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Assessment of Programs in Space Biology and Medicine 1991 Summary INTRODUCTION This report was undertaken at the request of the Space Studies Board to provide an up-to-date assessment of the status of the implementation in the civil space program of the various research strategies and recommendations published in previous reports. This report limits its comments to information contained in the three most recent reports (SSB 1979, 1987, and 1988). The most comprehensive strategy was the report published in 1987, A Strategy for Space Biology and Medical Science for the 1980s and 1990s (SSB, 1987), edited by Jay Goldberg, University of Chicago. The Goldberg Strategy (as the 1987 strategy report is referred to in this report) forms the primary basis for the current evaluation, although reference is also made to several previous reports concerning life sciences by the Committee on Space Biology and Medicine (CSBM) and the Life Sciences Task Group of the Space Science Board that was part of the 1988 Space Science in the Twenty-First Century report. Space biology and medicine includes—in addition to biological and medical subdisciplines—human behavior, radiation, and closed ecological life support systems. The Goldberg Strategy defined four major goals: 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.

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The first two goals have taken on new emphasis since the announcement of the Space Exploration Initiative (SEI), enunciated by the President in July 1959, for a sequential progression of human activities in space, and extending potential human missions to years in duration. In discussing the major imperatives for research in space biology and medicine, this assessment of the implementation of the research strategies has categorized research topics relative to the urgency that would be dictated by proceeding with a space exploration initiative. The conduct of research in space biology and medicine is influenced by the way the civil space agency, National Aeronautics and Space Administration (NASA), is structured and managed. Consequently, previous reports by. CSBM have contained numerous recommendations concerning science program and policy issues. Because of the importance of these issues in approaching the various research goals, progress in implementation of these goals is discussed at the outset. This is followed by topics that have the greatest potential of affecting human performance and/or survivability during sustained space exploration. These topics include research areas concerning human physiology in microgravity, human behavior during long-term missions, and the radiation environments of space. Finally, the report contains sections on developmental and cell biology, human reproduction, plant biology, and issues associated with the development of a closed ecological life support system. The latter topics reflect areas that, while not deemed crucial to survival in space for durations of a few years, could become critical to longer term human habitation. In addition, these topics represent major research areas in which space could be especially valuable in the study of basic biological phenomena. SCIENCE PROGRAM AND POLICY ISSUES Published strategy reports (e.g., SSB 1979, 1987, 1988) contain recommendations concerning how NASA manages its life sciences research and the design and utilization of laboratory space on a space station. In the area of management, recommendations were as follows: 1. Standing panels of 5 to 10 scientists be created to review, update, and refine research strategies in each subdiscipline of space biology and medicine. 2. Announcements of Opportunity (AOs) and NASA Research Announcements (NRAs) concerned with Shuttle flights and the space station should be targeted to a particular subdiscipline and should state explicitly the major research questions that the mission is intended to address. 3. NASA should actively solicit the participation of other relevant federal agencies such as NIH and NSF in the design and conduct of research related to the major questions that need to be answered.

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Recommendations related to a space station were as follows: 1. A space station should contain a dedicated life sciences laboratory, and research time should be allocated in 3- to 6-month increments for individual subdisciplines. 2. A variable force centrifuge of the largest possible dimensions should be incorporated into a space station. 3. Dedicated microprocessors should be used for process control, data storage, or both, and rapid communication in real time with ground-based research teams should be a goal. In the area of management, NASA either has implemented or is in the process of implementing all of the recommendations made. The internal life sciences advisory has been reorganized as recommended. The NRAs that are now being released are more highly focused, and NASA is now actively cooperating with other federal agencies such as National Institutes of Health (NIH), National Science Foundation (NSF), and the U.S. Department of Agriculture (USDA), as well as numerous foreign partners. None of the recommendations concerning design and utilization of the space station have been implemented in current plans for the facility; however, planning for inclusion of a centrifuge is under way. RESEARCH IN SPACE BIOLOGY AND MEDICINE Human Physiology There has been a general perception that since a small number of Soviet cosmonauts have survived in the microgravity of space in low earth orbit for as long as a year, there are no major physiological problems likely to preclude longer term human exploration beyond low earth orbit. The committee has had, over the years, access to anecdotal data from the Soviet space program. This anecdotal information is, while interesting, not sufficiently reliable for drawing conclusions or in planning the U.S. program for a number of reasons. There are differences in experimental protocols and controls in laboratory equipment, and the Soviets do not publish their results in refereed scientific journals. However, increased recent cooperative activities between the Soviets and the United States suggest promise for the future in standardized experimental procedures and data exchange. The current evaluation of progress in space biology and medical research illustrates that all of the major physiological problems characteristic of prolonged human exposure to the microgravity environment of space remain unsolved.

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First, and of greatest concern, is bone, muscle, and mineral metabolism; second, cardiovascular and homeostatic functions; and third, sensorimotor integration. Bone, Muscle, and Mineral Metabolism Eight major goals were defined for the study and bone and mineral metabolism: (1) determine the temporal sequence of bone remodeling in response to microgravity; (2) establish the reversibility of this process on return to a 1-g environment; (3) establish the relationship between muscle activity and bone function; (4) devise countermeasures to prevent bone loss; (5) establish the cellular mechanisms responsible for bone loss; (6) evaluate the interdependence of calcium homeostasis and bone remodeling; (7) determine the etiology of pathologic calcification; and (8) establish the biomechanics of the skeleton under microgravity conditions. Understanding the etiology of bone loss (osteopenia) is the focus of an enormous research program within the NIH as well as an area of research that has received major attention by NASA scientists—especially over the past 5 years. NASA scientists and others supported by NASA have developed an animal model to study bone loss. In addition, human studies correlating inactivity (bed rest) to factors such as diminished bone mass and increased urinary calcium have also proven to be useful models for potential changes during extended spaceflight. However, of the eight major goals listed above, only the first has been addressed in these studies, and the information that has been obtained using the animal model chosen (rat) is of limited value because of the dissimilarities between bone physiology in rats and normal human physiology. Considerable research remains to be conducted. Increased interaction with the major research effort at NIH would be of enormous value for solving the overall problems of bone and muscle atrophy that have been observed in microgravity. Cardiovascular and Other Homeostatic Systems The cardiovascular and neuroendocrine elements of the circulatory system focus respectively on basic cardiovascular function and the influences of regulatory systems on these functions. Additional areas under this topic include immunology, hematopoiesis, and wound healing. Circulatory Adjustments The major goals have been to (1) understand acute (0 to 2 weeks), medium-term (2 weeks to 3 months), and long-term (greater than 3 months) changes in the cardiovascular system in microgravity; (2) examine the validity of ground-based models of microgravity-induced changes; and (3) define measures (countermeasures) that will alleviate changes in microgravity and hasten human adaptation upon return to a 1-g environment. A better understanding of cardiovascular and pulmonary physiology in microgravity has been a major goal of previous, current, and planned

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investigations. Measurements on humans before, during, and after several Shuttle flights have provided echocardiographic data on cardiac dimensions and function. Some countermeasures such as oral saline loading have been tested to prevent post-flight orthostatic hypotension. A major drawback has been the limited number of subjects available for study. There is a need to develop animal models for both ground-based and flight experiments. Hormones that affect the cardiovascular system also remain to be tested in the context of cardiovascular changes that occur in space. Some hormone measurements were conducted on Skylab flights, and additional studies are planned on upcoming Shuttle flights. However, many of these experiments fail to take into account fairly recent observations concerning the rhythmic nature of changes as a function of circadian variations. Immunology Immune cells in mammalian bone marrow and lymphoid organs initiate and regulate lymphocyte and antibody responses as well as control the production and function of cells in the blood and connective tissues. The major goal in this area is to determine if cells of the immune system can proliferate in space and maintain a normal immune system. The occurrence of serious infections in space has been very uncommon, and most studies of immunity in space have been directed to the detection of abnormalities in human and animal lymphocyte numbers and morphology in space. Spaceflight is known to result in significant reductions of both plasma volume and red blood cell mass within days. Recent studies have shown that lymphocytes do not respond to stimuli that normally cause division, suggesting an impaired ability to proliferate in space. This could have profound implications to the immune and hematopoietic system. An expanded effort to investigate possible immune deficiencies coupled with the development of cell models to test immune and bone cell function in microgravity requires a higher priority. Sensorimotor Integration As indicated in the Goldberg report, the neuronal mechanisms underlying a sense of spatial orientation are complex, as yet poorly understood, and are directly relevant to assuring the effective functioning of humans involved in space missions. The 1987 strategy report recommended a vigorous program of ground- based and flight research aimed at understanding these mechanisms as they operate on earth, in space, and on return from microgravity to high-gravity environments. These studies become all the more significant if one considers the use of artificial gravity (rotating spacecraft) as an attempt to ameliorate the effects of microgravity on human physiology. Specific goals are to (1) study in microgravity how the vestibuloocular reflex (VOR) converts head motion into compensatory eye movement, (2) investigate the neural processing mechanisms in the vestibular system in both normal gravity and microgravity, (3) focus on adaptive mechanisms that alter vestibular processing in response to altered feedback from the environment, and (4) investigate more fully the etiology of motion sickness in microgravity.

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Overall, NASA has made a concerted effort to undertake appropriate, quality research in the sensorimotor area. These efforts include many studies supported through external investigators and the establishment of an excellent Vestibular Research Facility (VRF) at Ames Research Center. In spite of limited flight opportunities, considerable progress has also been made studying sensorimotor performance in microgravity. Several planned experiments are promising. However, in spite of this generally positive view, no single countermeasure has yet been developed that corrects the problem of space motion sickness. Perhaps the syndrome, with individual variations, is actually several distinguishable syndromes. This possibility, if documented, might dictate new research approaches. Behavior, Performance, and Human Factors The major goals for space research as it relates to human behavior are to develop (1) spacecraft environments, (2) interfaces with equipment, (3) work- leisure schedules, and (4) the social organization that will optimize the efficiency, safety, and satisfaction of crews during long-term spaceflight. With the exception of group and organizational factors, there is research in progress along the lines recommended in published research strategies. Much of the progress that has occurred derives from well-funded research programs in aviation sponsored by the Federal Aviation Administration (FAA) and to a lesser extent from NASA's aviation research program. However, this type of research, while useful, cannot provide all of the information needed to support a long-term human presence in space. As opportunities for experimentation that will exist during long-duration spaceflight will always be extremely limited, there must be a well-developed ground-based program of research employing a variety of research settings. At this point in time, NASA has no plans to develop long-term confinement studies using ground-based research settings. Developmental and Cell Biology The major goal for developmental biology as outlined in all three research strategies is to determine whether any organism can develop from fertilization through the formation of viable gametes in the next generation, i.e., from egg to egg, in the microgravity environment of space. In the event that normal development does not occur, the priority is to determine which period of development is most sensitive to microgravity. Potentially, research on specific developmental phases (e.g., fertilization to initial organ formation) would suggest detailed studies on the function and differentiation of individual cells or groups of cells. In approaching these goals, we have recommended studies on several representative organisms including both invertebrate and vertebrate animals. While the latter would include mammals such as mice, it also encompasses the

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question, can humans reproduce in space? The importance of these questions relates to the ability to establish permanent human colonies in space as well as to the possibility that the space environment could be a particularly advantageous environment to study basic developmental research. A number of diverse organisms have been subjected to microgravity for varying periods of time. The results of these studies have been inconsistent. Both normal and abnormal development have been observed, dependent on the organism and the stage of development at which the material was subjected to microgravity. To our knowledge, no animal species has ever been carried through one complete life cycle in the microgravity of space. Plant Biology Any strategy that visualizes a long-term sustained human presence in space absolutely requires the ability to continuously grow and reproduce various plant species over multiple generations. A related goal, which has implications for agriculture generally, is to understand the mechanism(s) involved in gravity sensing by plants. This requires an emphasis on ground-based research as well as research in space. For the most part, observations on plants exposed to microgravity have been anecdotal. It has been demonstrated repeatedly that plants do grow in microgravity. However, whether plants can grow normally remains to be determined. Significantly, results of studies on the German D-1 mission, which incorporated onboard 1-g centrifuge controls, indicate that single plant cells behave normally or even exhibit accelerated development. In contrast, the roots of seedlings germinated in microgravity grew straight out from the seed, and the same roots contained starch grains (statolyths) which were more or less randomly distributed in their cells. Control roots centrifuged at 1 g on the flight, were normally gravitropic. Cytological studies of roots flown under a variety of conditions in space have consistently revealed reduced cell divisions as well as a variety of chromosomal abnormalities. At the same time, some Soviet experiments using the plant arabdiposis indicate that at least this plant develops normally through the flowering stage. However, in the Soviet experiments, fruit set was decreased and seeds brought back to earth germinated less efficiently than ground based controls. Long-term flight experiments are required to determine if a variety of plant species can grow normally in microgravity and, in particular, if they can produce viable seeds. Closed Ecological Life Support Systems

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The closed ecological life support system (CELSS) program at NASA is attempting to create an integrated self-sustaining system capable of providing food, potable water, and a breathable atmosphere for space crews during missions of long-term duration. An effective CELSS must have subsystems both for plant and animal growth, food processing, and waste management. These have been described to some extent on previous pages. A CELSS must be much more than a "greenhouse in space." It must be a multispecific ecosystem operating in a small closed environment. Thus, although the concept is easily articulated, numerous areas of ignorance remain. Based on consideration of primarily agricultural plant species, a small number have been selected for further investigation. These include wheat, potato, soybean, and tomato. Growth chamber studies have been initiated, both at NASA and in university laboratories, with the aim of defining the conditions required for optimum rates of dry matter production. Although most research has been done with open systems, experiments with closed systems have recently been initiated. No attention has been paid to the use of techniques of plant breeding or genetic engineering to "design" ideal plants for a CUSS system. No experiments have yet been performed in microgravity to determine if current systems can function in space. In short, a considerable increase in research efforts, and support for those efforts, is required in order to reach the desired goals. Radiation Biology While the radiation environment within the magnetosphere is fairly well known, as are the biological effects of low energy transfer (LET) radiations from protons and electrons, considerably better quantitative data on LET dose rates beyond the magnetosphere are still required. In particular, better predictability of the occurrence and magnitude of energetic particles from solar flares is required; radiation from solar flares can be life-threatening in relatively short time periods. Major goals of radiation research are to quantify high-energy (HZE) particles in space and to understand the biological effects of HM particles. The likely long- term biological effects of exposure to HZE particles is an increased incidence of cancer and brain damage. NASA has maintained a limited but ongoing research program both in radiation dosimetry and radiobiology including ground-based programs on the effect of fragmentation of HZE particles and on the secondary particles. In the field of radiobiology, NASA has supported studies dealing with the biological effects of HZE particles. Limited flight data suggest a synergism between HZE particle hits and microgravity. This research requires increased attention. In particular, ground-based studies on biological effects of HZE particles are currently performed in the United States at the Billion Electron Volts Linear Accelerator (BEVALAC) at Lawrence Berkeley Laboratory. This research may be drastically curtailed if the facility is unavailable after 1993 as is currently planned. Use of similar facilities in other countries, while feasible, is not necessarily

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practical because of the necessity for transporting large numbers of animals and associated experimental controls, and regular transport and accommodation of U.S. research teams. CONCLUSIONS Over the past 30 or more years, the Space Studies Board and its various committees have published hundreds of recommendations concerning life sciences research. Several particularly noteworthy themes appear consistently: (1) balance—the need for a well- balanced research program in terms of ground versus flight, basic versus clinical, and internal versus extramural; (2) excellence—because of the extremely limited number of flight opportunities (as well as their associated relative costs), the need for absolute excellence in the research that is conducted, in terms of topic, protocol, and investigator, and (3) facilities—the single most important facility for life sciences research in space, an on-board, variable force centrifuge. In this first assessment report, the Committee on Space Biology and Medicine emphasizes that these long-standing themes remain as essential today as when first articulated. On the brink of the twenty-first century, the nation is contemplating the goal of human space exploration; consequently, the themes bear repeating. Each is a critical component of what will be necessary to successfully achieve such a goal.