D.C.