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Assessment of Programs in Space Biology and Medicine 1991 5 Developmental and Cell Biology The discipline of developmental biology concerns all aspects of the lifespan of an organism including gamete production, fertilization, embryogenesis, implantation (in mammals), organogenesis, and maturational changes that occur in tissues and organs after birth (postnatal development). Although development is a continuous process, research frequently emphasizes experimental questions concerned with specific developmental time periods (e.g., the period of organogenesis). The most pressing issue in developmental biology for space concerns the question, can any organism undergo a complete life cycle (fertilization through production of viable gametes in the adult) in the microgravity of space? Alternatively, are there developmental phases so sensitive to microgravity that normal development from fertilization of an egg to fertile adults does not occur in space? It is difficult to study the entire developmental process in a single organism, partly because of variable length in the life cycle. More importantly, different kinds of organisms exhibit diverse strategies for undertaking the complex processes associated with differentiation and organogenesis. Some invertebrate animals display highly ordered patterns of cell division, allowing precise studies on cell lineage. Thus, if microgravity leads to developmental abnormalities that are evident in the adult, the time at which various cells were altered can be traced backward in time. The development of vertebrates presents aspects that cannot be evaluated in invertebrates. For these reasons, research strategies require the use of several different kinds of organisms to fully understand effects of the space environment on developmental processes. Very little information on the development of animals in space exists. Much of the initial research on animal development will be of necessity observational in nature. Major advances in developmental biology increasingly have relied on studies at the level of individual cells. The field of cell biology was not discussed in the Goldberg Strategy, but recent evidence obtained from Shuttle flights indicates that such problems need to be addressed. Progress in cell biology research represents one section of this chapter. Whereas the study of development in various organisms addresses many

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questions of basic interest, the study of mammals in particular has fundamental interest that relates not only to the health and welfare of humans in space but also to any long-term plans for establishment of human colonies in space. For these reasons, the chapter on developmental biology also includes a summary of progress concerned with human reproductive biology in space. STATUS OF DISCIPLINE Major advances have occurred in the field of developmental biology since preparation of the Goldberg Strategy, especially in the use of modern techniques of molecular biology to study developmental processes. The use of specific "molecular markers" has enabled investigators to more precisely define the temporal aspects of cell and tissue differentiation. Studies on the effects of changing environmental cues on gene expression during the process of differentiation have become readily feasible and are under intense investigation in numerous laboratories. Related to this, molecular studies concerned with the mechanism(s) by which cells communicate with each other in the establishment of patterns have opened up several new experimental approaches. However, these advances do not necessarily alter any of the recommendations delineated in the SSB reports referred to in this document. Those recommendations dealt with the necessity to acquire basic information on the ability of various organisms to undergo normal developmental processes in microgravity. Once the initial data base has been obtained, research strategies designed to evaluate the mechanism by which microgravity affects developmental processes need to include modern molecular approaches as well as the more classical techniques of developmental biology. MAJOR GOALS The Goldberg Strategy recommended that highest priority be given to experiments on model organisms to determine at the outset if development from fertilization through the formation of viable gametes in the next generation, i.e., egg to egg, can occur in the microgravity environment of space. In the event that normal development does not occur, the next recommended priority is to determine which period of development is most sensitive to microgravity. A second goal is to evaluate the use of the space environment as a tool to study specific developmental phenomena in ways that cannot be accomplished adequately in ground-based research. To achieve these goals most efficiently, and within the limitations imposed by restricted flight opportunities, several model organisms were recommended for study in space including two representative invertebrate organisms, two representative nonmammalian vertebrates, and at least one representative mammal. Whereas it may not be necessary to stress all the specific organisms

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recommended in the Goldberg and earlier strategies, it is important to stress the recommendation to study the common house mouse as opposed to the more frequent emphasis by NASA on the use of rats. The house mouse is one-tenth the size of rats, has a relatively short gestation time, and has the advantage of an extensive genetic data base. These advantages allow studies in space revolving around the time of implantation and, on the same animals, the period of postnatal development. Finally, since the only rodent embryo that can be successfully cultured is the mouse embryo, it is possible to study phases of mammalian development in culture in parallel with studies on embryos in vivo. This would allow a distinction between maternal contributions to the embryo in a microgravity environment versus direct effects on the embryo. PROGRESS A number of diverse organisms have been subjected to microgravity for varying periods of time. These include invertebrates such as the fruit fly (Drosophila), vertebrates such as amphibians (Rana pipiens and Xenopus laevis), and mammals such as the rat. In addition, a number of eggs (fertilized prior to flight and fertilized in space) have been observed in microgravity including those of insects, frogs, and chickens. The results of these experiments have been inconsistent. Both normal and abnormal development has been observed, depending on the organism and the stage of development at which material was subjected to microgravity. However, in some cases, the length of the experiment was insufficient and almost none of the experiments have had an in-flight 1-g control. In addition, some of the "experiments" have been carried out under the auspices of undergraduate or high school students. In spite of the above limitations, the available data imply that microgravity may have serious detrimental effects on certain developmental processes including oogenesis (the formation of eggs) and the development of certain organs, especially those involved in gravity sensing. The D-1 mission flown in 1985 was the first mission containing an on-board 1-g centrifuge. Results from experiments on that flight showed clear-cut effects of microgravity on certain phases in the development of two insect species. A disruption in oogenesis was observed as well as a reduction in the number of eggs laid and an effect of sex ratio among developing offspring. These experiments further documented an effect of radiation on developmental processes, including synergism between radiation and microgravity. At least two upcoming missions contain experiments concerned with the effects of microgravity on the development of selected organisms. These include the Spacelab-J mission, which contains an experiment on development of the embryonic axis in frogs. In addition, the IML-1 mission contains the "frog experiment," one to examine development of Drosophila, and one to examine development of an additional insect (C. morosus). Finally, the proposed Space Biology Initiative (SBI) plans four areas of study including gravitational biology. The latter references studies on the role of gravity in shaping the growth and development of individual cells, plants, and animals. However, as this initiative has not yet been approved as a formal new start, no

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specific experiments have yet been proposed or selected. LACK OF PROGRESS To our knowledge, no animal species has ever been carried through one complete life cycle in the microgravity of space. Virtually none of the model organisms referred to in the Goldberg Strategy have been flown. Although some of these organisms are included in forthcoming flights, it is less clear that the experiments are designed to answer the first priority question, development from egg to egg. No experiments dealing with postnatal development, a critical issue described in the Goldberg Strategy, have been conducted or are planned. In many instances these problems result from the fact that the most immediate forthcoming opportunities include experiments which have been in the pipeline for some time; the queue is long and arose prior to publication of the strategy. Perhaps the most informative mission, the D-1 flight, was planned almost entirely by the European Space Agency prior to release of the Goldberg Strategy. In other instances, planning has emphasized other experimental questions. For example, much of the research proposed for LifeSat (a free-flyer proposed for a new start in FY 1992) is concerned predominately with radiation effects and dosimetry. Prior to availability of a space station, LifeSat is the only opportunity for these investigations. LifeSat will allow for mission lengths of sufficient duration to accommodate one or more complete life cycles. In short, the data base concerning the effects of microgravity on developmental processes remains almost nonexistent. Without question, the two major impediments to progress in developmental biology research have been, and remain, the low level of support for basic research in gravitational biology and extremely limited opportunities for access to space. CELL BIOLOGY Human lung cells were flown on Skylab 3 (1973) with the result that no significant changes were observed in cell function. This led to the view that microgravity has little effect at the level of individual cells. Research supported by the gravitational biology program has concentrated largely on whole organism studies. The 1987 strategy reflected this view and did not propose research to investigate changes at the cellular and molecular level. However, it has become clear; especially from D-1 flight data obtained after the publication of the Goldberg Strategy, that the microgravity environment of space does have effects at the cellular level. Status of Discipline

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As with developmental biology, major research advances have occurred in the field of cell biology, due in large part to use of molecular approaches to study cell function. For example, genes for many membrane receptors have now been cloned, allowing the design of experiments to determine how cells respond to specific extracellular signals. The intracellular pathways, which are activated (inactivated) in response to environmental cues, are being worked out in detail. Mechanisms by which cells synthesize and process proteins destined for secretion and proteins required in the construction of the cytoplasmic architecture (i.e., tubulin, actin, intermediate filament protein), are now amenable to precise analysis. Finally, several in vitro systems have been established in which the function of individual cells can be studied in detail. Of relevance to the goals of space biology and medicine, both bone and muscle cells can be induced to differentiate in culture. Thus, the opportunity exists to establish model systems using ground-based research that can then be used to study the effects of microgravity of specific cellular processes. Progress Changes in basic cellular and metabolic function were observed in tissues from animals on the Spacelab-3 mission (1985). These included reduced synthesis of RNA, reduced growth rates in blood cells, changes in tubulin and cytoskeleton synthesis and distribution, and changes in collagen secretion. The most complete studies carried out on the D-1 mission indicated significant alterations in single cells from both prokaryotes and eukaryotes. Thus, bacterial cells as well as cells of algae, slime mold, and protozoan organisms such as parameciums all grew more rapidly in space. Surprisingly, mammalian cells in tissue behaved in an opposite manner and divided more slowly in microgravity. The cause of this phenomenon is unknown, but the data suggest a reduced rate of glucose utilization and changes in membrane structure. Lack of Progress To our knowledge, no comprehensive experiments are planned to test the effects of microgravity on cell function, although additional studies are planned to confirm the microgravity effect on division of mammalian cells in culture. This is not, however, appropriately considered a lack of progress since the effects of microgravity on cell function have become apparent only recently. There is a need for the development of a comprehensive strategy in cell biology. Considering the long lead times for actual flight experiments, such strategies should become a high priority in order to allow for the conduct of appropriate experiments in the foreseeable future.

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HUMAN REPRODUCTIVE BIOLOGY Status of Discipline Subsequent to publication of the Goldberg Strategy, there have been significant advances in reproductive technology which would enhance the ability to monitor men and women during spaceflight for their reproductive status. These include assays for the sex hormones that can be performed on urine and saliva samples, reducing the need for serum sampling of the crew. In addition, analysis of a number of key parameters of sperm function has become fully automated and computerized. These advances enable the analysis of sperm chromosomes for gross structural abnormalities and point mutations as well as their ability to fertilize eggs. Such analyses become especially important when space crews become exposed to the radiation environment of deep space for prolonged time periods. Finally, recent studies in environmental toxicology have identified a number of strategies and endpoints for monitoring men and women for potential alterations in reproductive status. In addition, the effects of sex steroids on memory, aggression, and sleep are of increasing interest. Psychological ramifications of reproductive function may now be studied in relation to reproductive hormone function. Major Goals The major scientific goal is to characterize effects of the space environment on human reproductive function; more generally, effects on mammalian reproductive function. This includes characterization of stress and the microgravity environment as evidenced by hormonal and physiological alterations, including possible hyperestrogenism to bone loss and behavioral aspects of gonadal failure (see Chapter 4, Behavior and Human Performance). In addition, it is desirable to obtain direct evidence on the effects of the space environment on male and female gametes including the effects of radiation on gametes. Progress The Soviet COSMOS flights using rats have provided virtually all of the information that exists on mammalian reproduction in space. The first study was a 19-day flight during which rats were observed for mating and parturition in space. None of the females delivered offspring, which was hypothesized to result from fetal absorption caused by stress. However, there was no reported verification that mating had occurred. During a more recent flight an experiment using rats that became pregnant prior to flight successfully delivered live young in space. NASA has proposed a study, using mice, that will examine mouse embryos prior to implantation and will study their ability to develop in space.

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Concerning humans, a number of factors have been identified as having the potential to affect reproduction in space. Some of these come from studies made of men and women undergoing military training or strenuous athletic activities. Lack of Progress Aside from the proposed experiment using mice, no additional studies in space have been indicated. There are no indications that NASA intends to monitor the reproductive status of crew members or that consideration has been given to issues of the potential effects of the space environment (microgravity and radiation) on human reproduction.