Research Questions

The only way in which cells can make themselves independent of the conditions of the surrounding environment is by forming communities, which are large enough to include a self-made climate, and then developing mechanisms for stabilizing that climate to the advantage of all the constituent members. The mechanism defending and regulating the constancy of this climate is called homeostasis (Figure 1-11). The efficiency of living cells depends on the composition of the fluids by which they are surrounded. Single-celled animals can counteract small fluctuations in these fluids, but multi-cellular animals are much more resilient: they can enclose and defend an inland sea whose chemical composition is supervised and regulated by the kidneys and other organs. The survival of cells also depends on the stability of the materials from which they are made, and the energetic material surrounding them. The mechanisms responsible for maintaining life are virtually indistinguishable from the structures they support (Miller 1978). Fluid dynamics change in microgravity, it is therefore expected that microgravity exposure will affect the mechanical, biochemical, and physiological processes at cellular level. The flight environment presents a unique opportunity to study cell morphology and growth, as well as cell metabolism and interactions, in response to a change in the physics of the environment (Table 1-04).

Figure 1-11. The homeostatic mechanism preserves a constant internal environment in the face of wide variations in the outside world. But there is a limit to the physiological powers of compensation. If the external environment varies beyond what is physiologically expected, it is necessary to provide the subject with a portable version of his normal surroundings. This photograph shows an astronaut in a space suit and wearing a portable life support system when outside the space vehicle. Photo courtesy of NASA.

2.3.1 Effects of Gravity on Cell Shape, Function, and Growth

The modern view of adaptation is that the environmental forces set certain "problems" that organisms have to "solve", and that evolution, by means of natural selection and mutations, is the result of these solutions. By which mechanisms do cells sense gravitational forces and what is the role of gravity on growth and development? The use of the weightless state for unmasking factors operating at normal gravity is of decisive importance in the study of these problems. As of today, knowledge is still sparse in this research area, largely due to the constant gravity on Earth and the longstanding inability to reduce or null it.

A central feature of gravitational biology is the search for the presence of gravity sensors at cellular level, and the study of whether gravity affects molecular forces in living systems. For example, in the cytoplasm of cells, a continuous movement, referred to as protoplasmic streaming, and a binding of particles to cellular skeleton elements normally tend in some degree to oppose gravity-dependent stratification of particles according to their densities. The force of gravity undoubtedly affects the spatial relations among cellular organelles and structures. However, it is still unclear if prolonged weightlessness has an effect or not on the function of simple cells grown in culture.

Also, many cells are organized in a polarized manner, so that their contents are distributed non-uniformly along an axis, with different cytoplasmic components oriented towards either pole. Examples of highly polarized mammalian cells are the white blood cells and especially the leukocytes in which centrioles tend to occupy the geometric center of the cell, and pancreatic secretory cells in which the nucleus is found in a basal locality. The pathways of biosynthesis with the cell are orderly and related to the spatial arrangement of the various cell organelles. Complex processes such as DNA replication, RNA transcription (see this Chapter, Section 3.2) and the migration of proteins between organelles are strongly related to cell polarity.

Modification of molecular transport within cells by the force of gravity can be expected since transport affects morphology and vice-versa. Changes in pressure gradient and transport processes involving convection or diffusion might therefore result from an alteration in either magnitude or direction of the gravitational vector. Basic life processes in the cell, such as the regulation and distribution of water and ions, the turnover of cell membranes, secretion, absorption, division, and hormone and molecular interactions can also be assumed to be potential targets for such influence (Figure 1-12).

2.3.2 Specialized Cells in Vitro

In the recent years there has been rapid progress in the methods for maintaining the viability of specialized in vitro cell cultures. In many cases, the behavior of cells cultures in vitro may provide useful models for the study of cellular events as they occur in vivo in tissues and organs.

Loss of bone calcium and muscle mass and a decrease in red blood cell count are examples of disturbances occurring in humans during prolonged exposure to the microgravity environment. The availability of in vitro cultures of isolated bone and skeletal muscle cells provides a unique possibility for analyzing how bone and muscle formation, destruction, and regeneration are affected by microgravity.

Lymphocytes are the cells responsible for the immune response (see Figure 1-17). Previous studies on lymphocytes of crewmembers have shown delayed reactivity to agents, or mitogens, that normally stimulate cell proliferation. Experiments performed on lymphocyte cells from human blood allow evaluating the effect of microgravity on this mitogen-induced proliferation (see Chapter 4, Section 3.2).

Figure 1-12. Model of eel! division. The eel! cycle is an ordered set of events, which results in cell growth and division into two identical daughter cells (somatic cell division). This sequence of specific events includes cell growth, protein, DNA, and organelle replication, and nuclear (chromosomes separate during mitosis) and cellular (the cytoplasm divides during cytokinesis) division. The phases of the cell cycle are: the Gn phase where cells exist in a quiescent state; the Gj phase, which is the first growth phase; the S phase, during which the DNA is replicated; the Gj phase, which is the second growth phase, also the preparation phase for the cell; and the M phase or mitosis, i.e., the actual division of the cell into two daughter cells (as shown here). A surveillance system monitors the cell for DNA damage and failure to perform critical processes. If this system senses a problem, a network of signaling molecules instructs the cell to stop dividing. They can let the cell know whether to repair the damage or initiate programmed cell death, a form of which is called "apoptosis ".

2.3.3 Gravity-Sensing Mechanism

Complex organisms have special gravity-sensing organs, by which the direction of the gravitational vector is used for orientation. In mammals, these are the otolith organs of the vestibular apparatus in the inner ear. In vertebrates, the gravity-sensing system has the same basic structure from fish to humans. It consists of tiny calcium carbonate crystals, the otoliths, resting on a layer of specialized nerve cells, the macula. The relative weight and movement of the otoliths resting on them stimulate these hair cells. They respond to linear acceleration in three planes and signal information to the brain concerning the position of the head relative to gravity. In the adult, there is a precise interplay between these signals and those arising from many other receptors involved in the reflex muscular control of balance, posture and locomotion.

During the Neurolab mission it was found that, upon arrival in microgravity, the macular receptors compensate for the weightless calcium crystals by increasing the number of connections among hair cells. In other words, the nerve cells in the macula make new connections in space. After return to Earth, the additional connections generated in space were eventually deleted, as they were no longer needed in normal gravity (Ross et al. 2003). This result shows evidence for neuronal plasticity, or learning, at cellular level in a gravity-sensing area of the nervous system.

Gravity-sensing organs are also present in lower vertebrates and insects. These are even simpler systems, which are easier to analyze and develops faster. In snails, for example, the gravity-sensing component is lined with hair cells that send signals to the brain when they are triggered. The "triggers" are small particles of calcium carbonate, referred to as otoconia or statoliths (Figure 1-13). With gravity, these triggers weigh down upon and bed different groups of hair cells, which then send orientation signals to the brain. Ground-based experiments in which snails were developed in a centrifuge have shown that the size of the statoliths is determined by their weight. Somehow the pull of gravity signals the developing statolith when an appropriate level of growth is reached. In space, however, without this signal, these grain-like particles should develop to a larger size than they do on Earth. A related question is the following: If indeed statolith and otolith size increases in microgravity, will the behaviors of the snails and fish change also?

Crickets have even simpler gravity sensors, which are connected to a simple and well-studied nervous system. They develop rapidly, making them ideal for studies during spaceflight. Crickets roll their head when tilted, and this reflex is activated by the gravity-sensing system. By measuring this head movement, scientist can determine the efficiency and accuracy of the synaptic connections that have developed in the cricket's gravity sensors in microgravity (see Chapter 5, Section 4.1). Also, investigators can determine if the microgravity-exposed animals can regenerate the gravity sensor, as they accomplish it on Earth.

Similarly, jellyfish would serve as excellent subjects for research on gravity-sensing mechanisms, because their specialized gravity-sensing organs have been well characterized by biologists. Jellyfish and other invertebrates use structures called rhophalia or statoliths to maintain their correct orientation in water (see Figure 1-07). To determine the function of the statoliths and their adaptation to microgravity, investigations could compare, for example, their morphology and the swimming behavior of tiny jellyfish metamorphosed in space with those metamorphosed on Earth.

Utricle Saccule

Figure 1-13. Adult amphibians have otoconia located in their vestibular labyrinth. These otoconia are made of calcium carbonate in two crystal forms, with calcite in the utricle (left) and aragonite in the saccule (right). Compared to ground (top), there are changes in the appearance, morphology, and aystallographic structure of the otoconia in Pleurodeles wait developed in microgravity (bottom). Adapted from Oukda et al. (2001).

Modern genetics research has made available a variety of engineered mutations that affect the gravity-sensing systems of the brain and body. Space research provides the only way to gain a full picture of how these systems develop in microgravity, and will be key to unraveling some of these basic mysteries of gravity-sensing.

Some questions of fundamental interest are the following: Will the morphology of the vestibular apparatus or the sensorial functions of orientation, equilibrium, and locomotion be permanently affected by the loss of the gravitational stimulus? If the gravity-sensing otolith organs serve as a keystone in the development of posture and locomotion, what will be the consequences of a complete deprivation of the gravitational stimulus at the time of development of these functions? Will other functions related to the action of gravity, such as blood pressure control and bone formation at the cellular level, develop normally? Since critical stages in the functional development may also occur after birth, will only the animals that have been exposed to the spaceflight environment during certain phases of the postnatal period exhibit those changes? These questions are also addressed by research in Development Biology, as described in the section below.

Growth and differentiation of vertebrates' cell cultures Understand the effects of gravity on cells, animals and plants

Future

Cell reproduction, development, genetics

Cell characteristics/integrity

Cell metabolism and products

Cell-cell and cell-body interactions

Response to foreign agents

Other environmental factors than microgravity

Table 1-04. Current and future space research in Cell Biology.

Table 1-04. Current and future space research in Cell Biology.

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