Factors Affecting the Utilization of the International Space Station for Research in the Biological and Physical Sciences (2003)

Bioastronautics is the discipline that encompasses the knowledge needed to maintain the health, safety, and well-being of astronauts. It includes the research that might lead to countermeasures for the adverse effects on astronauts of the spacecraft environment. The Bioastronautics Research Division within NASA’s Office of Biological and Physical Research sponsors research in a large number of areas, including bone and muscle studies in animals and humans, radiation biology, and behavioral research. There is clearly some overlap with fundamental biological research in such areas as mammalian muscle and bone development, but the task group has generally chosen to use NASA’s categorization for individual experiments. Here, as in the other chapters, the task group has not attempted to discuss individually every program of research carried out in bioastronautics, but it does consider—either individually or in aggregate (such as in systems physiology)—most of the programs that had been expected to make significant use of the ISS. In the sections that follow, the research sponsored by NASA in several major areas is described, and the task questions relating to their implementation on the ISS are considered.

Delays or cancellations of the on-board installation of the animal habitats¹ means that there will be no non-human vertebrate research on the ISS until they are available. Delay of the life sciences glovebox, most recently scheduled for launch in 2005, would eliminate many critical cell culture experiments.

The absence of the 1 g centrifuge and the reduction of crew size have severely affected each of the bioastronautics disciplines. The reduction in crew size has a twofold impact on bioastronautics research. In addition to the loss of crew to perform the research, the number of crew available to serve as human subjects in the observation of physiological deficits caused by spaceflight, and in the development of countermeasures, is also reduced. While the relative significance of crew and facility reductions varies by discipline, the net result is a limit on the variety and quality of the science that can be performed on the ISS.

Systems physiology encompasses musculoskeletal, cardiovascular, neurovestibular, and immunological research directed toward maintaining humans for longer durations in space. There are two main goals of systems physiology research. The first is to understand the basic physiological mechanisms underlying astronauts’ adaptation to weightlessness and readaptation to 1 g . The other is to develop scientifically based countermeasures for the effects of weightlessness. These countermeasures should help maintain crew safety, optimize their performance, and allow for longer-duration missions. Systems physiology research is vital since maintaining humans for long durations in weightlessness will be critical to accomplishing NASA’s long-term goals in space. In addition, studies in this area add to the base of knowledge that can be used for understanding and treating similar problems on Earth, such as osteoporosis, muscle wasting, and low-blood pressure occurring with standing.

This section provides an overview of the problems facing all areas of systems physiology on the ISS, and the subsequent sections provide information on specific disciplines (cardiopulmonary physiology, muscle and bone physiology, radiation biology, and behavior and performance).

Several programs at NASA and at other agencies administer efforts relevant to systems physiology:

• NASA Research Announcement (NRA) program, a NASA program of competitive peer reviewed research that funds both intramural and extramural investigators;

• National Space Biomedical Research Institute (NSBRI), an extramural independent program focused on countermeasure development;

• Countermeasure Evaluation and Validation Program (CEVP), a NASA program for validating new countermeasures;

• Flight medicine, an intramural NASA program that prescribes countermeasures and makes ongoing measurements; in addition, flight medicine programs for individual nations can specify countermeasure programs for their astronauts (Ohshima et al., 2002);

• Russian biomedical research program, an independent Russian effort to study physiology and develop countermeasures;

• European Space Agency projects, ESA-sponsored experiments participated in by European astronauts who fly on the Soyuz to the ISS on taxi flights; and

• Individually sponsored projects. Mark Shuttleworth, who flew as a space tourist, brought along his own suite of experiments from South African researchers. This approach would appear to be open to others who fly via this route.

NASA’s NRA program tends to focus on studies of basic mechanisms but includes countermeasure studies as well. The NSBRI program is chartered to develop countermeasures, and the CEVP is designed to validate countermeasures. The flight medicine program provides the ongoing monitoring of crew members and prescribes countermeasures. A summary of the current efforts in system physiology appears in Appendix F.

Table 3.1, taken from the NASA Flight Equipment Experiments Information Package, shows what equipment was offered to potential investigators for use on the ISS (ISLSWG, 2001). The ESA-supplied equipment will be available on the ISS when the Columbus module arrives at the ISS. The U.S.-supplied equipment will be in place once both racks of the Human Research Facility (HRF) are installed. The first rack is already installed; the second, and final, rack of the HRF is scheduled for installation in January 2003. When the Columbus module and HRF are installed, the hardware that had been promised to human investigators will be in place. But it represents only a subset of what was available in the past on Spacelab flights, which contained not only the basic equipment for human physiology research (blood-pressure devices, gas analyzers, etc.) but also an animal habitat that is not present on the ISS. The main piece of equipment that would represent a major advance over Spacelab, the 1-g centrifuge, has been significantly delayed, and its future is uncertain.

For bioastronautics research the crew not only perform the experiments but also are often the key source of data on the adaptation to weightlessness. One major benefit of the ISS was to have been the ability to fly large crews so that adaptations could be documented, mechanisms determined, and countermeasures developed. The Rev. F ISS plan called for a crew of six to seven, with three to four of those devoted to scientific activities. A crew of six flying every 3 months would have provided the possibility of collecting data on 24 people in 1 year. Assuming that three crew members would have been devoted to scientific research full-time (40 hours/week), then about 120 hours a week would have been available for science.

The current Core Complete plan calls for a long-duration crew of three for flights that will be extended to 4-6 rather than 3 months. The maximum number of crew members who could be studied in 1 year in this scenario is approximately nine. This amounts to a 63 percent reduction in crew members available. This number is further reduced by the fact that not all crew members may participate in a given experiment. American crew members participate mainly in the U.S. research program, and Russians may participate to some extent in the NASA program, and the converse will probably also be true. An experiment that requires a significant number of participants (more than six or seven) to produce meaningful results could take years to complete, even assuming that all crew members agree to participate.

About 20 hours a week will be available in-flight for science, which is approximately an 80 percent reduction in the time available under Rev. F. Another important component of crew time is the

time available for training and for data collection before and after a flight. The original (Rev. F and earlier) plans allowed for some crew members to be dedicated to scientific activities, while others could focus on station operations. In this way, the time available for scientific training could be expanded for those crew members carrying out the experiments. This is no longer the case.

In the current Core Complete plan, a total of an hour and a half per crew member is available on landing day for all scientific measurements on the crew. Separate time is allocated for flight medicine measurements, but these are not considered research data by NASA.² More time is available on subsequent days. Compared with what had been available in prior programs (Skylab, Spacelab), time for crew training and pre- and post-testing are very limited (Table 3.2). These limitations indicate that only the simplest experiments requiring minimal crew training, time, and other resources could be performed.

Work can still be done on the ISS in the flight medicine and the Russian biomedical research programs. The work currently ongoing on the ISS in the area of countermeasures and physiology is mainly part of these programs. As has been outlined in various reports (NRC, 1998, 2001; IOM, 2001), these data are considered private medical data and so are not routinely available to researchers.

Several factors have to be considered to assess the value of the research capability in systems physiology. Among them are these:

• Availability of the crew for testing during the mission, since systems physiology research involves measurements on the crew.

• Availability of the crew for testing before and after the mission. Premission testing provides the baseline for comparison, and postflight testing shows the nature of the changes that have taken place and how long they last.

• Availability of the crew for training, since the complexity of the experiments is limited by how much time the crew members have to learn the equipment and procedures.

Table 3.2 provides a qualitative comparison of the ISS with other space research capabilities that have existed in the past

In its current form, the ISS program appears to be less capable than Skylab or Spacelab of supporting research. Studies on humans can be performed, but at a decreased rate, because of time and resource considerations. Studies of laboratory animals, e.g., rats, mice, and quail, will not be possible until the animal and avian habitats are available on the ISS. Without the 1-g centrifuge, the animal studies will not have appropriate controls.

When resources are critically limited, as with the ISS, it is vital to use them efficiently. Yet the several independent programs for research in systems physiology on the ISS are not well coordinated. In fact, they sometimes work in opposition or duplicate efforts. For example, the NRA program tends to focus on studies of basic mechanisms but has countermeasure studies as well. The Russian biomedical

program appears to measure the same kinds of parameters as the flight medicine program and other NASA programs (NASA, Public Affairs, 2002).

The connection between the CEVP and the other efforts is not firmly established. The NSBRI program is chartered to develop countermeasures. If a countermeasure is shown to be promising, the NSBRI investigator must wait for a research announcement from the NRA program and then submit a proposal and have it reviewed and approved before proceeding to flight. This process can typically take several years. There is no direct link to the CEVP. Flight surgeons can prescribe countermeasures that have not been evaluated by the CEVP. Moreover, NRA or NSBRI projects that lead to a countermeasure do not automatically get reviewed for the CEVP. When the CEVP was first proposed, it included a set of measurements that could be used to meet both clinical and research needs. This set of tests, known as the integrated testing regime, was not fully implemented, and ongoing monitoring of crew members is performed using requirements set by the flight medicine program. The flight medicine program, however, collects data that are classified as private medical data and so are not routinely shared, although a method is being developed to share grouped data. The Russian program collects data on both cosmonauts and astronauts, but this information is also not readily available. With the exception of the flight medicine program measurements and, possibly, the Russian program, participation in biomedical measurements pre-, in-, and postflight is voluntary, even though these measurements were cited in a recent review of the ISS as being one of the most important products of the ISS (IMCE, 2001).

The disjointed nature of the program detracts from its ability to achieve research goals that require measurements on many people or consistent measurements over time. These kinds of measurements are the essence of systems physiology research. Data collected for experiments that study human physiology or countermeasures clearly overlap with the measurements that are being taken by NASA’s flight medicine program. Despite this, no systematic way exists to integrate experiments with the measurement program that is already under way. Individual investigators need to negotiate this on their own—there is no NASA program in place to facilitate or enforce this integration. Funded investigators in the NASA program need to contact the flight medicine program or the CEVP to arrange sharing agreements. While this has worked successfully in many cases, it provides an advantage to those with the most knowledge about and experience with the system.

While the physiologic measurements made in the flight medicine program are mandatory, investigators with an approved countermeasure project need to “sell” their experiment to the crew members to encourage their participation. This arrangement could give rise to some confusing experiences for the investigators and flight surgeons. At present it is possible for an investigator to propose an investigation, pass peer and technical review, pass the institutional review boards at NASA and the investigator’s home institution, and be funded and manifested, but be unable to complete the project because of difficulties enrolling participants. Also, any experiment involving testing the validation of a countermeasure will probably overlap with ongoing flight medicine program efforts.

Resource limitations clearly affect the ability to complete currently manifested experiments, but they also affect the kinds of experiments that are proposed and selected. At present, to be selected, a flight experiment must have only minimal requirements for crew training, crew time, equipment (i.e., equipment that is not already in the inventory) or other resources. Box 3.1 lists the restrictions that were placed on flight experiments in the latest flight experiment announcement of opportunity from NASA. As a result of such restrictions, the current program screens out demanding experiments. Because investigators must review these restrictions in advance, many important experiments may not even be proposed to NASA. The restrictions listed in Box 3.1 refer to the assembly phase of the ISS, but due to the reductions in crew time on Core Complete it is unlikely that these restrictions could be relaxed after assembly has ended.

For instance, since most countermeasure validation experiments would, by their very nature, require collection of baseline data shortly before flight and immediately after landing, the restrictions placed by NASA on pre- and postflight testing (see Box 3.1)—limited baseline crew data collection on the two days after landing (R + 0 to R + 2) and limited baseline crew data collection during the 30 days prior to launch (L30 to launch)—would inhibit investigators from proposing experiments that required these resources. If such experiments were proposed, they would seem to require too many resources to be selected.

There are a number of ways to mitigate, to some degree, a few of the problems identified in the preceding discussion and to maximize the remaining research potential of the ISS. For example, the different research programs (NRA, NSBRI, flight medicine, ESA, the Russian program, independent research) should be coordinated to eliminate duplication and maximize the use of available resources.

NASA’s research objectives are often stated in general terms (i.e., develop countermeasures) rather than in a specific form (i.e., ensure that there is no significant change in bone mineral density in all crew members). As a result, there is no way to establish clear priorities or assess the effectiveness of the program. Without clear priorities, the limited station resources cannot be used effectively. The research objectives for systems physiology need to be stated in a specific way to help set priorities and measure progress. The Critical Path Roadmap process that has been established by NASA has been an excellent start in this direction and should be continued.

If a core goal of the ISS is to study the physiology of weightlessness and develop countermeasures, then crews should be selected on the basis of their willingness to participate in research studies. To date, participation by U.S. crew members in the research program has been very good. The involvement of Russian crew members also should be worked out in advance. An approach to this issue is outlined in a report by the Institute of Medicine (IOM, 2001).

Most of the data needed for countermeasure development and validation are collected by NASA’s flight medicine program and are not routinely available to other researchers. Participation in the flight medicine program is mandatory, and controversy exists over whether this program has a significant research component since it provides most of the ongoing monitoring data. As has been stated in several other reports (NRC, 1998, 2000b; IOM, 2001), a mechanism to share and review these data needs to be developed. The current effort to provide group data from the flight medicine program tests should be continued and supported.

Crew time is the major limiting factor for research activity in systems physiology. Without an expansion of the time available for pre- and post-training and testing, it will be difficult to accomplish

significant work. Time for pre- and post-training and testing should thus be increased to allow for meaningful experiments to be performed and proposed.

The ISS research program as initially proposed (Rev. F and earlier configurations) provided several crew members and a considerable amount of research time. The cuts in the program, however, make meaningful systems physiology work very difficult to accomplish. Programs should be coordinated and duplication eliminated, and long-standing issues surrounding data privacy and participation should be resolved.

The cardiopulmonary research program supported by NASA is a mix of studies on humans and animals that address the major effects of weightlessness on cardiopulmonary systems. A ground-based program exists to study these areas, along with a program for flight experiments. An ongoing program of cardiovascular monitoring and assessment of astronauts is also in place. In this report, just the flight portion of the cardiopulmonary program is discussed.

One significant cardiovascular effect of spaceflight is the reduction in blood pressure that can occur while standing postflight or during reentry after exposure to weightlessness (known as orthostatic intolerance). In addition to postflight orthostatic intolerance, other cardiovascular issues of importance for spaceflight include in-flight aerobic deconditioning, cardiac atrophy, and cardiac arrhythmias. The important pulmonary physiology concerns, and the main foci of pulmonary research, are adequate

denitrogenation prior to extravehicular activities (EVAs), increased aerosol deposition in spaceflight, and changes in pulmonary perfusion.

Several programs administer efforts that lead to flight measurements relating to cardiopulmonary physiology:

• NASA NRA program, a competitive Headquarters-based research program that funds intramural and extramural research, has three flight experiments in this area. A pulmonary experiment (PUFF) and a cardiovascular experiment (XENON) are both currently on the ISS. The third cardiovascular experiment is in the definition phase.

• NSBRI program, an extramural independent program focused on countermeasure development, includes cardiovascular efforts but has no flight projects.

• Countermeasure Evaluation and Validation Program, a program for validating new countermeasures, has one experiment that is studying midodrine as a countermeasure for orthostatic intolerance and also includes cardiovascular monitoring during reentry on the shuttle.

• Flight medicine program, an intramural program that prescribes countermeasures and makes ongoing measurements, makes a series of cardiovascular measurements, pre-, in-, and postflight. The AMERD document (NASA, 1998b) describes the components of this program, which include exercise tests, EKGs, and stand tests.

• Russian biomedical research program, an independent Russian effort to study physiology and develop countermeasures, includes two ongoing flight experiments (cardio-lower body negative pressure (LBNP and pulse). Monitoring is also done during reentry in the Soyuz capsule.

• European Space Agency projects. European astronauts who fly on the Soyuz to the ISS on taxi flights participate in ESA-sponsored experiments. One such experiment is the evaluation of a blood pressure monitoring device.

• Individually sponsored projects. Mark Shuttleworth, who flew as a space tourist, solicited research from South African investigators and participated in a cardiovascular study during his flight.

The initial equipment plans in Rev. F called for the HRF to provide the main equipment for U.S.-sponsored cardiovascular research, and the specific cardiovascular equipment promised is still expected to be in place on Core Complete. In addition, more equipment will be available when the Columbus module arrives at the ISS (see preceding section, “Systems Physiology”). The Russian program also includes cardiovascular research equipment, but whether Russian equipment could be shared to do U.S.-sponsored research is not clear.

Crew time, as well as crew to serve as subjects, however, are limiting resources. Cardiopulmonary research competes with every other discipline studying human physiology for its share of the limited amount of time available for training, preflight data collection, in-flight data collection, and postflight assessment. At present, the NASA program supports two experiments in this area, with one additional experiment in the definition phase. The flight medicine program and the Russian biomedical program have ongoing monitoring and assessment efforts.

Since the data collected in the flight medicine program are considered private medical data, however, they are not routinely shared. This is a problem that has been identified in other National Academies reports (NRC, 2000b; IOM, 2001).

With the limitations on in-flight crew time, training time, and pre- and postflight data collection, it is unlikely that any further NASA-sponsored research could be performed until the three currently planned experiments are completed. These limitations are also delaying the manifesting of peer-reviewed experiments still in the definition phase. The Soyuz taxi flights still offer the potential for short-duration experiments for the European Space Agency astronauts and private individuals.

A recent review of NASA’s biomedical research program (NRC, 2000b) listed four key areas for research in the cardiopulmonary area: orthostatic intolerance, cardiac atrophy, arrhythmias, and pulmonary changes. The research currently manifested is summarized in Appendix F. One ongoing NASA research project is studying midodrine as a countermeasure for orthostatic intolerance. Given the limited number of crew members to study and the constraints on crew time, it is unlikely that any other countermeasure validation studies could or should be supported. The flight medicine program makes ongoing orthostatic intolerance assessments, but their results are not available to the research community (although they are used to assess the effectiveness of the countermeasure program). The Russian cardio-LBNP experiment continues, as does the Russian pulse experiment. Whether these measurements are integrated into other measurements being made is not clear.

Cardiac atrophy will be addressed in the one pending flight experiment. At present, it is not clear if this experiment will be approved for flight. Cardiac arrhythmias could be detected using the equipment on the ISS, but there does not appear to be a formal program in place to monitor for these. Pulmonary measurements are ongoing with the one pulmonary flight experiment.

Overall, NASA has not deleted any cardiopulmonary experiments, but, as noted above, few experiments have been selected for flight. One approved experiment from the last announcement of opportunity for flight experiments (in 1999) is still not manifested.

For a potential investigator several factors limit utilization of the ISS for studies of cardiopulmonary physiology. These limitations can be divided into those that exist prior to submitting an experiment, and those that exist once an experiment has been approved for flight.

As discussed in the section “Systems Physiology” above, an investigator who did submit a research proposal in response to the Announcement of Opportunity in 1999 would have noted that there were many limitations on the type of flight experiments that could be submitted. Experiments that required a significant time commitment at any point (pre-, in-, or postflight) were discouraged by the language of the announcement. This meant that experiments that required measurements during recovery and rehabilitation would be difficult or impossible to perform. As a result, only the simplest cardiovascular experiments were likely to be submitted. One experiment that is currently approved for flight but not manifested remains in the definition phase because of its demands for pre-and postflight testing.

Several steps could be taken to maximize the research potential on the ISS. In the area of human physiology, the most critical resource is the number of crew members who can participate and the time

they have available for training, baseline measurements, and postflight data collection. Any increase in crew size, crew time (pre-, in-, or postflight), or operational efficiency would benefit research.

The research efforts of the NRA, NSBRI, CEVP, and flight medicine and Russian programs could be coordinated to eliminate conflicts, overlaps, and duplication of effort. Using different protocols and equipment to measure essentially the same set of cardiovascular parameters does not make the best use of the limited number of people who can participate in these studies.

Many worthwhile recommendations have been made in the past about spaceflight research that are of particular importance now in a time of tight budgets and limited resources. The guidelines outlined in three National Academies reports (NRC, 1998, 2000b; IOM, 2001) IOM should be used to focus the research program, set priorities, and establish guidelines for crew involvement.

This program deals with bone and muscle loss—major pathophysiological changes associated with microgravity and the spaceflight environment (NRC, 1995, 1998, 2000c; Schneider et al., 1995; Turner, 2000a). Reductions in bone mass and bone density, loss of muscle mass, and failure to repair these tissues after reentry put space travelers at risk for fractures and prolonged loss of neuromuscular activity, including muscle weakness, fatigue, lack of coordination, and muscle soreness. Bone and muscle loss is listed as a top-priority area in NASA’s Critical Path Roadmap, and the biotechnology research done as part of this program has implications for both NASA and human health.

Three types of studies were discussed throughout the 1990s in connection with preventing the bone and muscle loss encountered by astronauts and cosmonauts on short- as well as long-term spaceflights. These studies, which also addressed fundamental questions in bone and muscle physiology, were planned for the whole organism (humans and animals) and for individual tissues and cells. In 1998, the NRC Committee on Space Biology and Medicine provided a series of essential questions to be answered to understand bone loss in space (NRC, 1998). The committee suggested that a determination be made as to whether animals sustain bone loss comparable to the loss in humans. When and if an animal model showed changes similar to those in humans, the committee suggested that it be evaluated in ground-based experiments to see if that environment could be used to mimic bone loss in space. Muscle physiology studies were suggested that would determine how muscle alterations and atrophy could be minimized by understanding the hormonal and nutritional aspects of muscle change in weightlessness. Determination of how skeletal muscle deficits are reflected in other organ systems was also suggested. Concurrent muscle, bone, and blood flow studies were recommended. These are but a few of the recommended studies, many of which were included subsequently by NASA in its portfolio of bone and muscle physiology research on the ground and in flight. The ISS experiments in this area are listed in Appendix G.

The experiments needed to carry out these studies involve analysis of bone and muscle loss after short- and long-term exposure of humans, animals, and cells to altered gravity environments, with studies done in both simulated and actual hypogravity. The efficacy of a wide range of countermeasures hypothesized to prevent bone and muscle loss problems would also need to be analyzed in detail. Possible countermeasures include exercise regimes and pharmacological interventions. Another recommended countermeasure is exposure to 1 g in a centrifuge. Based on studies showing that intact rats and isolated bone and muscle cells exposed to hypergravity did not show the muscle and bone loss associated with weightlessness (Guignandon et al., 1997, 2001; Vasques et al., 1998), it was hypothesized that in the future exposing astronauts to 1 g while on the ISS would be a more effective countermeasure against bone and muscle wasting than defined exercise programs in low gravity (Wade et al., 1997; Kreitenberg et al., 1998). Exercise programs and evaluations of bone mineral density and urinary calcium are also being conducted as part of the flight medicine program studies, but as noted above, these data are not accessible.

The Rev. F design for the ISS included resources that would support bone and muscle research: six EXPRESS racks, six crew members, and a 1-g centrifuge for animals. Direct computer-based interaction between investigator and crew and new sensors for in-flight measurement of metabolism were also promised. Core Complete plans reflect extensive restructuring from the original Rev. F. Cell science and biotechnology research (which includes research on bone and muscle cells) will now be limited to two EXPRESS racks (in place of six). While cuts in the bone and muscle research program cannot be isolated from the list of bioastronautics microgravity research program cuts made by NASA, as discussed below, there will be significant reductions in equipment as well as in manifested experiments (Table 3.3) by 2004. The reductions in science equipment are compounded further by the decrease in crew size.

The list of items of equipment that were promised in Rev. F and are now delayed or deleted in Core Complete includes the “next-generation rotating wall perfused bioreactor system,” the advanced animal habitat, the avian habitat, the aquatic habitat, and the 1 g centrifuge. Loss of the animal habitat and the lengthy delays in the 1 g centrifuge are disastrous, as bone and muscle loss in nonhuman models cannot be evaluated without this equipment. NASA also indicated that cuts are planned for PI-unique hardware for looking at macromolecular biotechnology (which includes tissue engineering of bone, muscle, and cartilage). These cuts will have a major negative impact on bone and muscle cell biology studies, and on animal studies once the animal habitats are on board because, in order to do procedures on animals, the habitats must be linked to the life sciences glovebox. It should be noted that no vertebrate research can be accomplished on the ISS until the habitats are available. Table 3.3 indicates experiments deleted by NASA because of lack of availability of this equipment. The loss of these experiments will retard the accumulation of basic biology data on how bone and muscle loss occurs in microgravity, delaying the development of the most effective countermeasures.

The list of future studies in bone and muscle physiology manifested for flight on the ISS provided by NASA in early 2002 is given in Appendix G. Specific equipment available on the ISS for bone and muscle studies is discussed below.

The following equipment and facilities for bone and muscle research will be available on the ISS (NASA, OBPR, 2002):

• The advanced thermoelectric refrigerator freezer (ARTIC) is a permanent refrigerator freezer that fits in an EXPRESS rack and can store samples at –80^oC . It will be the main storage freezer/refrigerator for large and complex experiments. The unit was installed on the ISS in April 2002.

• The cellular biotechnology operations support system is on-station hardware dedicated to cultivating cells. It contains a biotechnology specimen temperature controller (BSTC), a biotechnology refrigerator, a gas supply module, and two biotechnology cell science stowage units. The BSTC’s chamber will act as a non-rotating bioreactor, in which the cells will be cultivated. The experimental tissues grown will be used for the study of human diseases. The rotating wall vessel was used for the establishment of cartilage and bone cultures on the shuttle; thus it is likely that this unit may be available for similar studies on the ISS. The unit was installed in August of 2001, and the first frozen set of cultures were returned on STS 108.

• Two EXPRESS racks provide a standardized refrigerated system for experiments. Each EXPRESS rack is housed in an international standard payload rack, which is a refrigerator-size container that acts as the EXPRESS rack’s exterior shell. Each rack can be divided into segments. The EXPRESS racks on the ISS have eight middeck locker locations and two drawer locations each. Experiments

contained within EXPRESS racks are controlled either by the crew or remotely from the ground by the payload rack officer on duty at the Payload Operations Center at NASA’s Marshall Space Flight Center in Huntsville, Alabama.

• The Human Research Facility (HRF) Rack 1 houses a computer workstation and portable laptop computer for crew members to command and test the rack’s equipment, collect and store experiment data, send data to and from scientists on Earth, provide a place for the crew to store notes, and for human life sciences experiments. Beginning with Expedition Two, the ISS crew will use the computers to transmit, among other things, the H-Reflex life sciences physiological experiments. Also housed in the rack is equipment for the gas analyzer system for metabolic analysis physiology and ultrasound human life sciences experiments. The Ultrasound Imaging System has the capacity with appropriate attachments to be used in the bone and muscle research programs to generate three-dimensional images of muscles, tendons, and blood vessels.

There are three pieces of equipment for exercise studies: a leg cycle ergometer, a treadmill, and an interim resistance-training device. The equipment is used extensively for a prescribed crew exercise program (NASA, OBPR, 2001); however, data are not accessible to outside researchers to evaluate the efficacy of these programs.

ESA has a bone analysis module for ultrasound measurements of bone density, a bone physiology module as part of the European physiology modules, a percutaneous muscle stimulator, and a muscle atrophy and exercise system, all of which are available to U.S. investigators on the ISS (ESA, 1999). All of these will be essential for conducting those human studies that are already approved for flight.

Animal studies cannot commence until the habitats are available. The original hope was that the ISS would enable long-term experiments, some initiated in microgravity, that could address hypotheses and interventions related to the effects of long-term spaceflight on musculoskeletal loss. These long-term experiments were designed to minimize physiologic changes known to occur as a result of launch and reentry either by starting cultures or embryonic growth after launch, or by maximizing the time in microgravity. The great advantage of these studies was their expected use of the promised centrifuge, which would have allowed the effects of changes in gravitational force to be separated from other effects.

Delay of the large 1-g centrifuge and the life sciences glovebox, and deletion of the advanced animal habitat, will have a major effect on the quality of the science, as ground controls are not subject to the other environmental challenges that ISS occupants and future space explorers face.

The research in bone and muscle physiology that can be done on Core Complete is limited, both in terms of the time available for experimentation and the reduced numbers of human subjects for study. However, some important investigations in bone and muscle physiology could still be initiated, recognizing that it will take a longer time for them to be completed. Noninvasive measurements of bone turnover, e.g., bone mineral density measurements made pre- and postflight, urine samples (excretion of calcium or collagen cross links) collected during flight for testing on the ground, and in-flight muscle force measurements, could in principle eventually be accomplished, even with a crew of three per mission. However, the number of years required to complete the studies with the Core Complete configuration may be much greater than originally planned by investigators because of the reduction in crew size. The three-person crew is likely to have less time available for collection of data on humans, let alone for running experiments. Since the crew of three also includes the international partners, it is not clear how participation in NASA-sponsored experiments is assigned, as other partners appear to be running similar experiments. Because flights currently alternate between two Americans and one Russian, or one American and two Russians, based on previous experience with joint missions, it can be estimated that it will take more than 6 months to collect 3 months worth of NASA data on six crew members.

Inclusion of exercise equipment for crewmembers, and its regulated use, was proposed to prevent bone loss (Keller et al., 1992) and is now in use in the flight medicine program. The data from Skylab, Mir, and NASDA studies (LeBlanc et al.,1998; Vico et al., 2000; Miyamoto et al., 1998) demonstrate that exercise diminishes bone and muscle loss but does not prevent it. Data on the long-term efficacy of exercise as a countermeasure are not available. Information from the flight medicine program studies using the treadmill, cycle ergometer, and resistance-training device, although lacking a no-exercise control, should provide a baseline for additional countermeasures. However, the data are not available to NASA investigators. Formal studies of drug-based interventions such as the use of bisphosphonates (Apseloff et al., 1993; Grigoriev et al., 1992; NewsRx.com, 2001), parathyroid hormone (Canadian Space Agency press release, 2001), or osteoprotegerin (Amgen, 2001; Bateman et al., 2000, 2001) could be accomplished were crew available and willing to participate. Unfortunately, these potential countermeasures can sometimes be prescribed by astronauts’ and cosmonauts’ physicians without being part of a study and without plans for formal evaluation.

Animal studies could be performed if the animal habitat on the Core Complete ISS (along with the 1-g centrifuge and the life sciences glove box) were available. Cell culture studies could then also be done if sufficient crew time were available for maintenance of long-term cultures. Without this and the other nonvertebrate habitats, the basic biological understanding needed to translate cell and organ culture information to human studies will be not be forthcoming.

Perhaps the biggest obstacle for investigators planning bone and muscle experiments for the ISS and recruiting student participants for these studies is uncertainty. There is uncertainty about whether the equipment for the planned ISS experiment will ever be available, uncertainty about when the experiment will be manifested and flown, and uncertainty about whether replicate experiments will be possible. Another major obstacle, caused by schedule delays related to ISS construction, is the extensive amount of time between selection of a project for flight definition and actual flight. During these long delays, the

science has often progressed so much that the entire study should be redesigned. These obstacles discourage students from building an interest in space science, and new investigators from becoming involved in ISS-based projects; cause concerns about promotions among non-tenured faculty; and are leading some long-time NASA investigators to question their continued commitment, as well as that of their students.

If there are not appropriate controls, such as that to be provided by the 1-g centrifuge, or if an experiment is postponed for so long that the graduate students who were scheduled to work on it have since finished their PhDs, or if the new and better measurement equipment exists but is not approved for ISS experiments, it will be difficult to retain existing investigators, let alone attract new ones.

As noted throughout this section, the ISS research potential for studies on bone and muscle physiology on Core Complete is particularly limited by the absence of three resources: the animal habitat (for vertebrate animal studies), the 1-g centrifuge (for in-flight control studies),³ and crew (both as volunteer subjects and as scientists performing the experiments). The life sciences glovebox is also a critical resource that is not expected to be flown until 2005 or later. While it would be preferable to have more EXPRESS racks available for cell culturing and other biotechnology experiments supporting bone and muscle research, and more importantly, for replicate experiments, the electrical power, stationary equipment, and refrigeration in Core Complete are acceptable for the studies currently proposed in muscle and bone physiology. With the current number of EXPRESS racks, however, and the difficulty of doing the number of studies required based on statistical considerations, it may be impossible to recruit new scientists into the discipline. There are currently investigators with proposed and planned experiments who, if they have reliable information as to when their experiments will fly and a commitment that they will be able to repeat these experiments, might consider remaining in the field.

To help maximize bone and muscle physiology research, the requirement for volunteer participants for human experiments might be met with a plan for recruitment, education, and training of crew members before they are scheduled for flight. Human studies that require a small number of subjects⁴ should be selected in preference to those requiring larger numbers until a larger crew is available. Of course, increasing the crew size would enable studies on the crew to be completed more rapidly and with less experimental variation. The sharing of data between bone and muscle researchers and with researchers in other areas of physiology, as stated in the section “Systems Physiology,” is essential and must be seamless and guaranteed. This should hold for both clinical data and data from basic science research.

Reestablishment of the animal habitat and its 1-g centrifuge as early as possible is essential for understanding the mechanisms of bone and muscle loss and developing methods to prevent such changes in these tissues. Animal studies cannot be manifested until the habitat is available, and should not be scheduled until NASA can guarantee that replicate experiments will be performed. Research on the ground to refine concepts based on animal models should continue until the habitat becomes available. Proposals for research on the ISS utilizing vertebrate animals in space should not be reviewed until then.

In conclusion, bone and muscle research is a top priority for maintaining astronaut health and is a promising area for microgravity research. However, the lack of crew time, equipment, and appropriate controls must be addressed in order to make progress in this area.

Ionizing radiation from the Sun and from galactic cosmic rays is not a significant health hazard on the surface of Earth. However, for long-term occupants of the ISS (~250 miles above Earth) and, for example, astronauts traveling to Mars, the hazards may be significant. The diminished shielding by Earth’s atmosphere and decreased diversion of charged particles by Earth’s magnetic field result in increased dose rates of ionizing radiation. Hence, it is important to know not only the radiation dose levels on the ISS and how they vary with time, but also the dose levels beyond low Earth orbit (i.e., at interplanetary distances). At such distances galactic cosmic radiation, including high-atomic-number (Z), high-energy (HZE) nuclei, takes on greater significance because the particles lose large amounts of energy per micrometer (and so are known as high linear energy transfer (LET) particles). It is important to know not only the health effects of LET particles, but also the countermeasures—shielding and potential biochemical modifiers—to reduce the health effects. It should be noted that radiation hazards, such as mutations and increases in cancer incidence after return to Earth, are estimated from data on reasonably large populations exposed to short-duration doses of low-LET radiation (Japanese survivors of the nuclear bombs and groups exposed to therapeutic doses of x rays). It is from these data that the effects of chronic exposures are inferred (NRC, 1990). The biological effects of HZE cosmic-ray nuclei are the subject of ongoing, ground-based research because, although doses received on the ISS are measurable, these doses are too low to result in observable acute or chronic effects on cells or animals.

NASA’s research is aimed at understanding and ameliorating both the physical and biological concerns raised by travel or residence in space. The physical concerns are (1) the radiation levels at the ISS as a function of location on the station at solar maximum/minimum and at times in between and (2) real-time monitoring of and shielding against the high radiation levels associated with solar flares. The biological challenges are to estimate mutagenic and cancer risks and risks to the integrity and functioning of the central nervous system from cosmic-ray nuclei and to determine if microgravity alters the radiation responses of cells in vitro and in vivo (NRC, 2000a) and whether radiation and microgravity stresses might affect the immune system synergistically (NRC, 2000b). It has been estimated that the probability that radiation will affect the immune system might be equal to or greater than the probability for its inducing mutations (Todd et al., 1999).

NASA has supported and continues to support ground-based ionizing radiation research of relevance to space travel. These experiments are essential for determinations of the relative biological effectiveness, compared to gamma rays, of the high-energy particles encountered in space. The 2001 task book for NASA life sciences describes 29 projects covering many different biological end points (NASA, 2001c). The experiments include determinations of the biological effects of energetic protons at Loma Linda University and the effects of HZE nuclei at an accelerator at the Brookhaven National Laboratory. The accelerator has been available for only ~10 days per year, but its availability will increase to an appreciable fraction of the year in 2003 and beyond, when the construction, supported by NASA, of a new accelerator (the Booster Applications Facility) is completed. NASA has also supported dose measurements, using tissue-equivalent proportional counters, on space shuttle flights at the ISS inclination (51.65 degrees) (Badhwar, 2002). The data showed that “given a shielding distribution for a location inside the Space Shuttle or inside an ISS module, this [radiation measurement] approach can be used to predict the combined GCR and trapped dose rate to better than ±15 percent for quiet solar conditions” (Badhwar, 2002, p. 69). The dose measurements in air must be converted to dose equivalents in tissue using estimated quality factors and actual doses in tissue. These tissue doses have been obtained by use of thermoluminescent dosimeters inserted into a human phantom (a dummy) (Badhwar et al., 2002). The dosimeter data were compared with those calculated from theoretical radiation transport models. The dose-rate prediction of the models at the level of the blood-forming organs was ~20 percent lower than the measured dose rates.

The physical measurements of radiation doses to astronauts can be performed with existing equipment, already on the ISS, and with existing data storage and transmission capabilities, and so will not be affected by the changes in research capability in going from Rev. F to the Core Complete ISS design. The determination of the doses received by astronauts is not an experiment but a continuous environmental monitoring effort. There are, at present, two radiation investigations planned for the ISS (see Appendix H). However, it should be noted that the determinations made in the experiment “Chromosome Aberrations in Blood Lymphocytes of Astronauts” on Increment 8 (scheduled for May-September, 2003) will have less statistical significance because of the reduction in crew (sample) size from six or seven members to three. There have been no cuts in existing dosimetric equipment, but the installation of the advanced animal habitat (accommodating 6-8 rats or 20-30 mice) and the centrifuge has been delayed for a number of years. Although the majority of the radiation-response experiments on biological systems can continue to be done on Earth (NRC, 2000b), the delays will eliminate important experiments that should be carried out on the ISS and cannot be done on Earth. The purpose of such experiments would be to determine whether the effects of radiation delivered in microgravity will be similar, qualitatively and quantitatively, to those observed on Earth. If they are, the extensive ground-based data on the effects of HZE nuclei may be extrapolated to microgravity. If they are not, more extensive experiments on-orbit would be necessary to determine the molecular/cellular explanations for the differences, and how to extrapolate radiation effects from ground to orbit. The deletion of the habitat (advanced animal habitat) for mice and rats, unless restored in the 2003 NASA budget, and the delay of the centrifuge module until 2007 or later mean that there can be no serious planning for animal experiments on the ISS that would measure the effects of radiation in microgravity on biological responses. Such responses include the effects of ionizing radiation on the killing or mutation of cells in vivo or the effects of radiation on the immune system. The centrifuge is needed to provide a 1-g control in the environment of the ISS. The relevant experiments are not listed in the ISS research plans through 2006, nor do preliminary ground studies on the effects of radiation on the immune system appear to have been planned (NRC, 2000b).

Among the biomedical research countermeasure goals listed by NASA (Fogleman, 2001) are “Radiation and Immunodeficient Correction.” These were estimated to be at Countermeasures Readiness Level 1-4.⁵ However, neither the radiation nor the immunodeficiency countermeasures can be evaluated without extensive experiments on the ground and in orbit, using the centrifuge module to supply a 1-g control. Ionizing radiation is mutagenic, and mutations at the DNA sequence level are best studied using known genes. A simple, suitable model system could be transgenic mice in which multiple copies of a known gene of a bacterial virus are inserted into each cell of the body. Following exposure to radiation, the gene may be isolated from different tissues and analyzed in bacteria infected with the viruses to determine the frequency and nature of mutations and their repair versus time following exposure (Swiger, 2001). Mice are also suitable for the detection of immune system changes. A radiation source, probably a compact source of x rays, is necessary and is envisaged on the ISS (Olsen, 2001). The minimum requirement for such experiments would be a small mouse colony, a source of x rays, appropriate dosimetry, and a centrifuge so as to repeat, on-orbit, the experiments at 1 g. Several doses would be needed at microgravity and at 1 g, Several repair times (times between exposure and assay) would also be required, and two end points (mutation and immunosuppression) would have to be assessed. Hence,

the task group estimates that the minimum colony size would be 50-100 mice in space. (The mutation assays could be done on Earth on frozen tissues transported from orbit, but the immunosuppression assays would probably have to be done on the ISS.) Such experiments, on-orbit, are labor-intensive and probably could not be carried out if there were only a three-member crew. Moreover, the lack of the advanced animal habitat and the centrifuge module eliminates the possibility of doing any such controlled vertebrate experiments relating biological effects of radiation with microgravity.

The principal radiation biology experiments that should be carried out on the ISS are the relative radiation effects on vertebrates at microgravity compared with 1 g , of a known source of radiation, say x rays, on (1) mutation induction and (2) the immune system. Extensive and relevant experiments have been carried out on Earth, but this is not the case for studies of radiation effects on the immune system. Similar results from immune system investigations on Earth are needed before designing immunosuppression experiments to be carried out on the ISS. The experiments on the ISS not only would require the specialized equipment described above but are labor-intensive as well. It is not conceivable that the experiments could be carried out by a crew of three. The task force estimates that a crew of six or seven, two of whom should have biological expertise, would be needed. When such experiments have been selected following peer review, and when the experiments are approved for flight, crew members or mission specialists will have to be trained to carry out the necessary procedures.

NASA’s research efforts in the area of behavior and performance fall under two multidisciplinary approaches that encompass diverse areas of investigation: neurobiological-psychosocial aspects and human factors engineering. The first approach includes research on the characteristics of sleep and circadian rhythms and changes in cognitive and perceptual performance associated with long-duration missions. It also covers the psychosocial aspects of living in a confined and isolated environment and how individuals, groups, and organizations respond to the environmental stressors associated with these environments. Human factors engineering addresses the design of the interfaces or systems with which astronauts interact in space. In 1998 NASA’s research agenda for behavior and performance on the ISS focused on two questions: (1) How do microgravity and the space environment affect human behavior and performance? and (2) How can we enhance human performance in spaceflight? To answer these questions, a strategy report (NRC, 1998) recommended that NASA develop noninvasive qualitative and quantitative techniques for assessing pre-, in-, and postflight behavior and performance. The report also placed a high priority on investigating the neurobiological and psychosocial mechanisms underlying the effects of physical and psychosocial stressors on cognitive, affective, and psychophysiological measures of behavior and performance. A final area in which research was recommended was the evaluation of existing countermeasures and the development of new countermeasures that effectively contribute to optimal levels of crew performance, individual well-being, and mission success.

The equipment necessary to conduct investigations involving human behavior and performance are provided by the two HRF racks on the ISS. Rack 1 of the HRF was deployed in May 2001 and rack 2 is scheduled for deployment on ULF-1 in January 2003. The HRF provides equipment for studies of

physiological, chemical, and behavioral changes in astronauts that are associated with spaceflight. Rack 1 includes an ultrasound imager, gas analyzer, computer workstation, and portable laptop computer that crew members can use to access various experimental protocols and to collect, store, and transmit experimental data (NASA, 2001a). No elements of the HRF have been deleted in response to the ISS restructuring in 2001, and there are no changes to planned flight hardware through 2005. However, rack 1 of the HRF was scheduled for deployment in March 2000 and rack 2 in December 2001. As a consequence of these delays in launch dates, 11 experiments (3 U.S. and 8 international) have been deselected from the ISS since October 2000 by the Bioastronautics Research Division. However, none of the deselected experiments are in the behavior and performance area.

The Bioastronautics Research Division has approved 21 experiments for the ISS that run through calendar year 2004. Beyond that, additional experiments will be manifested from those studies now undergoing definition and from new projects selected through future NASA research solicitations. At present, a single study in the behavior and performance area on the ISS is being conducted continuously from ISS flight increments 2-6. No other studies are scheduled for the ISS in the behavior and performance area. The objective of the current study is to identify and define interpersonal factors that can affect the performance of the crew and ground support personnel during ISS missions. Questionnaires are completed weekly by crew members using the workstation and personal computer. Data are also being obtained from ground control personnel supporting the missions in the United States and Russia.

The reduction in crew size from six to three will have a profound impact on the study of human behavior and performance on the ISS. This will be most evident in the limited data collected on each flight owing to the small number of subjects available for study, and this will be compounded by the limited time available for this three-person crew to participate in scientific studies. For many of the high-priority areas of research that have been identified for the behavior and performance subdiscipline, a large number of subjects is essential in order to derive meaningful conclusions from experimental data, owing to the inherent variability between subjects. This intersubject variability is likely to be an even more important issue in long-duration missions, in which time and the responses of subjects to prolonged habitation in space are now added factors in data analyses. These human performance data are essential to NASA’s development of reliable screening and selection procedures that consider individual personality characteristics and assess crew compatibility (NRC, 1998). Because the reduction in crew size also limits the number of experiments that can be conducted on the ISS, it impacts the scientific community’s readiness and willingness to participate in space research. With only a single experiment in behavior and performance scheduled over the next 4 years, it will be difficult to maintain the commitment of the scientific community to this area of study.

The factors limiting utilization of the ISS for research in human behavior and performance are clearly those that affect all discipline areas: the low rates of selection for funding, the shortage of flight opportunities, deselection of flight experiments, and across-the-board cuts in funding levels. The combined effect of all these factors serves to discourage new investigators from entering the field and alienates established researchers. Plans call for both HRF racks to be deployed by January 2003, so the physical resources are available on the ISS to conduct numerous studies of human behavior and performance; the primary physical factor limiting utilization of the ISS in this research area is crew time.

In addition to the paucity of research, no funding exists at all for advanced human support technology experiments on the ISS. This means that one of the two elements of NASA’s research agenda (NASA, 1998a) for the ISS in the behavior and performance area—namely, how human performance in spaceflight can be enhanced—will not be addressed in the foreseeable future. If, as the ISS IMCE Task Force recommended (IMCE, 2001 p. 9), “the highest research priority should be solving problems associated with long-duration human spaceflight, including the engineering required for human support

mechanisms,” then there will have to be a significant increase in funding for research activities on the ISS for the behavior and performance research program to answer this question.

As detailed above, the main factors limiting utilization of the ISS in the Behavior and Performance area are the absence of any significant research program for the ISS, which primarily reflects budgetary constraints, and the small crew size and limited crew time. The development of a research program on the ISS in the Behavior and Performance area will require stable and predictable funding for research. Since the crew size will be limited to three people for at least the next 6 years, information that is available on crew performance aboard the ISS from other sources should be used for scientific study. Information collected as part of the flight medicine program, for instance, on medication use, sleep-wake cycles, and cognitive assessments, could be used to provide further information on crew performance.