Neal R. Pellis, Ph.D.Neal R. Pellis, Ph.D.DirectorDirector

Division of Space Life SciencesDivision of Space Life SciencesUniversities Space Research AssociationUniversities Space Research Association

Houston, TX 77058Houston, TX 77058pellis@dsls.usra.edupellis@dsls.usra.edu

Terrestrial Life in Space What Can We Learn From Cells?

Clinical Problems in SpaceClinical 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 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 "There is a place in your brain, I think, reserved for 'the melancholy think, reserved for 'the melancholy of relationships past.'of relationships past.'

It grows and prospers as life It grows and prospers as life progresses, forcing you finally, progresses, forcing you finally, against your grain, to listen to against your grain, to listen to country music."country music."(K.B. Mullis et al., eds., The Polymerase Chain Reaction,(K.B. Mullis et al., eds., The Polymerase Chain Reaction,

Birkhauser: Boston, 1995, p. 427).Birkhauser: Boston, 1995, p. 427).

Terrestrial Life and MicrogravityTerrestrial 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 the 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?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 NatureInteractions in Nature

• Gravitational

• Electromagnetic

• Strong submolecular forces

• Weak submolecular forces

Interactions in NatureInteractions 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 BiologyAn Important Question in Space BiologyThe Relationship Between Gravity and Biological ActivityThe Relationship Between Gravity and Biological Activity

Log10 Gravity-6 -5 -4 -3 -2 -1 0 1

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An Important Question in Space BiologyAn Important Question in Space BiologyThe Relationship Between Gravity and Biological ActivityThe Relationship Between Gravity and Biological Activity

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Hypothesis: Hypothesis: Relationship Between Gravity and Biological ActivityRelationship Between Gravity and Biological Activity

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Areas of InvestigationAreas of Investigationfor Space Explorationfor 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 ScienceAreas of Investigation for Applied Science• Tissue engineering

• Vaccine and drug development

• Models of human disease

• Living reporter sensors

Fundamental QuestionsFundamental 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

• 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)?

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Scientific Questions to AddressScientific 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 QuestionsPractical 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 To investigate the cellular and tissue responses to microgravity it was essential to design systems that approximate the microgravity it was essential to design systems that approximate the some of the some of the microgravity conditions and provide the opportunity to microgravity conditions and provide the opportunity to study these phenomena study these phenomena on Earth in a more controlled and available on Earth in a more controlled and available venuevenue.

Analog SystemsAnalog Systems

Isopycnic Solution(Neutral Buoyancy)

Suborbital RocketsSuborbital Rockets

Parabolic FlightParabolic Flight

SuperconductingMagnet

Diamagnetic

Magnetic LevitationMagnetic Levitation Solid Solid Body Body Fluid Fluid RotationRotation

Drop Tower

6o Head DownTilt Bedrest

CentrifugationHyper G

Unique aspects of Unique aspects of GG

• 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 SpaceAnimal Cells in Space

1 G 1 G

GChanges:

fluid distributiongene expressionsignal transductionlocomotiondifferentiationMetabolismglycosylation

Theory of the Effect of Theory of the Effect of G on G on Mammalian CellsMammalian Cells

1 G G

Potential Change in membrane:StructureCompositionBileaflet organizationLipid raftsAssociation with the cytoskeleton

Perhaps the ‘forced’ shape change induces a cascade of responses otherwise unrelated to G

Bacteria in SpaceBacteria in Space

Changes:

Gene expressionShift to secondary metabolismQuorum sensing?VirulenceMechano-responsive mechanismsReplication ratesBiofilm formation

Bacillus spacecowboyum

1 G 1 G

G

Theory of the Effect of Theory of the Effect of G on Bacterial CellsG on Bacterial Cells Response of cell with non pliant cell wallsResponse of cell with non pliant cell walls

Bacteria

1 G G

?? Pin<<Pout??In bacteria, the cell wall is a rigid structure that surroundsthe 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 Cellular Responses to GG• 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

Physical Factors to Consider Physical Factors to Consider in Experimental Designin Experimental Design

• Gravity• Mechanical impacts• Hydrodynamic shear• Convection• Vibration• Radiation• Barometric Pressure• Hydrostatic pressure gradients

SignificanceSignificance•There is little doubt that cells as representative of terrestrial life respond 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• 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

Obstacles in Colonizing SpaceObstacles in Colonizing Space

• Financial• Political and philosophical• Propulsion• Dealing with the reality that it could be a multi-

generational mission• Managing health• Managing the logistics• Decreasing the energy requirements for life?

We are going to have to learn by We are going to have to learn by exploring the Solar Systemexploring the Solar System

• Candidates for colonization are:– The Moon– Mars

• Candidates for exploration– Europa (Moon of Jupiter)– Titan (Moon of Saturn)– Encelaedus (Moon of Saturn)