Neal R. Pellis, Ph.D.

Director

Division of Space Life Sciences

Universities Space Research Association

Houston, TX 77058

pellis@dsls.usra.edu

Terrestrial Life in Space What Can We Learn From Cells?

Clinical Problems in Space • Visual impairment

• Exposure to ionizing radiation

• Bone density decrease

• Muscle atrophy

• Cardiovascular deconditioning

• Psychosocial impacts

• Vestibular dysfunction

• Hematological changes

• Immune dysfunction

• Delayed wound healing

• Gastrointestinal distress

• Orthostatic intolerance

• Fluid shifting

• Renal stones

• Nutrition

Paradigms Lost • The Earth is the center of the universe

• Blood letting ameliorates most disease

• Accumulations of old rags in the attic

spontaneously generate rats

• Read my lips, no new taxes…

• I never inhaled…

• Humans cannot survive outside the

Earth’s environment

• Cellular and intracellular components are

too insignificant in mass to be affected by

the loss of gravity

"There is a place in your brain, I think,

reserved for ‘the melancholy of

relationships past.’ It grows and

prospers as life progresses, forcing

you finally, against your grain, to listen

to country music."

(K.B. Mullis et al., eds., The Polymerase Chain Reaction,

Birkhauser: Boston, 1995, p. 427).

Terrestrial Life and

Microgravity • As life evolved on earth, a multiplicity of physical

and chemical factors invoked adaptations and

participated in the complicated selection

process.

• For many factors, there are clear examples of the

role of changing physical forces in evolution.

• A notable exception is gravity. It has been

constant for 4.8 billion years.

• Therefore, there is little or no genetic memory of

life responding to force changes in the low

gravity range.

Why Space Cell Biology? • As is true for terrestrial based biomedicine,

analysis of the cellular response to

microgravity offers the prospect of

elucidating underlying mechanisms that can

be the basis for effective treatment.

• Observation of the cellular response to

variation in ‘G’ reveals novel adaptive

mechanisms.

• Understanding basic cellular mechanisms

necessary for the adaptation of terrestrial life

to low gravity environments.

Interactions in Nature

• Gravitational

• Electromagnetic

• Strong submolecular forces

• Weak submolecular forces

Interactions in Nature • Gravity is the weakest of the four but has a

vast radius of influence

• Among the four, gravity is considered the sculptor of the universe

• Methods for studying gravitational influences on biological processes (Microgravity Analogs) – Theoretical analysis and computer modeling

– Changing the weight loading

– Hypergravity

– Free fall strategies

– Space experiments

An Important Question in Space Biology The Relationship Between Gravity

and Biological Activity

Log10 Gravity

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Hypo-G Hyper

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Hypothesis: Relationship Between Gravity and

Biological Activity

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Moon

Areas of Investigation for Space Exploration

• Basic human physiology

• Plant life used for O2 and for food

• Bioregenerative microbes

• Normal flora

• Environmental monitoring

• Exploration proes

Areas of Investigation for Applied Science

• Tissue engineering

• Vaccine and drug development

• Models of human disease

• Living reporter sensors

Fundamental Questions

• What is the basis of the cellular response to

microgravity?

– Intrinsic response in the cell

(gravisensor?)

– Cellular response to environmental

changes induced by gravity

• Shear

• Mass transfer

• Surface contact

• No sedimentation

Fundamental Questions

• How is response different in microbial cells

(that are bound by a cell wall) vs.

eukaryotic/mammalian cells that do not have

a cell wall?

• How do changes in individual cells relate to

tissues, organs, and organisms?

• How does microgravity change cell response

thresholds to other stimuli (radiation,

magnetic fields, shear, toxins, other

chemicals)?

14

Scientific Questions to Address

• Adaptive responses of cells to microgravity

and to the space environment?

• Phenotypic and genotypic changes induced

by microgravity, space, and planetary

environments?

• Does the space environment invoke a

selective pressure on replicating cells?

• How much ‘G’ is required to maintain normal

function?

• What new cell biology applications can be

achieved in low gravity environments?

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Practical Questions

• How do changes in individual cells relate

to tissues, organs, and organisms?

• How does microgravity change cell

response thresholds to other stimuli

(radiation, magnetic fields, shear, toxins,

other chemicals)?

• Can we use cells to conduct missions

with unknown consequences?

To investigate the cellular and tissue responses to microgravity it

was essential to design systems that approximate the some of the

microgravity conditions and provide the opportunity to study these

phenomena on Earth in a more controlled and available venue.

Analog Systems

Isopycnic Solution

(Neutral Buoyancy)

Suborbital Rockets

Parabolic Flight

Superconducting

Magnet Diamagnetic

Magnetic Levitation Solid

Body

Fluid

Rotation

Drop Tower

6o Head Down

Tilt Bedrest

Centrifugation

Hyper G

Unique aspects of mG

• No sedimentation

• Loss of gravity driven convection

• Decreased hydrodynamic shear

• No hydrostatic pressure

• Mass transfer is limited to the rate of

diffusion

Animal Cells in Space

1 G 1 G

m G Changes:

Fluid distribution

Gene expression

Signal transduction

Locomotion

Differentiation

Metabolism

Glycosylation

Theory of the Effect of mG on

Mammalian Cells 1 G m G

Potential Change in membrane:

Structure

Composition

Bileaflet organization

Lipid rafts

Association with the cytoskeleton

Perhaps the ‘forced’ shape change induces a cascade

of responses otherwise unrelated to mG

Bacteria in Space

Changes:

Gene expression

Shift to secondary metabolism

Quorum sensing?

Virulence

Mechano-responsive mechanisms

Replication rates

Biofilm formation

Bacillus

spacecowboyum

1 G 1 G

m G

Theory of the Effect of mG on Bacterial Cells Response of cell with non pliant cell walls

Bacteria

1 G m G

?? Pin<<Pout??

In bacteria, the cell wall is a rigid structure that surrounds

the cell membrane. Perhaps the decrease in gravity

accentuates the attractive forces between fatty acid side

chains of triglycerides resulting in outward force on the

wall. This in turn activates mechano- and baro-

responsive mechanisms leading to the phenotypes seen

in space. May be applicable to plant cells

Cellular Responses to mG • Signal transduction

• Shape change

• Gene expression

• DNA damage

• Cell division rates

• Orientation of subcellular components – Changes in nucleoli morphology

– Synthesis and orientation of macromolecules

– Cytoskeleton

• Programmed cell death

• Cellular movement

• Cellular repair

• Cytokine synthesis and secretion

• Glycosylation

• Differentiation and tissue morphogenesis

• Biofilm formation and deposition

Significance • There is little doubt that cells as representative of

terrestrial life respond to decreased gravity environments.

• The mechanism of gravity induced responses in cells is

unknown.

• Nevertheless, microgravity affords a unique tool to probe

the underlying mechanisms in life systems at the cellular

and organismal level.

• We plan use of this tool:

In novel ways to increase our understanding of the

role of gravity in life processes.

To achieve goals in applied biological science and

technology development.

To elucidate the long term effects of microgravity on

terrestrial life by using cells as explorers.