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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.
