11
Programmatic and Policy Issues

The 1998 Strategy report raised concerns in the program and policy arena, including issues relating to strategic planning, the conduct of space-based research, and utilization of the International Space Station (ISS), as well as mechanisms for promoting integrated and interdisciplinary research and collection of and access to human flight data (NRC, 1998). The following sections summarize concerns remaining in these areas. In addition, the chapter describes several important issues having to do with countermeasure testing and validation and the role of the Space Medicine Program in human research that came to the committee’s attention during the course of the present study.

INTERNATIONAL SPACE STATION: UTILIZATION AND FACILITIES

The adequacy of research facilities on ISS remains a serious concern. One new issue has arisen with respect to the variable force centrifuge. The committee understands that the amount of power available for the centrifuge may be substantially below initial specifications. It is not clear to the committee whether and to what extent the usefulness of this crucial instrument may be compromised by possible power limitations.

Previous concerns about the effects of cuts in the utilization budget on the capacity of ISS to support high-quality research remain in force. Timetables for incorporation of relevant research facilities and equipment have been eroded by continuing budget cuts and delays in assembly schedules for research facilities, and the confidence of the user scientific community continues to be eroded by the perceived potential for downgrading of research capabilities and budgets. The most recent assembly sequence available to the committee (June 1999) is summarized in Table 11.1. Limited capability for human research is scheduled to begin in mid-2000, with further addition of instrument racks and a –80 °C life sciences freezer by mid-2001. The second human research facility is to be added in March 2001. However, habitat holding facilities and the life sciences glove box, necessary for animal and tissue culture experiments, will not be available until 2003, and the variable speed centrifuge is not scheduled until mid-2004.



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Review of NASA’s Biomedical Research Program 11 Programmatic and Policy Issues The 1998 Strategy report raised concerns in the program and policy arena, including issues relating to strategic planning, the conduct of space-based research, and utilization of the International Space Station (ISS), as well as mechanisms for promoting integrated and interdisciplinary research and collection of and access to human flight data (NRC, 1998). The following sections summarize concerns remaining in these areas. In addition, the chapter describes several important issues having to do with countermeasure testing and validation and the role of the Space Medicine Program in human research that came to the committee’s attention during the course of the present study. INTERNATIONAL SPACE STATION: UTILIZATION AND FACILITIES The adequacy of research facilities on ISS remains a serious concern. One new issue has arisen with respect to the variable force centrifuge. The committee understands that the amount of power available for the centrifuge may be substantially below initial specifications. It is not clear to the committee whether and to what extent the usefulness of this crucial instrument may be compromised by possible power limitations. Previous concerns about the effects of cuts in the utilization budget on the capacity of ISS to support high-quality research remain in force. Timetables for incorporation of relevant research facilities and equipment have been eroded by continuing budget cuts and delays in assembly schedules for research facilities, and the confidence of the user scientific community continues to be eroded by the perceived potential for downgrading of research capabilities and budgets. The most recent assembly sequence available to the committee (June 1999) is summarized in Table 11.1. Limited capability for human research is scheduled to begin in mid-2000, with further addition of instrument racks and a –80 °C life sciences freezer by mid-2001. The second human research facility is to be added in March 2001. However, habitat holding facilities and the life sciences glove box, necessary for animal and tissue culture experiments, will not be available until 2003, and the variable speed centrifuge is not scheduled until mid-2004.

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Review of NASA’s Biomedical Research Program TABLE 11.1 International Space Station Assembly Sequence for Biomedical Research Facilities Date Flight Element Deployed June 2000 5a.1 Human Research Facility-1 January 2001 UF-1 Minus Eighty Degree Freezer March 2002 12A.1 Human Research Facility-2 February 2003 UF-3 Habitat Holding Rack-1 Life Sciences Glovebox September 2003 UF-5 Habitat Holding Rack-2 August 2004 UF-7 Centrifuge Accommodation Module NOTE: Based on Revision E assembly sequence. Questions also remain about the role of Russian cosmonauts in the conduct of biomedical research, especially during the early phases of ISS utilization. Issues that must be clarified include the nature and extent of the training these crew members will receive for the conduct of ISS-based research protocols, their commitment to participate as subjects in human studies, and the nature and adequacy of postflight longitudinal follow-up to such human research studies. In conclusion, the adequacy of the life sciences research facilities that will actually be in place on the ISS at its final build-out remains an issue of serious concern. Possible design changes, the mounting delays in utilization timetables, and the perceived potential for downgrading of research facilities and budgets have continued to erode the confidence of the user scientific community. Important questions also remain about the role of Russian cosmonauts in the conduct of biomedical research, especially in the early phases of ISS utilization. COUNTERMEASURE TESTING AND VALIDATION The availability of effective countermeasures against the deleterious effects of spaceflight on astronaut health and performance will be an increasingly critical issue as longer-duration flights become the norm on the ISS and beyond. Development of effective, mechanism-based countermeasures requires three well-integrated phases: (a) basic research, ground-based and in flight, to identify and characterize mechanisms of spaceflight effects; (b) testing and evaluation of proposed countermeasures, to determine their efficacy in ground-based models of the flight environment; and (c) validation of promising countermeasures by well-designed clinical studies in flight as well as pre- and postflight. Maintenance of a longitudinal database documenting relevant physiological and performance parameters in the presence and absence of the given countermeasure will be crucial to validating efficacy. Basic research whose ultimate goal is the development of improved countermeasures is a primary mission of the National Space Biomedical Research Institute (NSBRI) and a major component of the life sciences NASA Research Announcement (NRA) program overall, while Johnson Space Center (JSC) has primary responsibility for ground-based testing and evaluation of proposed countermeasures. There has been no well-established, standard procedure whereby newly proposed countermeasures can gain access to the evaluation pipeline, and well-defined, published criteria for accepting candidate countermeasures for testing appear to be lacking. A defined process for carrying out such testing and evaluation is currently under development at JSC but has not yet been implemented. It is essential that

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Review of NASA’s Biomedical Research Program the process be readily accessible to all investigators, extramural as well as intramural, and that criteria for acceptance into the testing program be clearly defined. Just as a drug must be proven safe and effective before being used clinically, a countermeasure must be validated to establish that it prevents or ameliorates the problem it addresses and does not show significant unanticipated side effects in physiological systems. Initially, the Detailed Supplemental Objective (DSO) program, based at JSC, provided the mechanism for studies to validate countermeasures in flight. Its successor, the Extended Duration Orbiter Medical Project (EDOMP), was established when Shuttle flights became 16 days or longer. EDOMP has continued the practice of including testing as a secondary mission objective, with the goal of optimizing crew performance. In general, however, the practice of carrying out countermeasure validation as a secondary mission objective has not succeeded in providing definitive answers, even when tests are well designed, because of in-flight modifications or suboptimal conduct of protocols. Countermeasure validation can take many forms and requires a firm definition when spaceflight countermeasures are discussed. The committee considered three types of validation for spaceflight countermeasures: (a) controlled trials in space, (b) comparison with historical controls, and (c) empirical observation of effects. Controlled Trials in Space The double-blind, placebo-controlled trial is the standard for many therapies in clinical practice and should be the standard whenever possible for spaceflight investigations. Several factors, however, have limited the number of these trials in space. First, the number of subjects is necessarily limited. The number of subjects required to show a statistically significant effect is based on a power calculation. For example, consider a study of bone loss in which two treatments are compared with a placebo and the end point is to detect a 1 percent difference in bone density. Based on published data on machine precision and measurement variability, it could take approximately 64 subjects per group to provide an 80 percent probability of seeing a significant effect at a 95 percent confidence level. Clearly, this would take years to complete on the Space Station, even if other confounding factors could be removed. The second limitation involves the environment and the variability of mission length, medication, exercise protocols, diet, and so forth, which cannot be controlled reliably over a series of missions with different goals. The third limitation is blinding. Not all treatments (exercise protocols, for example) can be evaluated in a double-blind fashion. Finally, the use of placebos is problematic. Depending on the nature of the clinical problem, operational pressures are likely to lead to preferring some treatment, even if unvalidated, rather than letting the problem develop uncountered. To deal with these limitations, each countermeasure and problem has to be scrutinized carefully. Can a meaningful trial be performed with the sample size available, or is only a less rigorous validation possible and sufficient? Will an unblinded trial or a comparative trial without placebo be acceptable? Recent advances in statistical theory have made the conduct of small-sample clinical trials more feasible. Use of expert statistical consultants on a continuing basis to assist in the design and analysis of countermeasure studies would be an important addition to the overall countermeasure program. In addition, ground-based trials in analogue settings provide important information on the potential effectiveness of candidate countermeasures in spaceflight. Only the most critical countermeasures should have the highest level of validation, but if this is the required approach, all of the resources needed to do the study correctly must be provided.

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Review of NASA’s Biomedical Research Program Use of Historical Data Although a placebo-controlled trial may not be possible, a comparison of the effects of the countermeasure on the variable of interest with historical data may still provide some level of validation. An example might be the effects of a drug or treatment on urinary calcium excretion. This approach would provide some evidence that a drug or intervention is having a positive effect. Unfortunately, existing data are fragmentary and are not generally available to investigators. A rigorous, active program is required to collect and tabulate data from Shuttle and Space Station missions. Without an accurate and accessible database on the human responses to weightlessness and the incidence of various conditions, the historical approach cannot work. This means that the data collected on any mission are critical and may be essential for evaluating countermeasures in the future. A well-defined set of baseline data collected on all missions and available to investigators is crucial for the development and validation of optimally effective countermeasures. Empirical Observation Countermeasures have generally been implemented without in-flight validation. Some have been implemented with little or no evaluation, and others have been implemented based on effectiveness in ground-based studies or in analogue settings. It is likely that the pressures of operations and the difficulty of conducting controlled trials may continue to make this approach a frequent basis for implementation. However, for this level of validation to work, the ground-based analogue setting must have high fidelity to flight conditions, and a rigorous and consistent method of review is essential. The efficacy of the countermeasure must be monitored by continued, ongoing evaluation and assessment. Data should be collected to ensure that the problem is in fact being addressed and that other unanticipated effects are not occurring. For example, the fluid loading countermeasure against orthostatic intolerance has been implemented for spaceflight. Is this being well tolerated? Are there problems with gastric upset or vomiting due to the high osmotic load? What is the level of participation? Has the incidence of pre-syncope decreased? Without ongoing review, the countermeasure cannot be improved, problems will not be uncovered, and astronauts will be exposed to increased risk. The committee recognizes the difficulties involved in proving that spaceflight countermeasures are effective. Validation, however, is essential and should be explicitly addressed for every proposed and implemented countermeasure. The main questions should be the following: Is this a countermeasure that requires validation in flight, and if so, how many subjects will be needed to prove the effect? Are appropriate data currently being collected that are likely to be useful for countermeasure development in the future? Is a rigorous countermeasure evaluation and assessment program in place to monitor any adopted countermeasure? The need for effective countermeasures against deleterious effects of spaceflight on astronaut health and performance will become increasingly critical as longer-duration flights become the norm on the ISS and beyond. Development of effective, mechanism-based countermeasures requires three well-integrated phases: (a) basic research to identify and understand mechanisms of spaceflight effects; (b) testing and evaluation of proposed countermeasures to determine their efficacy; and (c) validation of promising countermeasures by well-designed clinical studies. Re-

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Review of NASA’s Biomedical Research Program cently NASA has begun to develop a standard procedure for the testing and evaluation of countermeasures, but this has not yet been implemented. It is essential that the process, once in place, be readily accessible to all investigators, extramural as well as intramural, and that criteria for acceptance into the testing program be clearly defined. OPERATIONAL AND RESEARCH USE OF BIOMEDICAL DATA As discussed above for countermeasure validation, historical data are essential to establish in-flight physiologic norms and the incidence of adverse events. For example, the mean urinary calcium excretion in space is high. If a drug were used to decrease calcium excretion, one way to measure its effectiveness would be to compare calcium excretion from people on the drug to an accurate historical mean. For long-duration flights, a series of medical evaluation requirements, the Integrated Testing Regimen (ITR) has been proposed. Many of these tests, such as blood analyses, body mass, and extravehicular activity (EVA) heart rates, will be important not just for the health and safety of the person providing the data, but also for clinical research intended to establish norms and trends to benefit future flyers. Clinical investigators should be involved in identifying the parameters to be tested. Access is limited to these in-flight data, as well as to data collected in postflight longitudinal monitoring of astronaut health. Incomplete availability of human data to qualified investigators was highlighted as a major concern in the Strategy report. Individual data collected as part of the medical operations program are confidential. However, aggregate data, which cannot be attributed to an individual, are not. These data are critical for detecting trends and for developing and evaluating countermeasures. The rationale for selection of measurements to be made in flight and postflight is not clear, and should be held to the same high standard as the selection of research protocols. In fact, they should be treated as research data using the same rigor and control found in research studies. Data should be provided to the scientific community and reviewed periodically to ensure that a useful, accurate database is being established. The Strategy report recommended that expert scientific panels be employed to determine which data must be collected to serve research purposes appropriately. Long-duration human spaceflight is an ongoing research and development effort. The right to individual privacy and confidentiality is an established national policy; therefore, nonattributable medical data are essential to the future of crewed spaceflight and require careful oversight, review, and publication. The Role of Medical Operations in Human Research and Countermeasure Validation Role of the Crew Surgeon The ISS Medical Operations Requirements Document proposes routine nominal health and fitness evaluations for crews during flight (NASA, 1998b). The crew surgeon will play a major role in defining crew member activities before, during, and after flight. The surgeon will participate in and provide oversight of the medical care of crew members during the launch, in-flight, and landing phases of the mission; perform medical certification; monitor medically hazardous training events; require biomedical baseline data collection; develop and implement in-flight countermeasures; review mission payload activities; establish in-flight time line and scheduling constraints; develop mission-specific aeromedical flight rules; and staff the Mission Control Center during flight. A mandatory period of postflight rehabilitation with milestones for return to 1 g normal health will be imposed. The high priority and demanding nature of this medical operations program leave little room for scientific investigation on humans. Given the command position of the crew surgeon, who is responsible for implementing and

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Review of NASA’s Biomedical Research Program verifying countermeasures, rigorous training in clinical and basic research is recommended. Such training would greatly facilitate the communication and working relationship of investigators with NASA operational medicine programs during the flight investigation and would enhance scientific returns. In addition, better coordination in flight is necessary to minimize the deleterious effects of operational exigencies on the successful conduct and completion of research experiments. Collection of Longitudinal Human Data for Research Purposes The Astronaut Medical Evaluation Requirements Document requires extensive blood work on landing day, but minimal blood work later (NASA, 1998a). From a research perspective, the list of measurements and the sampling schedule have not been optimized to give the most useful information on in-flight development of problems and postflight recovery of normal physiological function. As recommended by the Strategy report, the definition of what and when measurements should be taken in flight and in longitudinal studies postflight (e.g., for the integrated testing regimens) requires input from experts in the relevant disciplines to optimize the return of health and science information. As long as the use of this information remains restricted and scientific input into what should be measured is lacking, the utility of this information in aiding the development of countermeasures will be severely curtailed. In addition, it will be important for NASA to foster the development of advanced technologies to provide automated noninvasive and minimally invasive in-flight and longitudinal monitoring for acquisition of the desired data. Effects of Spaceflight on Drug Efficacy and Pharmacokinetics There have been a number of largely anecdotal reports of altered drug efficacy or changes in pharmacokinetics in spaceflight. Although clinical pharmacology was not emphasized in the Strategy report, carefully designed clinical research is needed to determine whether there are significant changes in the effectiveness of drugs of interest, to define likely causes, and to develop effective countermeasures. Availability of Stored Clinical Samples A large bank of frozen clinical samples (urine, blood, etc.) has been saved over time and stored at JSC. If the quality of the samples has been maintained, these materials could be of significant interest and value for ongoing and future research purposes. However, the quality of some or all of the older material may have been compromised by freezer malfunctions over the years, and the issue of patient confidentiality as related to ongoing availability of samples to the investigator community has not been addressed. Efforts should be made to determine which sets of samples are of appropriate quality and to explore means of making them known and generally accessible to the relevant investigator community. Data Archive Timely completion of an archival research database was assigned high priority in the Strategy report. The Life Sciences Data Archive within the Program Integration Office at JSC is responsible for this activity, which is ongoing. However, the committee is concerned that uncertainties in funding for data entry have impeded the ability of the office to bring the archive up to date. The data archive is an

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Review of NASA’s Biomedical Research Program important tool in making the results of NASA’s biomedical investigations accessible to the research community, and NASA should consider completion of the project a priority. In summary, access to in-flight biomedical data, as well as to longitudinal data collected in postflight longitudinal monitoring of astronaut health, is limited. The partial and incomplete availability of human data to qualified investigators was highlighted as a major concern in the Strategy report and continues to be an issue. The committee urges that NASA explore ways in which these data and samples, collected in the past and future, can be made available to investigators. Additionally, steps are needed to ensure that future data collection includes measurements and sampling that have been optimized to give the most useful information on in-flight development of problems and postflight recovery of normal physiological function. The role played by the crew surgeon is especially critical to collection of these data, and rigorous training in both clinical and basic research is recommended as a requirement for the position. SCIENCE POLICY ISSUES Support of Operational Research Operational or applied research can be defined as research that is targeted to solve a specific, often narrowly defined, problem—for example, the optimal prebreathing protocol for EVAs. Operational research of this kind has generally been carried out intramurally, via the DSO or more recent EDOMP program. There is concern that in the context of peer review carried out under the life sciences NRA program, such research may sometimes be considered of lesser interest and priority than “basic” studies, even though the problem in question may have significant import for astronaut health, safety, and performance. However, extramural investigators will often bring important expertise and insight to issues requiring operational research and should be encouraged to carry out such studies. Focused NRAs designed to elicit proposals dealing with operational research issues, in conjunction with focused peer review groups, would provide a mechanism for the entire research community, intramural and extramural, to address areas of specific need more effectively. In addition, NASA should make a greater effort to acquaint applicants and investigators with the flight milieu as it relates to practical issues of space-based research protocols and expectations. International Cooperation The Division of Life Sciences is to be congratulated on its successful establishment of a process of international peer review with its European partners that provides scientific review of all investigator-initiated proposals. This is an important advance and a noteworthy example of international cooperation. The committee looks forward to the possibility that additional members of the international space community will enter the international peer review process in the future. The recent establishment of an International Space Life Sciences Working Group is also a positive step toward ensuring coordination of research activities among the international partners in the ISS. In addition, however, the era of ISS construction and utilization, with its increased emphasis on international crews and operations, raises important issues with respect to acquisition and management of human data. Mechanisms are needed to ensure that protocols and facilities for pre- and postflight monitoring and testing are consistent across national boundaries. There have to be common criteria for evaluation and utilization of countermeasures and international cooperation in their development.

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Review of NASA’s Biomedical Research Program Integration of Research Activities Roles of Program Constituents With the advent of NSBRI, continued attention will be necessary to define the roles of the institute, NASA centers, NASA Specialized Centers of Research and Training (NSCORT), and the broader extramural biomedical community in the conduct of NASA’s overall biomedical research program. The primary mission of NSBRI is to conduct basic research aimed at development of countermeasures, and the 1998 NSBRI Annual Report gives solid evidence of progress in establishing institute programs and initiating high-quality disciplinary and interdisciplinary research in many of the relevant areas of study. Interactions between NSBRI and JSC are still evolving. Effective collaborations appear to be in place between some intramural scientists and NSBRI members, but it is not entirely clear to what extent the goal of interaction is being met in practice. Indeed, the problem of coordination among and within the various program constituencies is a general one and requires continuing NASA oversight of the entire program and implementation of mechanisms, such as the recently initiated Biennial Biomedical Investigators’ Workshop, to facilitate coordination of efforts. A second significant concern noted in the Strategy report is the role of NSBRI in the overall biomedical NRA program. As the boundaries of NSBRI activities continue to expand, there is a growing need to delineate carefully the roles and responsibilities of the institute in relation to the broader NRA program. It is important for NASA to maintain a healthy NRA program as the primary mode for support of space-related biomedical research. The NRA program is the channel for support of space-related research for the entire community of investigators—extramural, intramural, and NSBRI affiliated. Exploration of novel ideas and approaches is best accomplished by maintaining access of the entire investigator community to NASA research programs. The research mission of NSRBI is focused on a limited number of areas, whereas the NRA program is more broadly based. In addition, since the NSBRI mission under current policy is limited to ground-based studies, a vigorous NRA program is also crucial to proper development of flight experiments. Thus, the potential impact of NSBRI funding on the overall biomedical research budget in the coming years should be carefully monitored and evaluated on a regular basis. Intramural scientists are and will remain an essential component of the overall research program, both to provide expertise to the extramural principal investigator (PI) community in the utilization of unique research facilities and in the conduct of applied and operational research, and to provide an interface between the extramural PIs and NASA engineers in the development of experimental protocols and flight hardware. Intramural investigators operate under a number of constraints in their efforts to collaborate with extramural scientists. Investigators are given little institututional support or incentive to conduct research or to publish results in peer-reviewed journals. The heavy operational workload, attributed to staffing cuts, undermines the ability to do active research. The committee notes that very limited travel funds for intramural scientists have had a negative effect on their ability to attend and participate in meetings with their extramural peers. Such interactions are important both to the maintenance of the scientific knowledge base on which new research is based and to the reputation of NASA scientists as respected members of the research community. Consequently, intramural investigators risk becoming second-class members of research teams that include extramural principal investigators. Integration of research activities and facilitation of collaborative and interdisciplinary research are dependent on open and effective communication among researchers over the entire program. Thus, the highly successful First Biennial Biomedical Investigators’ Workshop, held in January 1999, which brought together all funded biomedical investigators, marked the beginning of an important new program

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Review of NASA’s Biomedical Research Program (see NASA and USRA, 1999). The committee strongly supports its continuation and commends publication of the workshop proceedings as an especially valuable tool for the community. Interagency Collaboration Convincing testimony to the extent and value of collaborations between the Division of Life Sciences and the National Institutes of Health is provided by the success of Neurolab, as well as by jointly funded grants under the NRA and NSBRI programs. The National Science Foundation’s Antarctic program provides a laboratory for behavioral research in isolated environments that is increasingly important as the era of prolonged occupation of the ISS approaches, and collaborations with the Department of Defense, the Department of Energy, and the Office of Naval Research have significant benefits for advanced technology development. The committee strongly supports such interagency collaboration, both as a means of stretching tight budgets for research and development and as a means of adding new scientific expertise to important problems of mutual interest. In summary, operational research—that is, targeted research directed at solving a specific, well-defined problem—has generally been carried out by NASA intramural investigators. The larger extramural investigator community should also be encouraged to engage in this type of research, by the use of NRAs and peer review groups focused on issues in operational research. The era of ISS construction and utilization, with increased emphasis on international crews and operations, raises important issues with respect to acquisition and management of human data. Mechanisms are needed to ensure that protocols and facilities for pre- and postflight monitoring and testing are consistent across national boundaries. There have to be common criteria for the evaluation and utilization of countermeasures and international cooperation in their development. NASA funding for biomedical research is increasingly distributed among a diverse set of organizations and programs. These include the program of NASA Research Announcements, intramural investigators in NASA center science programs, the NSBRI, and NSCORT. NASA science benefits from the unique strengths of each of these program constituents. However, careful planning is required to delineate the roles, responsibilities, and appropriate funding levels for each; to ensure effective collaborations; and to integrate research findings. In particular, NASA should maintain a healthy NRA program as the primary mode for support of space-related biomedical research because of the advantages it offers in accessing the widest investigator community and exploring novel ideas and approaches. REFERENCES National Aeronautics and Space Administration (NASA). 1998a. Astronaut Medical Evaluation Requirements Document (AMERD), JSC 24834, Rev. A. Houston, Tex.: NASA. NASA. 1998b. International Space Station Medical Operations Requirements Document (ISS MORD), Baseline SSP 50260. Houston, Tex.: NASA. NASA and Universities Space Research Association (USRA). 1999. Proceedings of the First Biennial Biomedical Investigators’ Workshop, January 11-13, 1999, League City, Texas. Houston, Tex.: NASA and USRA. National Research Council (NRC), Space Studies Board. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. Washington, D.C.: National Academy Press.