1
Introduction

The core of the National Aeronautics and Space Administration's (NASA's) life sciences research programs lies in understanding the effects of the space environment on human physiology and on gravitational biology in plants and animals. The space environment exposes occupants not only to microgravity, but also to many other potentially perturbing factors, ranging from radiation to the vicissitudes of a confined, enclosed environment in which noise, vibration, temperature, atmospheric quality, and other aspects of the surroundings are generally less than ideal. This report, like its predecessors,1 2 emphasizes the importance of investigating fundamental mechanisms of the effects elicited by microgravity and other aspects of the space environment, in contrast with the largely descriptive studies of the earlier era of space biology and medicine.

To achieve an understanding of the mechanisms underlying relevant biological and biomedical phenomena, it will be necessary to approach the problems at all levels of biological organization—the molecule, the cell, the organ system, and the whole organism. For example, loss of bone mass from weight-bearing bones is one of the issues of greatest concern in maintaining astronaut health and safety during prolonged spaceflight and upon return to Earth. Understanding the mechanisms responsible for the observed bone loss and the development of effective physical and/or pharmacological countermeasures will require the following at a minimum: characterization of the effects of microgravity on the cells responsible for bone growth and bone resorption; analysis of the molecular and cellular mechanisms whereby cells in weight-bearing bone perceive and respond to the force of gravity; identification and analysis of possible effects of microgravity-induced changes in muscle activity and blood flow on bone metabolism; and determination and understanding of the changes in levels of the many hormones induced by stress and the environment that contribute to the regulation of bone metabolism, both positively and negatively. This example, which spans a range of experimental approaches from molecular biology to organismic physiology, illustrates the integrated, multidisciplinary approach necessary to meet the goals set for NASA life sciences research in the next decade.



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--> 1 Introduction The core of the National Aeronautics and Space Administration's (NASA's) life sciences research programs lies in understanding the effects of the space environment on human physiology and on gravitational biology in plants and animals. The space environment exposes occupants not only to microgravity, but also to many other potentially perturbing factors, ranging from radiation to the vicissitudes of a confined, enclosed environment in which noise, vibration, temperature, atmospheric quality, and other aspects of the surroundings are generally less than ideal. This report, like its predecessors,1 2 emphasizes the importance of investigating fundamental mechanisms of the effects elicited by microgravity and other aspects of the space environment, in contrast with the largely descriptive studies of the earlier era of space biology and medicine. To achieve an understanding of the mechanisms underlying relevant biological and biomedical phenomena, it will be necessary to approach the problems at all levels of biological organization—the molecule, the cell, the organ system, and the whole organism. For example, loss of bone mass from weight-bearing bones is one of the issues of greatest concern in maintaining astronaut health and safety during prolonged spaceflight and upon return to Earth. Understanding the mechanisms responsible for the observed bone loss and the development of effective physical and/or pharmacological countermeasures will require the following at a minimum: characterization of the effects of microgravity on the cells responsible for bone growth and bone resorption; analysis of the molecular and cellular mechanisms whereby cells in weight-bearing bone perceive and respond to the force of gravity; identification and analysis of possible effects of microgravity-induced changes in muscle activity and blood flow on bone metabolism; and determination and understanding of the changes in levels of the many hormones induced by stress and the environment that contribute to the regulation of bone metabolism, both positively and negatively. This example, which spans a range of experimental approaches from molecular biology to organismic physiology, illustrates the integrated, multidisciplinary approach necessary to meet the goals set for NASA life sciences research in the next decade.

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--> History It has been 10 years since publication of the report A Strategy for Space Biology and Medical Science for the 1980s and 1990s (known as the Goldberg report),3 in which for the first time, the Space Studies Board (then the Space Science Board), through its Committee on Space Biology and Medicine (CSBM), outlined a broad-based scientific strategy for research in space biology and medical science. The strategy and the major scientific goals remain generally valid today. However, during the 1990s there has been an explosion of new scientific understanding catalyzed by advances in molecular and cell biology and genetics, and substantially more information derived from flight experiments. New opportunities for long-term experiments in space biology and medicine are anticipated on completion of the International Space Station, and there is renewed interest in human exploration of the solar system, which will require long-term survival in space. All of these developments indicate the desirability of reevaluating the opportunities and priorities for NASA-supported life sciences research into the new century. Recent advances in areas of biology and medicine relevant to space offer the promise of better identifying and understanding factors that may be important for astronauts who have to live and work effectively in space for several years at a time and readapt successfully to Earth's environment upon return. The Goldberg strategy had two main purposes: "(1) to identify and describe those areas of fundamental scientific investigation in space biology and medicine that are both exciting and important to pursue; and (2) to develop the foundation of knowledge and understanding that will make long-term manned space habitation and/or exploration feasible."4 To achieve these purposes, the Goldberg report identified four major goals of space life sciences: "1.   To describe and understand human adaptation to the space environment and readaptation upon return to Earth. "2.   To use the knowledge so obtained to devise procedures that will improve the health, safety, comfort, and performance of the astronauts. "3.   To understand the role that gravity plays in the biological processes of both plants and animals. "4.   To determine if any biological phenomenon that arises in an individual organism or small group of organisms is better studied in space than on Earth."5 The Goldberg report was noteworthy in its emphasis on basic research in gravitational biology and its call for vigorous ground-based programs aimed at addressing fundamental biological mechanisms that underlie observed effects of the space environment on human physiology and other biological processes. Five areas of clinical and basic research related to the effects of microgravity and the space environment were highlighted: Sensorimotor integration, focusing on vestibular function and space motion sickness; Cardiovascular adaptation, particularly the fluid shift induced by microgravity and the orthostatic intolerance experienced upon return to normal gravity; Muscle remodeling and the loss of mass in weight-bearing muscles; Bone and mineral metabolism as related to the demineralization of weight-bearing bone; and Human behavior and the effects of stress. In addition, two areas of fundamental research in gravitational biology were emphasized: plant gravitropism and developmental biology, especially the question of whether the space environment could support the normal reproduction and development of plants and animals, including mammals, for one or more complete generations.

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--> A follow-up report from CSBM in 1991 (the Smith report)6 assessed progress in reaching specific scientific goals identified in the Goldberg report and called attention to several additional areas of research, including radiation biology and aspects of immunology, endocrinology, and stress that merited new or renewed consideration. Interestingly, this report was the first to consider cell biology explicitly as a discipline relevant to space biology and medicine. Because of the continuing hiatus in the shuttle program during the intervening period, most NASA studies were ground-based, although international flights yielded some new flight data. The 1991 Smith report cited progress in the development and analysis of ground-based model systems (both animal and human) used to study the effects of weightlessness on the functioning of the cardiovascular and musculoskeletal systems, and it noted significant progress in understanding of the physiology of the sensorimotor system and vestibular function. However, little progress was apparent in elucidating the fundamental cellular mechanisms underlying the observed physiological phenomena. Similarly, progress in plant gravitropism was thought to suffer from limitations in-flight opportunities and continued slow progress in identifying basic cellular and intercellular mechanisms responsible for gravity-dependent responses. Since publication of the Smith report in 1991, resumption of the shuttle program has provided a substantial number of flight opportunities, notably the dedicated Spacelab flights SLS-1, SLS-2, the German D-2 mission, and the recent Neurolab mission. In addition, the development of cooperative programs between NASA and the Russian space agency has made newly available some data pertaining to the effects of long-duration (6- to 12-month) flights. The 1991 Smith report offered as a major conclusion, and as the first priority in any relevant research strategy, the need to focus on ground-based research aimed at understanding basic mechanisms underlying microgravity-induced changes. The current report strongly reemphasizes that conclusion. Although the overall goal of safeguarding the health, safety, and performance of astronauts (most especially during long-term flight) is an eminently practical one, understanding the true nature of risks and developing maximally effective countermeasures will require analysis of the mechanisms whereby cells, tissues, and whole organisms respond to changes in the magnitude of the gravitational vector. Effective use of the entire armamentarium of contemporary molecular and cell biology, as well as contemporary physiological techniques, will be necessary to achieve this goal. Spaceflight experiments will continue to be required to test and validate mechanistic hypotheses and potential countermeasures developed in ground-based investigations. Although ground-based models of hypogravity have provided important insights into specific aspects of gravitational biology, no ground-based model gives an adequate representation of the microgravity environment. However, experiments carried out in space need a solid foundation in ground-based research that uses a limited number of carefully chosen model systems, resulting in formulation of key hypotheses and identification of the key experiments that require the space environment. Gravity and Low Gravity Gravity, Microgravity, and Weightlessness Orbital spaceflight and parabolic flight generate conditions of weightlessness. These are generally termed "microgravity conditions" and for convenience are so designated in this report. However, they are not actually conditions involving low levels of gravity. In orbital spaceflight, it is the force of Earth's gravity that keeps the vehicle in an orbital path. The gravitational attraction between Earth and the vehicle (and its occupants) provides the centripetal force (mv2/r) that maintains the vehicle's orbital path about Earth, where r is the distance from the center of Earth to the orbit, v is the velocity of the

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--> vehicle, and m is the vehicle's mass. The variation of Earth's gravity g at altitude h above Earth's surface is governed by g = g0 × re2 / (re + h)2, where g0, Earth gravity at sea level, is 9.8 m/s2 and re, the radius of Earth, is 6.38 × 106 m. At an orbital altitude of 250 miles (4.4 × 105 m), g would be about 8.6 m/s2, or 87.5 percent of Earth's gravity at sea level. Orbital flight represents a condition of free fall in which the balance of forces acting between the craft and its occupants is effectively zero, except when the occupants apply forces to the vehicle so that they can move or operate within it. To interpret experiments carried out in such "weightless" conditions, the importance of contact forces acting on objects under terrestrial conditions must be realized. Einstein's principle of equivalence states that no measuring device can distinguish between inertial and gravitational forces. The same is true of the sensors of the human or animal body. It is the contact surface on which a person or animal stands that provides reaction forces to gravitational or inertial accelerations, allowing the person or animal to attain posture and locomotory control. It is this reaction force acting on an object that a scale measures as weight. Direct and Indirect Effects of Microgravity In considering the possible effects of microgravity conditions on biological systems, it is necessary to distinguish between direct effects of microgravity, in which the system perceives changes in the gravitational force per se, and indirect effects, in which the system responds not to the gravitational force itself, but rather to changes in the local environment that are induced by microgravity conditions. The major effect of low-gravity environments is a reduction in gravitational body forces, thus decreasing buoyancy-driven flows, rates of sedimentation, and hydrostatic pressure. Under such conditions other gravity-independent forces, such as surface tension, assume greater importance. Transport processes, such as heat transfer and solute mixing, are reduced in the gas phase and at interfaces with solids. Alterations in fluid dynamics in the low-gravity environment have significant implications for the behavior of biological systems, both isolated cells as well as intact organisms. Thus, for example, in cell culture experiments, the diffusion of nutrients, oxygen, growth factors, and other regulatory molecules to the plasma membrane, as well as the diffusion of waste products and CO2 away from the cell, will be reduced in the near absence of convection unless countered by stirring or forced flow of medium. Such effects might account, at least in part, for the reduced growth rates or decreased rates of glucose utilization sometimes encountered in cultured cells in-flight. It is also possible that increased accumulation of CO2 adjacent to the plasma membrane could result in deleterious changes in local pH. Examples of indirect effects of microgravity on intact plants are also known. Effective delivery of water to roots is compromised by the greater tendency of water droplets to cohere and ball up because of the now dominant effects of surface tension, so that roots may become either water deficient or waterlogged. Similarly, reduced rates of gas exchange at the leaf surface decrease the availability of CO2 for photosynthesis and thus perturb the plant's carbohydrate and energy production. In addition, decreased diffusion of transpired water away from the leaf may result in excessive local humidity and waterlogging. The physiological importance of the reduction in air convection in microgravity conditions has been dramatically demonstrated by Musgrave's recent experiments on flower development and sexual reproduction in Arabidopsis thaliana (see also the section "Role of Gravity in Plant Processes" in Chapter 4).7 If the purpose of the 1987 Goldberg report was to guide the infant field of space biology through its next phase of development, the current report may be said to have the purpose of guiding an adolescent field in its further development toward maturity. The body of this report aims to summarize recent advances in fields relevant to space biology and medicine; recommends directions for future research,

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--> emphasizing integrative, multidisciplinary approaches to both ground-based and space-based investigations; and considers program and policy issues that may affect the nature and quality of NASA research programs in the life sciences. References 1. Space Science Board, National Research Council. 1987. A Strategy for Space Biology and Medical Science for the 1980s and 1990s. National Academy Press, Washington, D.C. 2. Space Studies Board, National Research Council. 1991. Assessment of Programs in Space Biology and Medicine 1991. National Academy Press, Washington, D.C. 3. Space Science Board, 1987, A Strategy for Space Biology and Medical Science for the 1980s and 1990s. 4. Space Science Board, 1987, A Strategy for Space Biology and Medical Science for the 1980s and 1990s, p. xi. 5. Space Science Board, 1987, A Strategy for Space Biology and Medical Science for the 1980s and 1990s, p. 4. 6. Space Studies Board, National Research Council. 1991. Assessment of Programs in Space Biology and Medicine 1991. National Academy Press, Washington, D.C. 7. Musgrave, M.E., Kuang, A., and Matthews, S.W. 1997. Plant reproduction during spaceflight: Importance of the gaseous environment. Planta 203: S177-S184.

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Part II Physiology, Gravity, and Space

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