Programmatic and Policy Issues
Programmatic and policy issues raised in the 1987 Goldberg report and its 1991 follow-up centered largely on (1) strategic planning for life sciences research, including planning for facilities and research on the projected space station; (2) accessibility and timely publication of research data, especially results of flight experiments; and (3) the need for improved cooperation with the National Institutes of Health (NIH) and National Science Foundation (NSF) as well as international space life sciences agencies and investigators.1 2 The response of the National Aeronautics and Space Administration (NASA) to a number of these concerns and recommendations was prompt and effective. Research management and strategic planning were significantly improved by reorganization of NASA's advisory structure. Creation of a universal peer review process has settled long-standing concerns of the Committee on Space Biology and Medicine (CSBM) and the external life sciences community. Initiation of the NASA Specialized Centers of Research and Training (NSCORT) program fostered the development of specific, interdisciplinary research foci and increased the scope of interaction of the agency with the academic community. Effective programmatic interactions with NIH and, to a lesser degree, NSF were put into place and have prospered. International cooperation has been a focus for the International Space Station (ISS) as well as for shuttle-based research, and the cooperative programs with Russia, most notably the residence of U.S. astronauts on Mir, have developed to an extent that could not have been predicted at earlier times.
However, significant concerns in the program and policy arena remain unresolved. These focus principally on issues relating to various aspects of strategic planning and conduct of space-based research, utilization of ISS for life sciences research, mechanisms for promoting integrated and interdisciplinary research, collection of and access to human flight data specifically, and publication of and access to space life sciences research in general. The following sections summarize the committee's concerns and provide recommendations for NASA's consideration.
Criteria for Space Research
Flight opportunities for the life sciences will continue to be precious for the next decade, and facilities—especially expert crew time—will be extremely limited, at least until assembly of the International Space Station is complete. It is therefore crucial that priority for these limited opportunities be given to experiments of the highest possible quality. In the past, a number of factors, including pressures on funding and limitations in crew time and on-board facilities and resources, have led to compromises in experimental rigor that have resulted in diminished quality of study results. A renewed emphasis is now required on experimental best practices, as defined in the following guidelines, which should be clearly disseminated to the proposing research community.
- Justification. A thorough prior justification should be made, based on solid experimental evidence and/or theoretical considerations, demonstrating or clearly predicting that a measurable and significant change due to effects of microgravity on the phenomenon under investigation can reasonably be expected during spaceflight. Flight experiments should be carried out only when ground-based experiments have demonstrated a clear and critical need for space-based data. The experiments chosen for support should be those that promise the greatest reward in terms of science and address the major questions. They should not be selected because they fit some preexisting or planned facility. If a facility such as the ISS is not the appropriate place of a particular, important experiment, it should not be carried out there.
- Hypothesis. A clear-cut hypothesis should be presented that can be tested in a convincing manner under the conditions of the flight experiment.
- System. A limited number of model systems should be selected and studied in detail in order to build a comprehensive database of flight results. Model systems should be chosen that have been well characterized in ground-based studies and/or have been demonstrated to have some unique advantage for the space experiment under consideration. Where possible, the use of organisms or cells with well-characterized genetics and genetic manipulability will be advantageous. Conditions should be designed to avoid, or at least adequately account for, confounding variables of the space environment (see item 5).
- Hardware. Flight hardware must be tested extensively prior to flight in ground-based simulation experiments in order to demonstrate the capacity of the apparatus to maintain normal function and to demonstrate any differences induced by the hardware compared with standard conditions. Hardware design should take into consideration the effects of microgravity on fluid dynamics and gas exchange. If necessary, equipment modifications must be made and the apparatus retested sequentially until a satisfactory baseline is attained. Any equipment that cannot meet a minimal standard should not be used for experiments.
- Controls. For in-flight experiments, it is crucial to distinguish among the following:
- Effects resulting directly from microgravity per se;
- Indirect effects of microgravity, such as the lack of convective flow and the profound attendant effects on solute and gas exchange; this may be a particularly debilitating problem for cell culture experiments (although it is presumably minimized in flow systems such as the Bioreactor), and consideration must be given to the possibility of decreased rates of renewal of nutrients and oxygen and/or buildup of waste products, maintenance of bubbles, surface tension effects, and so forth;
- Other flight- and space-related perturbations of the environment, including changes in gravity (acceleration and deceleration, including those due to crew movements, causing changes in space
- platform momentum during the course of the experiment), vibration, and temperature and atmospheric fluctuations. As noted above, these environmental stresses induce stress responses in biological systems and may result in significant perturbations of physiology. Since such variables are difficult to reproduce on the ground and render unambiguous interpretations of in-flight results essentially impossible, it will be critically important to minimize these variables in the construction of hardware and ISS facilities. An important control for nongravitational effects of the space environment is the use of ground- and space-based variable force centrifuges; the variable force centrifuge is properly considered an essential facility for research carried out on ISS. However, it is important to emphasize that the centrifuge does not allow an investigator to distinguish between direct effects of microgravity on the biological system and indirect effects resulting from changes in fluid dynamics in microgravity. For experiments employing cell and tissue cultures, plants, or mice, it may be possible to detect the presence and extent of effects of environmental stress using cells or transgenic organisms containing indicator genes coupled to specific stress-inducible promoters (see Chapter 4).
- Data collection and interpretation. Data collection should be made in such a way as to allow valid statistical analyses, and the number of experimental subjects should be large enough to permit this. Conclusions drawn from data obtained during spaceflight must be made in the context of the controls summarized in item 5. Efforts should be made to utilize the growing capacity for the application of dedicated microprocessors for process control, data storage, and rapid communication in real time with ground-based teams (see next section).
- Repetition of experiments. Care should be taken to ensure that repetition of experiments is possible in order to directly compare independent sets of data and make solid conclusions about experimental consistency and statistical significance.
- Publication. Every effort must be made to bring data and conclusions to a timely formal written presentation for stringent peer review and publication in a readily accessible scientific journal. For investigators with previous NASA funding, publication of the earlier results in peer-reviewed journals should be an important criterion for continued support.
NASA should emphasize the criteria described above in NASA Research Announcements (NRAs) and scientific peer review for flight experiments, in funding decisions, and in the development of flight protocols.
Development of Advanced Instrumentation and Methodologies
All future life science flight experiments, and especially the utilization of the International Space Station to best advantage, will depend on the availability of advanced instrumentation capable of carrying out the sophisticated measurements and analyses required by the research questions and experimental approaches described in the preceding chapters. In many cases, adaptation and/or miniaturization of existing technologies will meet investigators' needs. Examples from space physiology might include dual-beam x-ray absorptiometry for measurement of bone density; automated, submicroassay methods for assay of hormones and other blood chemicals; and mass spectrometers and ultrasonic flow meters for respiratory gas measurements. Similarly, for cell biological experiments, the adaptation of newly emerging technologies, such as automated screening for expression of reporter genes or molecular force measurements on single cells, may ultimately be needed. However, the development of
entirely novel flight-certified instrumentation will also be necessary if the scientific objectives described in this report are to be achieved. NASA should work with the broad life sciences community to identify those capabilities that will be essential within the next decade, and with industry to catalyze their development. In developing advanced instrumentation, NASA must recognize that although the apparatus must be as adaptable as possible, generic equipment may not be adequate or appropriate to meet the needs of all experiments. False economies in equipment choices may result in unacceptable costs in failed experiments. Several experiments on the International Microgravity Laboratory (IML) missions, for example, were seriously compromised by the requirement to use generic equipment that was not actually adequate for the experiment.
NASA should take every opportunity to make use of advanced instrumentation developed in other countries. There is no justification for money to be spent developing a piece of equipment in this country when a suitable item has already been developed elsewhere. Likewise, NASA must coordinate its own efforts so that it does not support multiple projects for development of the same instrument. For example, NASA is currently supporting four competing projects for the advanced plant growth facility.
In addition, the importance of facile data and information transfer between space-and ground-based investigators cannot be overestimated. The capability for direct, real-time communication between the station-based experimenter and ground-based principal investigator (PI) at the investigator's own laboratory is vital for the efficient conduct of experiments and is considered a high priority by astronaut-experimenters. Rapid responses to unanticipated experimental difficulties or mid-experiment questions about protocols or methods are generally impossible when communication must go through Mission Control, and it is clearly unrealistic to expect ground-based PIs to travel to the Johnson Space Center (JSC) for the duration of their experiments. Filtering question and response through intermediate layers of Mission Control is slow, inevitably degrades the quality of the information transfer, wastes crew time, and is a significant impediment to appropriate conduct of the experiment. This will be even more important for the longer-term, more complex experiments that will be possible on ISS. Current plans for ISS do not appear to be responsive to this need.
On-board data storage and analysis capacity and the capability for fast, real-time down- and uplinks are of the first importance. The ability to uplink a recorded video of new experimental procedures would increase crew flexibility and allow greater iteration in experimental protocols, while on-board cameras would allow the PI to observe and evaluate both experimental procedures and experimental samples.
The centrifuge facility at Ames Research Center will continue to be valuable for future ground-based experiments employing hypergravity to probe mechanisms of response to changes in the gravitational force. For example, it is likely that the response of the musculoskeletal system to gravitational force represents a continuum from microgravity through normal gravity to hypergravity. In such cases, mechanistic studies carried out in a relatively cost-effective way in hypergravity would be valuable in predicting responses and formulating hypotheses for critical testing under microgravity conditions.
- 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 International Space Station.
Utilization of the International Space Station for Life Sciences Research
Issues relating to design and utilization of the ISS are a major concern for the committee. Repeated changes in design of the ISS and the diversion of funds intended for scientific facilities and equipment into construction budgets have provoked alarm among the life sciences user community. Construction of the variable force centrifuge, essential for controlled life sciences experiments, has been substantially delayed, and there is concern that increases and overruns in construction costs may force additional delays in the design of hardware and the availability of other equipment or research facilities, and/or downgrading of their specifications. Involvement of the user community in the design of hardware and software remains problematic. If ISS is to meet its objectives as an advanced facility for the conduct of space life sciences research, the user community must continue to be brought into the actual planning phases. Although there have been multiple meetings and committees convened to define the scientific requirements for ISS, implementation of the resulting recommendations into the actual decision-making process concerned with ISS design seems to be deficient. If there is to be a viable, effective community of life sciences investigators to make use of ISS, researchers must be more directly involved in planning and design decisions made now. Issues relating to the adequacy of power, data transmission to and from Earth, and availability of crew time for research are also matters of significant concern.
In addition, delays in the schedule for station construction have greatly constrained flight opportunities for the life sciences over the next 5 years because of the shift of shuttle missions from science to construction. This hiatus poses a real and serious threat to the integrity of the academic space life sciences communities. Although limited, small-scale shuttle flight opportunities may be programmed in the intervening period, it is entirely unclear whether these will be adequate to maintain the momentum or interest of existing NASA-supported life scientists, much less attract the new investigators who will be important for future new directions in space-based research. Given the delays in bringing ISS to effective utilization, NASA should seriously consider reinstituting at least one additional Spacelab flight. The facility is already built and available, and the previous Spacelab flights have been highly successful in terms of science return. The cost to the progress of space life sciences (including perhaps research important for the success of a crewed Mars mission) of a prolonged period without any ability to conduct major flight experiments is likely to be high.
It is not completely clear that, even after the ISS is available, it will necessarily be the most cost-effective platform for all flight experiments. There will continue to be high-priority experiments that require relatively short times (1 to 2 weeks) in space and do not have to be conducted on ISS, especially in its early years when available crew time will be extremely limited. NASA should investigate the possibility that continued use of Shuttle missions for such purposes might be of economic and scientific advantage.
- 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.
Science Policy Issues
The Division of Life Sciences initiated a system of peer review in 1994 for all NASA-supported investigators, in which investigator-initiated proposals from NASA scientists as well as from the external community are subjected to the same rigorous, NIH-style, initial scientific peer review by expert panels drawn from the total scientific community. The new process has answered long-standing concerns of the academic community and CSBM, and has the committee's strong support. The committee also strongly endorses the current policy that places responsibility in the NASA Headquarters Division of Life Sciences for establishing peer review panels and for funding decisions. The impact of recent changes in NASA organization—specifically, the transfer of the Office of Life and Microgravity Sciences and Applications to the Human Exploration and Development of Space enterprise, and the transfer of program management responsibilities from the Headquarters Division of Life Sciences to Johnson Space Center—is not yet clear. Even though peer review remains a function of NASA Headquarters, the committee is concerned that decentralization may make coherent oversight and strategic planning difficult to maintain.
The new universal peer review system has been in place only 3 years at the time of this writing. Analyses of the results of the competition have been carried out annually, and plans for periodic review of the process are appropriate. It will be especially important to evaluate regularly the composition of scientific review panels as it relates to review of space-based research where hardware, environmental factors, and the availability of crew time and expertise may place limits on the feasibility of experiments that are otherwise scientifically worthy of 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.
Integration of Research Activities
Early Development of Integrated Teams for Planning of Flight Experiments
Flight experiments, with their inherent complexity and high cost, are dependent on a degree of teamwork far greater than that required for most ground-based research, which allows for ongoing modification and improvement of instruments and facilities. This teamwork must begin with a close interaction and exchange of ideas between the investigators and NASA managers and engineers. There must be agreement at the outset on the objectives of the experiment and the requirements for instrumentation and crew time to meet these objectives. Because of the long lead times, high costs, and inflexibility of space-based research, it is crucial that investigators be brought together with design engineers at the beginning of the project planning process as an integrated team, responsible for operating specifications, design and testing of necessary hardware, and working together through all phases of the project. No instruments or experimental facilities should be flown that do not adequately meet the investigators' needs as stated and approved.
Funding and Guiding of Interdisciplinary Research
This report has as a major theme the need for multilevel, multi- and interdisciplinary approaches to address problems in all areas of ground-based research in space biology and medicine. Two mechanisms for funding and oversight of interdisciplinary research programs are currently in operation within the life sciences program: NASA Specialized Centers of Research and Training (NSCORT), first established in 1991, and the new (1997) National Space Biomedical Research Institute. The NSCORT program, which focuses on designated priority areas of disciplinary research in universities, represents a "classical" mechanism for fostering and support of interdisciplinary research, and the potential advantages and problems of center-type programs are relatively well understood, given the extensive experience of funding agencies such as NIH and NSF, as well as NASA itself. However, NASA should carefully assess its relative funding priorities for individual versus multi-investigator and center grants, and should consider whether NSCORTs are, in fact, the most productive way to foster interdisciplinary research and increase the value of the research program in life sciences. The life sciences program is small, and few, if any, universities have more than a handful of investigators conducting space-related life sciences research. This raises the potential concern that any one institution may not have a sufficient number of high-quality researchers to create a critical mass in the area of the NSCORT program. On the other hand, creation of multisite NSCORTs, like the recently established New Jersey Center of Research and Training, complicates the development of mechanisms ensuring the close interaction among investigators that is a prime objective of the centers.
The very recent establishment of the National Space Biomedical Research Institute as a multi-university, multi-investigator consortium with close ties to Johnson Space Center marks a major change in the conduct of NASA life sciences research. The institute concept has promise as a mechanism to foster and facilitate multidisciplinary research and to bring highly qualified biomedical investigators into space physiology and related areas of research. However, establishment and maintenance of true collaborations and interdisciplinary activities are likely to be complicated by the geographical dispersion of institute members, whose research continues to be conducted in their own laboratories on their home campuses. Thus, the development of effective mechanisms for fostering close communications and interactions among the component laboratories will be crucial to success, as will the development of effective procedures for oversight and review of the institute's progress and performance. It will also be essential that potential impacts of the very substantial institute funding on the life sciences research budget and overall program over the coming years be adequately monitored and evaluated. The committee is concerned that in a continuing era of tight budgets, funding of the overall life sciences research program might fall into a "rob-Peter-to-pay-Paul" mode, in which areas of research and biomedical investigators external to the institute are frozen out.
- 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 planning, design, and testing. This integration of scientists and engineers 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 program and budget.
Human Flight Data: Collection and Access
Collection of Baseline Data
The disciplinary chapters of this report have repeatedly stressed the need for improved, systematic collection of baseline data on astronauts, preflight, in space, and postflight. In the past, in-flight tests and sample collection were often done at single, seemingly arbitrary times and at random and undefined points in the subjects' diurnal circadian cycle. In many cases, experimental depth and rigor have fallen victim to an unrealistic and overambitious scheduling of mission projects. Similarly, postflight testing has often suffered from variable timing and insufficient long-term follow-up. The resulting data are incomplete and even potentially misleading. In order to understand the changes induced by spaceflight and their significance for astronaut health and safety, as well as the effectiveness of countermeasures, it is essential that testing and sample collection be done on a well-considered and rigorous schedule, with a sufficient number of time points in-flight and postflight to define adequately the time course of changes in-flight, and of recovery postflight. The opportunity for sophisticated systematic monitoring of the effects of spaceflight over longer periods on the ISS is particularly important in thinking ahead to a future that includes crewed interplanetary missions.
Because the number of subjects will necessarily continue to be small, and individual variations in response are often large, each astronaut should serve as his or her own preflight control. Successful completion of sample and data collection will depend on the availability of advanced, miniaturized instrumentation for carrying out sophisticated physiological tests in-flight, on the utilization of microand submicro-methods for analysis of small samples, and on the availability of appropriate cryostorage equipment in-flight. Success will also be critically dependent on the cooperation of the astronaut subjects, who must understand and accept the rationale for the requisite testing and its long-term role in improving their health and ability to function for prolonged periods in space and in optimizing their return to Earth-normal physiology after return. Every effort should be made to encourage the astronauts to "buy into" the necessary clinical research—for example, by bringing investigators and astronauts together, early in the planning phase, for full and frank discussion of the experimental rationale, methodology, and long-term significance. Selection of astronaut crews should take into account the need to participate in experiments and to make the resulting data accessible to the relevant scientific community.
Access to Astronaut Data
According to the current NASA policy on protection and confidentiality of human subjects, astronauts may withhold permission for publication or dissemination of data obtained from their participation as subjects in clinical studies. Given the small number of participants in any given study, successful blinding of data to prevent identification of individual subjects is indeed difficult, and the issue of confidentiality is an important and complicated one. In large-scale clinical studies with statistically significant numbers of subjects, data can be presented without loss of significance in an aggregated form that essentially precludes the identification of individuals. This is not the case with studies involving a small number of subjects (e.g., a spaceflight crew) where inclusion of clinically significant physical
characteristics and past histories may make the participant immediately identifiable. On the other hand, exclusion of these data and, certainly, total withdrawal of study results for members of a very small study population necessarily bias the results and risk their correct interpretation, with a waste of precious resources as the end result. The risk of drawing misleading conclusions is especially acute because individual variations in response tend to be large and lack of access to outlier data may mask significant problems.
Up to the present, only a small fraction of astronaut data has actually been released for use by qualified investigators, and the quality of the affected studies and the validity of the conclusions remain impossible to assess with confidence. The issue will become even more critical as ISS comes online, and longer-term human studies will be a high priority. The problem is particularly difficult because it sets two positive goods—confidentiality and accessibility of complete data—in potential conflict. However, the committee believes that the current policy and practice are counterproductive with respect to the cost-effectiveness of the affected—and in the worst case, unusable—research and already impede the search for ways to improve astronaut health and safety in space. NASA should seriously consider modifications of policy and practice that would better ensure full astronaut cooperation and compliance with the need for complete access to clinical data by qualified investigators. Results from medical experiments should not be used administratively to restrict subsequent flight opportunities for the participant astronauts.
- 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.
Publication and Outreach
An essential outcome of scientific research is publication—dissemination of results to the scientific community at large—and scientific peer review of findings and conclusions before publication is rightly considered a crucial component of the publication process. If any aspect of NASA's life sciences program has been deficient, it is its publication record, most especially in spaceflight experiments. There are several reasons for this poor publication record. A significant factor is that NASA has sometimes failed to provide funds (Research and Analysis funds) for data analysis and publication of flight experiments. Funding for such experiments has often been terminated before the principal investigator has had sufficient time to access the data and carry out the necessary analysis after the flight, leaving the investigator to somehow find other funds for data analysis and publication. NASA should provide a flexible mechanism whereby additional funding can be made available for these purposes for a reasonable period of time after completion of the flight to facilitate data analysis and publication of the results.
A second factor is that, in the past, NASA has not insisted on timely publication of results in peer-reviewed journals, for example, by including the publication record of NASA-funded investigators in peer-reviewed journals as an important criterion for continuation of research support. Too often, the results, if available at all, are found in NASA technical bulletins, which are not readily available to the
scientific community and may not contain sufficient methodological information to allow adequate evaluation of the data. As an alternative to publication of individual experiments in separate journals, NASA might consider publishing a timely, detailed, single-volume, peer-reviewed compendium of the results of each flight, either in hard copy or online.
The Spaceline Archive, currently available online through the National Library of Medicine, was developed to make data from flight experiments more readily accessible to the general scientific community, and a second online archive has recently been established by JSC. However, entry of data from past flights is not yet complete at either site, access is not yet transparent, and much of the human spaceflight physiological data remains sequestered because of the current policy regarding release of data from human subjects, discussed above. The archive will be of limited value to the scientific community until data are complete and immediately accessible. The costs to the investigator of preparing data for archiving are real and an intrinsic part of the publication costs of the project; such costs should be included in NASA funding of flight experiments. Again, evaluation of the quality of the available data will be compromised unless attention is paid to including adequate detail on experimental conditions.
- 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 publication and dissemination of the results of space life sciences research in peer-reviewed journals. 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. Funds for the preparation of data for archiving should be considered part of the direct costs of research projects.
NASA should make every effort to ensure the professional training of graduate students and postdoctoral fellows in space and gravitational biology and medicine. Training programs should include components to enhance the retention of trainees in research areas of importance to NASA. These needs would be well met by a small, highly competitive program separate from the existing National Research Council fellowship program, designed to award individual postdoctoral fellowships to highly qualified candidates for training in laboratories of NASA-supported investigators outside NASA centers. Such a program could achieve the high visibility necessary to attract and catalyze the development of potential future leaders in the fields of space biology and medicine.
NASA should make every effort to support a small, highly competitive program of individual 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. 1967. A Strategy for Space Biology and Medical Science for the 1980s and 1990s. National Academy Press, Washington, D.C.
2. Space Studies Board, National Research Council. 1991. Assessment of Programs in Space Biology and Medicine 1991. National Academy Press, Washington, D.C.
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