3

Selection and Outreach

SELECTION PROCESS, OUTREACH EFFORTS, AND COMMUNICATION AMONG PROGRAM PARTICIPANTS

NASA research in cell science and protein crystal growth is funded through a collection of 4-year grants. As of 1999, NASA's biotechnology research grants totaled approximately $19 million dollars per year. The roughly 90 principal investigators supported by this program are split evenly between cell science and protein crystal growth; each project receives about $200,000 per year. Applications for these grants are solicited every other year via a NASA Research Announcement (NRA) released by the biotechnology section of NASA's Microgravity Research Division. The focus of the NRAs is developed with advice from the extramural science working groups, and both ground-based and flight projects are considered. NRAs are released to the science community through mailings, the Internet, and announcements in a variety of journals. Proposals are submitted to NASA headquarters, which convenes several peer-review panels to evaluate and rank the applications based on scientific merit. For applications proposing flight experiments or flight hardware development, NASA staff convene a second level of review to focus specifically on issues related to the design of experiments for space. Once approved, ground-based research grants are monitored on an annual basis by NASA's program personnel at the Marshall and Johnson Space Flight Centers; each project submits an annual report and a list of publications, and the investigators jointly attend and present results at a NASA-organized meeting. Flight investigations are monitored and assessed for flight hardware requirements by NASA staff at headquarters and at the space flight centers. Flight experiments are subjected to a Science Concept Review to determine the need for microgravity, the availability of hardware, and resource requirements. NASA staff help flight investigators define protocols, simplify and minimize requirements for crew time, and prepare for flight. Selected experiments are queued and flown based on volume availability and flight specifications and capabilities.

Improving the Dissemination of NRAs and NASA Program Results

In the most recent biotechnology NRA (opportunity announced in December 1997; selections made in November 1998), there were 165 proposals, of which 48 (29%) were funded. While the NRA mechanism is appropriate, it is inadequate to attract the involvement of the best scientists or bioengineers. The task group believes that as the program goes forward, it would benefit from a strengthening of the outreach, selection, and support offered by NASA to ensure that the proposals submitted for consideration are of the highest quality and that everything possible is done to give flight experiments the best chance of success. On the following pages, the task group offers observations on and suggestions for improving the processes associated with selecting and executing research in space; another NRC report (NRC, 1999) has provided a discussion of an administrative institution designed to facilitate research on the ISS.



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Future Biotechnology Research on the International Space Station 3 Selection and Outreach SELECTION PROCESS, OUTREACH EFFORTS, AND COMMUNICATION AMONG PROGRAM PARTICIPANTS NASA research in cell science and protein crystal growth is funded through a collection of 4-year grants. As of 1999, NASA's biotechnology research grants totaled approximately $19 million dollars per year. The roughly 90 principal investigators supported by this program are split evenly between cell science and protein crystal growth; each project receives about $200,000 per year. Applications for these grants are solicited every other year via a NASA Research Announcement (NRA) released by the biotechnology section of NASA's Microgravity Research Division. The focus of the NRAs is developed with advice from the extramural science working groups, and both ground-based and flight projects are considered. NRAs are released to the science community through mailings, the Internet, and announcements in a variety of journals. Proposals are submitted to NASA headquarters, which convenes several peer-review panels to evaluate and rank the applications based on scientific merit. For applications proposing flight experiments or flight hardware development, NASA staff convene a second level of review to focus specifically on issues related to the design of experiments for space. Once approved, ground-based research grants are monitored on an annual basis by NASA's program personnel at the Marshall and Johnson Space Flight Centers; each project submits an annual report and a list of publications, and the investigators jointly attend and present results at a NASA-organized meeting. Flight investigations are monitored and assessed for flight hardware requirements by NASA staff at headquarters and at the space flight centers. Flight experiments are subjected to a Science Concept Review to determine the need for microgravity, the availability of hardware, and resource requirements. NASA staff help flight investigators define protocols, simplify and minimize requirements for crew time, and prepare for flight. Selected experiments are queued and flown based on volume availability and flight specifications and capabilities. Improving the Dissemination of NRAs and NASA Program Results In the most recent biotechnology NRA (opportunity announced in December 1997; selections made in November 1998), there were 165 proposals, of which 48 (29%) were funded. While the NRA mechanism is appropriate, it is inadequate to attract the involvement of the best scientists or bioengineers. The task group believes that as the program goes forward, it would benefit from a strengthening of the outreach, selection, and support offered by NASA to ensure that the proposals submitted for consideration are of the highest quality and that everything possible is done to give flight experiments the best chance of success. On the following pages, the task group offers observations on and suggestions for improving the processes associated with selecting and executing research in space; another NRC report (NRC, 1999) has provided a discussion of an administrative institution designed to facilitate research on the ISS.

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Future Biotechnology Research on the International Space Station As NRAs are released, more should be done to disseminate them widely to the communities that might be interested in using NASA biotechnology facilities on the ISS. Protein crystal growth scientists and cell science researchers, but especially the latter, identify themselves with a variety of different professional organizations, publications, and conferences. Currently, the NRAs are sent to NASA's own mailing list, as well as to lists obtained from the Biophysical Society, the Society for In Vitro Biology, and Protein Science. Notices about the NRAs are also posted in Nature and Science and in publications of the American Society for Cell Biology and the Federation of American Societies for Experimental Biology. There are many other publications through which funding opportunities could be communicated. For protein crystal growth, some examples are the newsletters of the International Union of Crystallography (IUCr) and the American Crystallographic Association. For cell science, possibilities include journals such as Trends in Cell Biologyand the newsletters of organizations such as the American Institute of Chemical Engineers' Food, Pharmaceutical, and Bioengineering Division, the American Chemical Society divisions of Biochemical Technology and Biological Chemistry, the Biomedical Engineering Society, the American Society for Bone and Mineral Research, and the American Society for Biochemistry and Molecular Biology. Although the NRAs are currently posted on the Internet, NASA maintains so many Web pages that the online NRA is probably useful more as a reference for those who are already aware of the opportunity than as an introduction to the program. Another approach to expanding the pool of potential researchers would be to issue NRAs in collaboration with other federal agencies, such as the National Institutes of Health (NIH), the Biotechnology Program in the Engineering Directorate of the National Science Foundation (NSF), the NSF Biological Sciences and Regulatory Biology Divisions, and the Department of Energy. Cross-cutting projects could also be supported via memos of understanding with these other government agencies. In addition to broadening the dissemination of NRAs, more could be done to provide sufficient background information for potential investigators who are not familiar with NASA programs. In particular, new investigators interested in flight experiments typically need to be introduced to the special opportunities and constraints of ISS-based research. A lack of familiarity may inhibit some investigators from submitting proposals and may also decrease the probability that paradigm-challenging proposals will be submitted. This difficulty in recruiting new investigators could be alleviated by NASA's hosting biotechnology workshops at relevant, widely attended national and international meetings. The task group recommends that these workshops focus not only on the biotechnology research topics currently supported by NASA but also on the hardware available for experiments on the ISS. Potential new investigators need this information about the specialized systems available and the limitations of space-based research in order to craft proposals that can reasonably be expected to reach the flight definition stage of grant review. More information on hardware opportunities, limitations, and constraints would assist new and experienced investigators in efficient and effective experimental design. Another way to increase the quality and quantity of proposals submitted in response to NRAs is to more broadly disseminate the results of completed and in-progress NASA-funded work. The most comprehensive presentation of recent results in cell science is at the Investigators Working Group (IWG) annual meeting. Attendance at this meeting has grown rapidly; however, the attendees are already familiar with the NASA program and are composed exclusively of researchers and staff involved in the cell science work funded by NASA's Microgravity Research Division; broadening membership in the IWG to include investigators and NASA staff in the Life Sciences Division would increase cross-fertilization. Also, the task group recommends that NASA consider inviting outside speakers and guests to the IWG meetings to extend the reach of the presentations. Another mechanism to increase potential user awareness would be to encourage NASA-funded researchers to speak at a wider range of conferences. The task group cautions, however, that care must be exercised to ensure that presentations give a balanced portrayal of successes and limitations so as not to raise unrealistic expectations. Incorrect perceptions of the NASA programs can also arise from press releases that target the general public and portray potential future applications of the areas under study in NASA-funded fields as completed or current work. This publicity often leads to misconceptions about NASA's goals (the cell science program does not aim to grow artificial human organs in space) or accomplishments (the protein crystal growth work has not produced a new flu vaccine). NASA is a federally funded agency, so the importance of its work does need to be communicated to Congress and the public, but by allowing the widespread dissemination of vague or even inaccurate descriptions of the programs, NASA is seriously diminishing the credibility of its work within the scientific community.

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Future Biotechnology Research on the International Space Station In the past 2 years, NASA protein crystal growth personnel have attended the American Crystallographic Association Annual Meeting, the IUCr Congress, the International Conference on Crystallization of Biological Macromolecules, the annual meeting of the Federation of Analytical and Spectroscopy Societies, and the Annual Meeting of the American Society for Cell Biology. Other meetings that attract audiences who would be interested in the results of NASA programs include the annual meetings of the Protein Society and the American Society for Biochemistry and Molecular Biology and the Gordon conferences on protein chemistry and structural biology. In cell science, much of the current ground-based scientific program is of high quality, and early flight-based results are intriguing and promising. However, the larger scientific community is generally unaware of both the quality of this recent work (since much has only recently been submitted or is in press) and the opportunities for future projects. The impression is that the cell science program in NASA's Microgravity Research Division has focused on generating three-dimensional tissue constructs for potential commercialization. From the presentations to the task group and the latest NRA, it is clear that NASA is actually interested in a broader program in cell science and in moving beyond the qualitative phase of observational science in tissue constructs to probe the underlying biological and engineering questions. NASA personnel have attended the annual meeting of the American Society for Cell Biology, the general meeting of the American Society for Microbiology, the Congress on In Vitro Biology, NASA/Juvenile Diabetes Foundation technology workshops, and the Space Technology and Applications international forum. Other conferences at which NASA could expand its audience include the Engineering Foundation Conference on Cell Engineering, the Tissue Engineering Society meeting, the Society for Biomaterials meetings, and meetings of the American Chemical Society's Division of Biochemical Technology and of the American Institute of Chemical Engineers' Food, Pharmaceutical, and Bioengineering Division. Also worth considering for work related to bone and cartilage cells are the American Society for Bone and Mineral Research, the Orthopedic Research Society, the Arthritis Foundation, the American Association for Aging Research, the National Osteoporosis Foundation, and the International Association for Dental Research. Another important element in increasing the quality of experiment design for NRA-inspired proposals is to more widely disseminate information about past negative results. While information about successful experiments is likely to be published, negative results are often unavailable. The task group recommends that NASA make information about unsuccessful experiences available via the World Wide Web and reference this source of potential difficulties in the NRAs. Making this information more widely available would allow researchers to focus their time and effort on new ideas with a higher probability of success. Recommendation:  NASA should improve its outreach activities in order to involve a broader segment of the scientific community in its biotechnology research program and to increase the number of cutting-edge projects submitted for funding. It needs to disseminate NRAs and program results more widely and to provide more complete background information on failed projects and how to design flight experiments. Improving the Selection Process As the pool of applicants expands, the process of evaluating proposals may need to be adjusted. Some concerns about the current process include the 2-year gap between NRA grant submission opportunities. 1 This schedule is likely to inhibit applications directed at the most cutting-edge research issues. In addition, the 2-year gap may discourage the resubmission of proposals that need revisions. Another problem with NASA's current system is that after funding, the delay between project selection and flight manifesting of an experiment may dissuade even a researcher whose first experience has been successful from instigating a follow-up project. Such delays also mean that NASA does not always have the hardware flexibility to respond to changes in the field based on new developments in ground-based research (such as the increased reliance on cryoprotection and freezing of 1   As a point of comparison, the NIH accepts proposals throughout the year, with review groups convening every 4 months. Successful projects are awarded funding within 9 months of the date of submission.

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Future Biotechnology Research on the International Space Station crystals or the use of scaffolding for three-dimensional tissue constructs). Finally, the uncertainties surrounding the NASA budget and the continual schedule changes make people cautious about getting involved in a program that is unable to reliably predict the availability of money or the schedule for access to the ISS. These fiscal uncertainties also affect the quality of NASA's internal programs, because periods with low funding may result in the permanent loss of experienced contract workers to other positions and projects. Improving Connections to Relevant Communities and Attracting the Best Science One critical step toward raising the profile of the NASA program and the quality of the grant application pool would be to counter the current perception of recipients of NASA funds as a closed community with a fixed membership. The same names tend to appear repeatedly on NASA lists of grantees, advisory groups, peer review panels, and institutes. For example, the scientists in the virtual NASA Space Biomedical Research Institute seem to be concentrated in only a few institutions. Also, in the protein crystal growth's Guest Investigator Program, access to flight is not centralized and arrangements depend in part on connections with the principal investigators who developed the relevant hardware. On the whole, external input into NASA's priorities for the biotechnology program seems to be relatively limited. Current advisory mechanisms include the extramural Science Working Groups involved in developing research announcements, panels formed by NASA headquarters to peer-review grant applications, and the Biotechnology Discipline Working Group (DWG).2 These groups are currently composed of many of the same people who make up the pool of grantees, contributing to the perception that NASA is not really interested in input from outside. By reaching out to a broader slice of the protein crystal growth and cell science communities, NASA would not only increase the quality of the advice it receives but would also be able to educate a new group of people about its programs. One of the difficulties that comes from the lack of a single appropriate forum (conference, association) for a program-wide evaluation of NASA protein crystal growth or cell science work by the community is that sometimes NASA personnel are not in contact with all of the right people in all of the right fields. Expanding the groups represented on NASA advisory panels should help resolve this issue. According to NASA, the Biotechnology DWG is currently the main mechanism for receiving advice about the strategic direction of the Microgravity Research Division's biotechnology programs. It has been difficult for NASA to attract prominent outside researchers to the DWG. The task group offers two recommendations to address this difficulty. One problem is the name, which masks the group's high-level advisory role. It is recommended that the name be changed, perhaps to “Research Advisory Panel” or “Strategic Planning Committee.” The other problem is the mixing of protein crystal growth and cell science within one committee. It is recommended that the DWG be split into two separate groups. This would allow each panel to focus on the issues most relevant to its respective scientific area. The greater number of slots available for each area would also give the panels greater breadth. Care must be taken in selecting new members to ensure that there is not a bias toward those already working with the NASA program; a new name for the DWG might help to attract outsiders of high stature in the macromolecular structure determination community and the cell science community. The revamped groups should be able to provide more useful advice on a variety of issues related to the scope of research announcements, peer review practices, and future programmatic directions. The importance of recognizing the differences between the two facets of NASA's biotechnology program and allowing each to develop its own identity is also relevant to NASA's outreach efforts. The current practice is to include both protein crystal growth and cell science in the same NRAs, publicity releases, and meeting events, such as the session at the annual meeting in 1999 of the American Society for Cell Biology. The task group believes that outreach efforts would be more effective if separate workshops, presentations, and opportunity notices were used to communicate with the wide array of communities that could be affected by and involved in 2   The program also receives occasional input in the form of reports published by National Research Council committees, such as the standing Committee on Microgravity Research.

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Future Biotechnology Research on the International Space Station the biotechnology work supported by NASA. The composition of the peer-review panels may also need to be adjusted. For example, as the cell science program moves forward with a focus on fundamental research, the task group believes that the representation of bioengineers on the peer-review panels should be increased (from 1991 to 1998, bioengineers made up only about 10% of the cell scientists on the panels). Recommendation: The separate identities of the protein crystal growth and cell science sections of NASA's biotechnology research program should be emphasized. One key step should be splitting the Discipline Working Group into two strategic advisory committees to reflect the different issues facing each area of research. Prominent scientists not familiar with NASA's programs but aware of the broader issues facing the fields should be recruited to serve on these committees. One element that may help to broaden the community involved in space-based biotechnology research is the international nature of the ISS. In addition to the facilities described in this report, an array of protein crystal growth and cell science equipment is being developed for the ISS by NASA's international partners, specifically by the European Space Agency and by the National Space Development Agency of Japan.3 While one country's space agency will not directly fund foreign researchers, bilateral interagency agreements to share hardware are possible, and international announcements of opportunity are planned. Currently, the International Microgravity Strategic Planning Group, which includes representatives from the U.S., Canadian, Japanese, European, Italian, French, and German space agencies, has been meeting two or three times a year to discuss cooperative efforts on hardware development and strategic plans for microgravity research on the ISS. Work on international announcements of opportunity is under way; an announcement specifically about microgravity research on biotechnology is scheduled for 2001. Coordination: Investigators and Operations Personnel An important issue for execution of research in the unforgiving environment of space is the potential for conflict between the scientific goals of an experiment and the engineering limitations associated with a space-based platform like the ISS. Many scientists in the biotechnology community believe that in the face of such conflicts, NASA has always opted for ease of operation over support of science. Indeed, the perception is that the NASA culture does not emphasize the importance of communication between scientists and operations personnel, nor does it provide tangible assurances to the research community that the execution of high-quality research in hardware designed to answer the most cutting-edge scientific questions is a NASA priority. The task group believes that to enable important research to be performed effectively on the ISS and to attract the best scientists to the NASA program, this perception must be changed. For example, the task group learned that the computers and operating systems to be used on the ISS for experiment manipulation and data storage have already been determined. While it is understandable that a uniform interface will make astronaut training easier and simplify system engineering and design, the rapidly changing nature of computer technology and the wide variety of systems in use by outside investigators indicate that some flexibility on this point not only would permit researchers to select and tailor computer systems to their specific experiments but also would allow NASA to utilize the most advanced technologies on the ISS. Biotechnology is a rapidly evolving field, and the key questions in both cell science and protein crystal growth are changing quickly. For biotechnology facilities on the ISS to be effective, a flexible, modular system is required to allow for changing scientific needs and to take advantage of ground-based technological innovations. The task group recognizes that the unique constraints of space-based research, including the need to plan experiments and develop hardware far in advance in order to schedule astronauts' training and resource allocation on the ISS, may 3   For links to descriptions of the European and Japanese biotechnology facilities, see <http://www.science.sp-agency.ca/K3-IMSPG-Facilities.htm>.

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Future Biotechnology Research on the International Space Station limit NASA's ability to respond to changing scientific goals. However, technological breakthroughs often occur because cutting-edge scientific problems require new equipment, so close collaboration between investigators and the operations personnel responsible for fabricating hardware and planning flight manifests will benefit all aspects of the program. NASA personnel or contractors responsible for infrastructure development and operations have no incentive to make scientific goals their priority unless scientists evaluate their performance and their products (hardware, support functions, etc.) based on how well they have advanced the science. Another factor in attracting the best investigators to the program is the ability to create an environment in which the investigators are confident that their flight experiments will be successfully carried out and that they will be able to observe and modify their experiments on orbit. Two important communication issues need more attention: (1) communication between astronauts and investigators about the analysis of results and experiment manipulation and (2) communication between investigators and decision makers in times of ISS resource adjustment and crises. The first area includes not only preflight training but also telemanagement of experiments and coordination during flight. In its discussions of instrumentation for both protein crystal growth and cell science, the task group emphasizes the value of remote management of experiments by automating routine tasks and developing specialized robotics. The second area is particularly vital for cell science work, where continuous power is needed to maintain environmental control and crew time is needed to perform a variety of tasks that have not been automated. A system that enables efficient communication between the NASA operations staff making resource allotments and the investigators flying experiments is one important way of attracting qualified researchers to the program and maximizing their ability to perform successful experiments. This issue is discussed further in the cell science section in this chapter. Recommendation: The NASA culture tends to limit communication and coordination between operations personnel and researchers during hardware development; between astronauts and investigators before and during experiment execution; and between decision makers and scientists about the allotment of resources in times of crisis. To attract the best investigators to its biotechnology program, NASA must create an environment geared toward maximizing their ability to perform successful experiments. PROTEIN CRYSTAL GROWTH The Guest Investigator Program In addition to NRAs and hardware development grants, the NASA protein crystal growth program created a guest investigator program to involve external investigators in flight experiments. In this program, when a NASA principal investigator is manifested on a flight, he is authorized to recruit other scientists (guest investigators) interested in providing macromolecular samples to be crystallized in space. No fiscal support is offered, only the opportunity for flight. Interested guest investigators are then screened by a small group consisting of the principal investigator, NASA staff, and one other scientist experienced with flight experiments. Between 1985 and 1998, 67 individuals participated in the program, with a total of 147 guest investigations occurring in that time period. While this program has provided hardware developers with useful information about the capabilities of new equipment, it does have several flaws that limit its effectiveness. As the program is channeled through individual principal investigators, there is no opportunity for centralized review of proposals and guest investigators are limited to the hardware being flown by the principal investigator recruiting them into the program. In addition, without formal grant agreements, there is no mechanism to ensure that appropriate experimental controls are studied in tandem with the space experiments or that all results, both positive and negative, are reported. These constraints suggest that the program 's focus is more on testing equipment and less on providing an environment to investigate protein crystal growth in microgravity or solve important structure determination problems. As discussed in Chapter 1, some of the results that have come out of the guest investigator program (such as the work on EcoRI-DNA and on insulin) indicate that microgravity has the potential to be an important tool for crystallization. Overall, however, the set of data produced in the 13 years of this program has failed to definitively demonstrate that space-based crystallization can be a key step in structure determination research. The program

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Future Biotechnology Research on the International Space Station has been undersubscribed, and the level of control allotted to the principal investigators and the relatively limited number of external investigators involved have reinforced the belief of many researchers that the NASA program included only a small, closed community. The task group recommends that the current guest investigator program be phased out. Hardware developers should still be given some flexibility and allowed input into some of the samples that are flown while the equipment is on testing flights, but in general control over which protein crystallization efforts are flown should be centralized at NASA, where a peer-review process should be employed to build a coherent program with clear strategic goals. Funding Research on Biologically Challenging Problems The focus of the NASA program should be on demonstrating microgravity 's effect on protein crystal growth. To that end, the task group proposes that NASA instigate a high-profile, nationwide series of grants. These would be 3-year grants, in which investigators would receive roughly $200,000 per year, and NASA should award only five each year (for 5 years). (The total amount given out in the 25 grants would be $600,000 per grant for a total of $15 million over 7 years.) These grants would be given to researchers to support simultaneous efforts to get the best possible crystal on the ground and the best possible crystal in space for biologically important macromolecules. (To make the opportunity attractive, NASA would have to guarantee that at least one flight opportunity would occur within the grant period, preferably in the last year.) If in several cases out of the 25 the space-grown crystal turns out to be better and enables the solution of a hot scientific problem, the microgravity crystallization program will have been validated. Also, the scientists who experienced success will be good spokespeople for the program (especially if they had no previous microgravity experience or connection with the NASA program). The task group believes that this is the best way for NASA to validate the program and to obtain community buy-in. In research on the structure determination of biologically important macromolecules, the crystallization samples take considerable time, money, and effort to produce and hence are very precious to the researchers, who will need some incentive to engage in a risky research environment (space) where their control over the samples is limited. A generous grant would provide such an incentive and lower the risk. Note that the selection criteria should favor macromolecular systems where efforts are already under way but crystallization has been difficult and the results have been borderline. Some examples of classes of systems that currently meet these criteria include membrane proteins, molecular motors, biopolymer synthetic machinery (e.g., origin of replication complexes and transcriptional pre-initiation complexes). All of these systems are elaborate and fragile, which makes them difficult to crystallize unless the conditions are just right; microgravity might improve the quality of the crystals enough to lower the resolution to a level at which key structures can be discerned. For project selection, NASA must assemble a review panel of renowned structural biologists to ensure that projects selected resonate with the community's perception of what problems are important and difficult. An international panel might serve NASA's needs best, because European and Japanese scientists often have a greater appreciation for technical and instrumental achievement and innovation. Also, more international scientists on the selection committee means that more U.S. laboratories can apply without any appearance of conflict of interest with the panel members. NASA needs to encourage the largest possible pool of candidates, not only to ensure that the highest quality applications are selected but also because the grant publicity and application process will educate a broader research community about the capabilities of the equipment available for microgravity research. NASA does recognize the importance of community outreach and long-term grants, as can be seen in other NASA programs. In the Life Sciences Division, a memorandum of understanding with NIH created a set of grants that could be applied for by NIH grantees, and the applications were reviewed by the NIH study sections. This program introduced NASA to a new community and educated the NIH grantees about the goals and hardware of NASA life sciences research programs. In astrophysics, NASA has given out a series of 5-year grants, valued at roughly $250,000 per year, to encourage long-term projects that either exploit NASA 's technical capabilities in this field or investigate theoretical issues that will affect future equipment needs in astrophysics. The projects funded by the grant program proposed by the task group should address many of the uncertainties

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Future Biotechnology Research on the International Space Station that have plagued the NASA protein crystal growth program so far. By using the ISS for a long-term, reliable microgravity environment, by comparing space-grown crystals to the best Earth-grown crystals available, and by focusing on challenging systems and “hot” scientific problems, the investigators should be in a position to produce the data that the research community has been seeking about crystal growth in microgravity. The results of these cutting-edge research projects should provide a definitive answer as to whether higher quality crystals can be grown in microgravity than by using the best technologies available on Earth. If none of the projects produce a space-grown crystal that enables a breakthrough for structure determination of a biologically important macromolecular assembly, NASA should be prepared to terminate its protein crystal growth program. However, if the projects supported by this high-profile, nationwide series of grants succeed in validating the use of crystallization in microgravity to tackle important and challenging problems in biology, demand for the facilities on the ISS can be expected to increase. At that time, NASA should develop an external user program (similar to synchrotron user programs) in which a peer-review committee selects the projects. The committee would include NASA staff on an ex-officio basis to provide information about the feasibility of proposed experiments and advice about equipment capabilities. The reviewers would evaluate applications and select participants in the program so that when a flight opportunity arises, NASA could coordinate the external users and match accepted proposals with the most appropriate available hardware. Information about the equipment for the ISS must be available to all the external users so that (1) they can participate in the decision about which hardware best fits the needs of their experiment and (2) they have confidence in the equipment and will entrust their samples to it. Recommendation: NASA should fund a series of high-profile grants to support research that uses microgravity to produce crystals of macromolecular assemblies with important implications for cutting-edge biology problems. The success or failure of these research efforts would definitively resolve the issue of whether the microgravity environment can be a valuable tool for researchers and would determine the future of the NASA protein crystal growth program. Throughout this report, the task group has emphasized NASA's need to demonstrate that the microgravity environment can be a valuable tool for determining macromolecular structures and will therefore have a major impact on key biological questions. This focus is a reflection of the unique attitude of the scientific community engaged in protein crystal research. In cell science, as well as in other areas of microgravity research, such as materials science, the NASA program is geared toward supporting basic curiosity-driven research, and the research communities embrace that approach. Among investigators studying macromolecular assemblies, however, the main goal is solving structures of interesting crystals, and these scientists believe that the value of NASA's program should be measured in terms of the quality of service provided to the research community; in short, does microgravity directly affect their efforts to determine structures? While continued work on understanding the crystal growth process could bear dividends, it is of secondary importance to scientists at this time. However, if a crystal grown in microgravity turns out to be better than the best version of that crystal produced on Earth, it is certainly worth asking the researcher to investigate exactly which characteristics of the microgravity environment produced the positive result so that attempts could be made to reproduce those characteristics in ground-based laboratories. NASA could make extensions of funding for projects contingent on the researchers trying to tackle these questions, as understanding the mechanisms at work would increase the likelihood of future success. The sort of issues that would arise in such research, such as the impact of microgravity on convection and sedimentation, would provide an excellent opportunity for collaboration and coordination between scientists funded by NASA's biotechnology section and investigators supported by other parts of the Microgravity Research Division, such as the materials science program. Mechanisms to encourage such cooperative projects should be considered, as well as ways to increase communication between NASA staff whose programs may be tackling fluid behavior in microgravity from a variety of directions. Possible approaches include newsletters devoted to general findings or the formation of a committee to discuss which results have the potential to cross disciplinary boundaries.

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Future Biotechnology Research on the International Space Station CELL SCIENCE Cooperation with NASA's Life Sciences Division and with Other Federal Agencies As NASA looks to involve a broader community in its cell science programs, it would make sense to take advantage of other federal agencies' existing relationships with cell scientists in a variety of fields. As mentioned above, joint grant solicitations with the NSF, NIH, or the Department of Energy might be effective. In addition, the work in cell science could be more closely coordinated with NASA 's own Life Sciences Division. It is recommended that joint NRAs be established or incentives offered to encourage applications linking in vitro and in vivo work through cross-program collaborations. The cell science work could also benefit from interactions with the fluid physics program in NASA's Microgravity Research Division. Expertise in fluid mechanics might enable better understanding and control of various mechanical factors, such as shear stress and convective flow, that affect the culture environments. NASA has already built a very productive relationship with NIH based on the development and use of rotating-wall vessels. The NASA/NIH Center for Three-Dimensional Tissue Culture was started in 1994 to expose a wider community to bioreactor technology by allowing researchers from government agencies (e.g., NIH, the Food and Drug Administration, and the Department of the Navy) to test new model systems for biomedical research and basic cell and molecular biology in the rotating-wall vessel hardware with technical assistance from experienced NASA personnel (NASA, 1995). Phase I projects allow researchers to use the bioreactors at the NASA/NIH tissue culture center to see if the technology might be useful; Phase II projects involve grants that allow the researchers to purchase their own bioreactors and refine their research in this equipment. This approach has been an effective way to allow the community to familiarize itself with the possibilities of the rotating-wall vessel bioreactors. The task group believes that this outreach program is an excellent idea and recommends that a wider range of investigators be reached by expanding the Phase I part of this program to include extramural (non-government) researchers. Continuing ground-based research will play a critical role in helping to define the key biological questions most likely to be answered via space-based experimentation. The first steps include determining methodologies that can distinguish between the effects of microgravity on cells and on the cell culture environments and adapting innovative analytical equipment and culture instrumentation for space use. When enough information and appropriate technologies have been gathered to define specific areas in cell biology in which NASA's “big breakthrough ” might occur, the NASA cell science program might consider launching a special program of significant grants similar to the one described in the section “Funding Research on Biologically Challenging Problems ” from the protein crystal growth section of this chapter. The goals of this program would be in-depth study of particular mechanisms and careful comparison between ground-based and space-based experimentation to determine how the microgravity environment offers opportunities for investigation and knowledge that are unobtainable on Earth. Resource Management and Communication in Times of Crisis The need for a strong scientific voice in operational decisions must be stressed. Someone trained in biology and engineering should be made responsible either for maintaining the cultures on the ISS or for interacting, from the ground, with both the investigator and the responsible astronaut. Placing someone with a scientific background and perspective in a key decision-making position will enable more effective communications when experimental results dictate changes in the sampling or reagent-manipulation protocols. Additionally, strengthened communications will be very important when reacting to shortages in crew time or ISS resources (such as power). It is crucial that there be a coordinated effort between investigators and operations personnel to use resources effectively, giving each experiment the highest probability of success (NRC, 1998). In this regard, it may help to establish a liaison position staffed by a bioengineer who can bridge the communications gap. Currently, NASA is considering creating the position of lead increment scientist to coordinate scientific input into engineering decisions and decisions on the distribution of scarce resources (power, crew time, etc.). Serious problems can arise during a crisis if there is a nonscientist in the decision-making process. While crew safety and ISS operational

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Future Biotechnology Research on the International Space Station integrity obviously have to come first, it is important that experimental payloads not be shut down when there are other options, just because shutting down is the easiest thing to do. NASA has historically demonstrated a certain rigidity about protocols for such things as the timing of missions, the manifesting of various experiments, and access to astronauts, and this rigidity has had a negative impact on investigators ' ability to carry out experiments. In the future, decision-making processes should be more flexible to accommodate the needs of biotechnology researchers. The research community would be reassured by seeing NASA place bioengineers and biological scientists with the appropriate appreciation of research goals and scientifically oriented reflex responses in high enough decision-making positions to ensure that research opportunities are optimally utilized.