Good Health: The Impact of Space Science on Precision Medicine

Good Health:The Impact of Space Science on Precision Medicine
Julie Robinson, Ph.D.
CHIEF SCIENTIST, NASA ISS PROGRAM
Anita Goel, M.D., Ph.D.
CHAIRMAN & CEO, NANOBIOSYM
Steven R. Steinhubl, M.D.
DIRECTOR, DIGITAL MEDICINE, SCRIPPSTRANSLATIONAL RESEARCH INSTITUTE
Joan A. McGowan, Ph.D.
DIRECTOR, DIVISION OF MUSCULOSKELETAL DISEASES, NIAMS, NIH
Mark Shelhamer, Sc.D.
CHIEF SCIENTIST, NASA HUMAN RESEARCH PROGRAM
TimYeatman, M.D., F.A.C.S.
CHIEF SCIENTIST, CASIS
MODERATOR:
PANEL:

Julie Robinson, Ph.D.
CHIEF SCIENTIST, NASA ISS PROGRAM

NASA
Human
Research
Program
Flight
Medicine
NASA Space
Biology
NIH, Pharma
R&D
Medicine
ISS Research
and Precision
Medicine
Value of Knowledge for Human Health Solutions
Clinical
Fundamental Translational Clinical
ValueofKnowledgeforExploration
FundamentalTranslational
GeneLab

Steven R. Steinhubl, M.D.
DIRECTOR, DIGITAL MEDICINE, SCRIPPSTRANSLATIONAL RESEARCH
INSTITUTE

Steven R. Steinhubl, MD July 8, 2015
Moving from the Quantified- to the
Understood-Self

Identifying Important Changes Before They Happen in
Complex Systems – Weather
Lewis Fry Richardson, physicist
& mathematician, was first to
demonstrate “weather
prediction by numerical
processes” using barometric
pressure, wind and
temperature.
1916

IBM Bluefire – NCAR Super
Computer
Complex Systems – Weather
Satellites, Aircraft, Sea, Land Sensor Data
Position Ocean temperature at depth
Wind movement Rain
Atmospheric temperature Wind fields
Moisture Waves
Barometric pressure Currents
Wind intensity Ocean Salinity
Weather Forecasting-
350% Improved Accuracy Over the
Last 25 Years

Complex Systems – Human Health
Blood Pressure -1881
1904
Electrocardiogram
1901
1911
~1900
1852
Stethoscope/
Auscultation
1816

Resting heart rate in
4,452 healthy
adolescents
Important Physiologic Changes Based on
Population Norms
Mackowiak PA. JAMA 1992;268:1578-80
Cad. Saúde Pública, Rio de Janeiro 2010; 26(10):1963-71
Stroke. 2014; 45: 315-35
700 oral temperatures
in 148 young, healthy
adults

Topol EJ. Cell 2014 Mar 27;157(1):241-53
Individual Geographic Information System
# of unique human biomarkers

Non-Invasive Human Biomarkers
“Anything that can be used as an indicator of the physiologic state of an organism.”
Gorodeski EZ. Circ Cardiovasc Qual Outcomes 2011;4;521-532
Syed Z. Sci Trans Med 2011;3: 102ra95
ECG
• 477 individual biomarkers through
a single 12-lead ECG. 14
associated with long-term
(median 8.1 yrs) CV outcome.
• Computationally derived
biomarkers from continuous ECG
in 4500 ACS patients

Non-Invasive Human Biomarkers
“Anything that can be used as an indicator of the physiologic state of an organism.”
Breath
• 300-500 VOC per breath.
• 3256 different VOCs across a
population of 252 individuals
Smolinska A. PLoS One 2014;9(4):e95668
Martinez-Lozano Sinues P. PLoS One 2013 8(4): e59909.
We each have individual breath phenotypes.
The overall breath-mass spectrum to breath-donor recognition score was 76%
over 193 samples.

Science Trans Med April 15, 2015

The Near Future of Wearable Sensor Data
1. Activity
2. Pulse
3. Sleep stages
4. Blood pressure
5. Cardiac Output / Stroke Vol.
6. ECG
7. Stress
 HRV
 EDA
8. Respiration rate
9. Oxygen saturation
10. CO2 levels
11. Temperature
12. Hydration
13. Glucose (?)

Multi-parametric Sensors
Continuous collection and tracking of skin temperature, heart rate, cutaneous blood perfusion, O2
sat, respirations, activity, and sweating.
ECG
Heart Rate (HR)
HR Variability
O2 Saturation
Respiration Rate
Respiration depth
Activity Level
Temperature
Detection of relative Blood
Pressure changes is under
development.

Multiparametric Monitoring to Enable Personalized Physiologic
Analytics
Pipke M. Wireless Health 2013, Baltimore, MD, USA

DIRECTOR, DIVISIONOF MUSCULOSKELETAL DISEASES, NIAMS,
NIH

Good Health for All: The Intersection of Space
Science and Public Health on Earth
Director, Division of Musculoskeletal Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
July 9, 2015

Preview
• NIH Overview
• History of NIH Interest in Space
• Current Activities in Space and on Earth
• NIH and NASA Precision Medicine Initiative

The NIH mission is to seek fundamental knowledge about the nature and behavior of living
systems…and the application of that knowledge to enhance health, lengthen life, reduce
illness and disability.
NIH: Steward of Medical and Behavioral
Research for the Nation
• Research
• Training
• Information dissemination

Center for
Scientific
Review
Clinical
Center
Center for
Information
Technology
National Institute
on Minority Health
and Health
Disparities
National Center
for Complementary
and Integrative
Health
Fogarty
International
Center
National Center
for Advancing
Translational
Sciences
National
Library
of Medicine
National
Human Genome
Research Institute
National Institute of
Biomedical Imaging
and Bioengineering
Nursing Research
National Institute
of Environmental
Health Sciences
General Medical
Sciences
National Institute
of Mental
Health
National
Institute on
Drug Abuse
National
Institute on
Alcohol Abuse
and Alcoholism
National Institute
on Deafness and Other
Communication
Disorders
Dental and Craniofacial
Research
National
Eye Institute
Neurological Disorders
and Stroke
National Institute
of Child Health and
Human Development
National Institute
of Allergy and
Infectious Diseases
National
Institute on Aging
National Institute
of Arthritis and
Musculoskeletal and
Skin Diseases
Diabetes and Digestive
and Kidney Diseases
National Heart, Lung,
and Blood Institute
National
Cancer Institute
The 27 Institutes
and Centers of
the
NIH

Dear Terence:
… your proposal does not fall in the
health and related sciences fields for which they
recommend support. On the other hand, they agreed
enthusiastically that you should receive the funds
requested and contributed as individuals to make the
support possible…
… Please accept our very best wishes for a
successful project.
The Rocket Boys of NIH (1957)
Dear Sir,
My friend and I [are] very interested in space travel and have a great idea for a
rocket ship. We were wondering if we could have a little sum of money
($10.00 maybe) to fulfill our project.
We would [be] most grateful if you
would send it to us.

Bone Density and Calcium Balance Studies on Project
Gemini
Gemini VII capsule from Gemini VI-A. Photo credit:
NASA
Published March 1967
Gemini IV, V, and VII
Funded by
• NASA Contract NSR-33-024-006
• NIH Grant FR-00254

Examples of NIH Science on Shuttle and Station (1994
and beyond)
Model
organism
Bone
physiology
Muscle
physiology
Neuro-
physiology
Dev. biology Fluid
dynamics
Other
Cell culture STS-59
STS-66
STS-63
STS-69
STS-72
STS-77
STS-80
STS-95
ISS-43/44
STS-59
STS-66
STS-63
STS-72
STS-77
ISS-7
ISS-8
ISS-10
ISS-13
ISS-3
ISS-4
ISS-39/40
ISS-41/42
Fruit flies STS-93
STS-106
Oyster
toadfish
STS-90
Rats STS-66 STS-66
STS-90
STS-90 STS-66 STS-66
STS-72
STS-80

Memorandum of Understanding
Between the NIH and NASA
• NIH will use reasonable efforts to
– Publicize, to the intramural and extramural communities, the availability of the ISS as a
research environment...
– Give careful consideration through the standard review process to well-developed,
investigator-initiated extramural applications and potential intramural activities related to
space-related health research...
September 12, 2007: NIH Director Dr. Elias A.
Zerhouni and NASA Administrator Dr. Michael D.
Griffin shake hands after signing the MOU at the
U.S. Capitol while Senators Kay Bailey Hutchison
and Barbara Mikulski stand by.

BioMed–ISS Program
• Biomedical Research on the International Space Station (BioMed-ISS) Program was
developed to facilitate NIH mission relevant research on the ISS to benefit human health
on Earth.
• An NIH Funding Opportunity Announcement (FOA) was released on March 17, 2009
using the NIH UH2/UH3 mechanism. Its emphasis was on molecular- or cell-based
studies.
• The BioMed-ISS program was complementary to NASA’s Human Research Program.
Space-related human research was not be accommodated under this FOA.
• Investigator-initiated biomedical research that would use the unique microgravity and
radiation environment and resources of the ISS to test innovative hypotheses that would
benefit human health on Earth.

Three Ongoing BioMed-ISS Projects
• Microorganism virulence and host
immunity
– T-Cell Activation in Aging ISS-39/40 and
ISS-41/42
• Bone biology
– Osteo-4 (Osteocytes and
Mechanotransduction)
ISS-43/44
– Gravitational Regulation of Osteoblast
Genomics and Metabolism
Graduate student Jordan Spatz (left)
and Dr. Paola Divieti Pajevic
Harvard Medical School
Dr. Millie Hughes-Fulford
University of California, San
Francisco
Dr. Bruce Hammer
University of Minnesota

The U.S. Precision Medicine Initiative

“And that’s why we’re here today. Because something called precision
medicine … gives us one of the greatest opportunities for new medical
breakthroughs that we have ever seen.”
President Barack Obama
January 30, 2015

Precision Medicine
Concept is not new
 Consider prescription eyeglasses, blood transfusions…
 Prospects for broader application raised by recent advances in basic research,
technology development, genomics, proteomics, metabolomics, EHRs, Big Data,
mHealth, etc.
 Reinforced by 2011 National Research Council report
What is needed now
 Development of rigorous research program to provide scientific evidence needed to
turn concept into reality
 Recruitment of the best and brightest from multiple disciplines to join the team

EHRsPatient Partnerships
Data Science
GenomicsTechnologies

Summary of NIH/NASA’s Shared Interests
Medicalcountermeasures
Health care delivery
technologies
Behavioral and
Psychological
Processes
BiologicalProcesses
Cell Structure
OrganSystems
TissueEngineering
Pulmonary system
Car d io v ascular
system
Eyes
Musculoskeletal system
Neurophysiology
Aging
Cancer
Development
Hemodynamics
Immunology
Injury and healing
Metabolism
(e.g., pharmacodynamics, pharmacokinetics)
Sensory-motor
processes
Tissue Structure
Biological rhythms
Development of Tools
for Land- or Space-based Activities
Health monitoring technologies
Physical activity

CHIEF SCIENTIST, NASA HUMAN RESEARCH PROGRAM

National Aeronautics and Space Administration
Human Research Program
Good Health: The Impact of Space Science on Precision
Medicine
NASA Human Research Program Perspective
ISS R & D Conference – 8 July 2015
Chief Scientist
mark.j.shelhamer@nasa.gov

Humans in Space
 NASA needs to better understand human adaptation to space
 Provide better countermeasures
• Integrated approaches to minimize resources
 Provide tools for autonomy
 Assess and maintain resilience
• Individual
• Team
 Averages and overall changes are characterized for many systems
 Need to understand individual variation
 Personalized countermeasures
 How to enable this?
37

MagnitudeofDecrement(ArbitraryUnits)
Time After Launch (Months)
642 8 10 12
Immune, OSaD,
Atherosclerosis
VIIP
Orthostatic
Tolerance
Aerobic
Capacity
Muscle
Bone
Sensorimotor
• Notional qualitative view of changes assuming currently known and effective countermeasures
• Increased dash size = increased uncertainty in trend
• Individual variability not shown
In-Flight Physiological Changes
?
?
?
?
?
?
?
Acceptable
Decrement (based on
current standards)
trend dynamics unknown

• Depressive symptoms (n=1)
• Increased stress (n=3)
• Elevated levels of confusion and bewilderment (n=3)
• Elevated conflict (n=2)
Onset of symptomology usually occurred in the first quarter, but
some symptoms showed up later.
Behavioral Health in Spaceflight Analogs
Psychological and Behavioral Changes during Confinement in a 520-Day Simulated Interplanetary
Mission to Mars (Basner et al., 2014)
39

Sibonga et al. 2014
Bone Density Changes in Space Flight
40

Visual Impairment / Intracranial Pressure
• To date 22 of 31 U.S. astronauts have developed some or all of the following
findings either during or following a six-month spaceflight:
• Hyperopic shift
• Choroidal folds
• Optic Nerve Sheath Distention
• Optic nerve kinking
• Globe flattening
• Optic disc edema (papilledema) N=7
• Cotton wool spots N=3
• ↑ CSF pressure postflight

Head-ward fluid shift due to microgravity Increased intracranial pressure (ICP)
Elevated ICP transmitted to the eye and optic nerve
VIIP Proposed Mechanism

Evidence: Elevated ICP post-flight
• 6 LPs conducted postflight in crewmembers with optic disc edema
• No preflight baseline, postflight only if clinically indicated
• Postflight elevated ICP:
– 15-20mmHg. Clinical intervention recommended when ICP>20.0mmHg.
– Does not reflect in-flight ICP, may be higher due to fluid shift & CO2
Case
Opening pressure (cm
H2O)
Normal range 10-20
Opening pressure (mmHg)
Normal range 5-15
Time after flight
(days)
D 28.5 21.0 57
C 28 20.6 12
A 22 16.2 66
F 21.5 15.9 6
B 21 15.4 19
E 18 13.2 8

Is there a genetic predisposition to
developing VIIP in the spaceflight
environment?

One-Carbon Metabolism
AA/AG GG
CPG = 1-4
CPG = 0
Homocysteine,mol/L
- 1 8 0 - 4 5 - 1 0 1 5 3 0 6 0 1 2 0 1 8 0 R + 0 R + 3 0
0
2
4
6
8
1 0
1 2
1 4
P r e f l i g h t I n - f i g h t P o s t f l i g h t
O C -
O C +
P < 0 . 0 0 1 , s i g . g r o u p e f f e c t
Smith & Zwart et al. 2015
• Serum homocysteine (Hcy), cystathionine, 2-
methylcitric acid (2MCA), and methylmalonic acid
concentrations higher (before, during, after flight) in
astronauts with vision changes
• Altered folate2 and vitamin B-12 dependent 1-carbon
transfer metabolism
• Polymorphisms in enzymes of this pathway may
interact with microgravity

Twins Pilot Specific Aims
• Conduct a pilot demonstration project focused on the use of integrated human -
omics analyses to better understand the biomolecular responses to the physical,
physiological, and environmental stressors associated with spaceflight.
1. Genome
2. Epigenome
3. Transcriptome
4. Proteome
5. Metabolome
6. Microbiome
7. Physiology
8. Neurobehavioral
HRP/ Craig Kundrot / 2014 46

Scott Kelly – ISS for one year
Mark Kelly – Earth control
Telomere Length
Bailey
DNA Mutations
Feinberg
DNA Hydroxy-methylation
Mason
Chromatin
Feinberg
large/small RNA
& RNA Methylation
Mason
Proteomics
Lee/Rana
Antibodies
Mignot/Snyder
Cytokines
Mignot
DNA Methylation
Feinberg & Mason
B-cells / T-cells
Mignot
Targeted and Global Metabolomics
Lee/Rana, Mignot/Snyder & Smith
Microbiome
Turek
Cognition
Basner
Vasculature
Lee

ISS as a Research Platform
for Personalized Medicine
 Advantages
 Relatively homogeneous, motivated, well-characterized subjects.
 Well-defined and characterized environment.
 Subject compliance rarely an issue.
 Disadvantages
 Small population.
 Not analogous to terrestrial populations on Earth.
48

CAMPAIGN GOOD HEALTH
Timothy Yeatman, M.D., F.A.C.S.
CHIEF SCIENTIST, CASIS
GRAND CHALLENGES:
SCIENCE IN SPACE FOR THE
BENEFIT OF LIFE ON EARTH

OVERVIEW: GOOD HEALTH
Goals & Objectives
• Understand the mechanisms that underpin the transition from wellness to disease—
where disease onset and progression are accelerated by microgravity—so that
interventions can be designed to preserve health on Earth.
• Leverage data, technology, and resource infrastructure developed by NASA and OGAs to
ensure the highest probability of campaign success.
• Integrate systems biology and meta-data from humans and non-human models into an
open science platform.
Campaign Good Health:
A CASIS initiative in partnership with NASA to translate observations on the ISS U.S.
National Laboratory to health benefits on Earth
50

GOOD HEALTH COLLABORATION
Stakeholders and their roles/data
resources include:
• SLPS & IPs – Discovery research in space biology,
physical sciences, and human research
• HRP & NSBRI – Exploration-related research to
support long-term human presence in space
• CASIS & OGAs – Translation of discoveries in
microgravity into Earth benefits
Good Health is an ISS NL Collaboration
GeneLab (SLPS) = an
open source
integrated omics
database
HRP/NSBRI =
human health in
space
51

STUDYING HUMAN DISEASE IN SPACE
Top Tier
• Musculoskeletal effects
• Radiation effects, particularly on the
nervous system
• Microbiome alterations
Common Disease Areas of Focus
Defined in Collaboration with HRP/NSBRI
Second Tier
• Immune dysfunction
• Cardiovascular deconditioning
• Intracranial hypertension
• Nutrition and metabolomics
• Pharmacology and Pharmacokinetics
• Cell Differentiation and Cancer
• Aging
52

HUMAN MODELS FOR GOOD HEALTH
CASIS seeks to build an Astronaut Cohort for the Precision Medicine
Initiative Consortium of Cohorts2
• Expand the NASA Repository to include samples from ISS
US/international crew
• Enhance sample collection/preservation protocols to enable omics-based
analyses of astronaut data for a longitudinal study and the NIH Precision
Medicine Initiative
NASA Biological Specimen Repository: a storage bank to maintain biological
specimens over extended periods under controlled conditions. Samples from ISS (e.g., blood
and urine) are collected, processed, and archived preflight, in-flight, and post-flight.1
1. http://www.nasa.gov/mission_pages/station/research/experiments/981.html
2. http://www.nih.gov/precisionmedicine/workshop.htm
• Develop data and privacy standards for inclusion of crew data in the GeneLab Data System
open-access repository.
53
Balance disorders
Cardiovascular deconditioning
Decreased immune function
Muscle atrophy
Bone loss

CHANGE IN ASTRONAUT DXA BMD
AFTER LONG-DURATION SPACE FLIGHT
Bisphosphonate
ARED
Pre-ARED
A. LeBlanc et al. (2013) Osteoporosis International 24:2105–2114
54

DISEASE MODELS FOR GOOD HEALTH
Short-term Objectives
• Identify institutional partners for disease model
resources on the ISS National Lab.
• Define required ISS resources/data requirements to
generate integrated systems biology data to inform the
study of wellness-to-disease transitions.
• Establish Good Health Reference Missions to the ISS
NL in which model organisms and/or cell models are flown
in space to accelerate disease onset/progression.
Human disease priority areas on the ISS NL can be studied using model organisms (e.g.,
rodents, zebrafish, fruit flies, roundworms, flatworms, yeast, etc.) and/or cell lines.
55

DISEASE MODELS FOR THE ISS NL
Non-human Model Organisms
3D Mammalian Cell-based, Spheroid, and
Organotypic Models
S. mediterraneaG. tigrina
Caenorhabditis elegans
Danio rerio
Oryzias latipes
Drosophila melanogaster
Mus musculus
Rattus norvegicus
Dictyostelium spp.
Arabidopsis thaliana
N. crassa S. cerevisiae
ARCHAEA BACTERIA VIRUSES
Images: Courtesy of the National Institutes of Health unless otherwise noted.
Xenopus laevis
56
iPS cellsFibroblast cells
Image: Kim et al. (2012) PLoS ONE.
TUMOR SPHEROID MODELS ORGANOTYPIC MODELS
transformation
factors
Human stem cells grown into early-stage ureteric
buds, kidney precursors. Mouse embryonic kidney
cells (red) coaxed human stem cells to form buds
(blue and green). (Xia et al. (2013) Nature Cell
Biol.)
endoderm
mesoderm
ectoderm
Image: Salk Institute for
Biological Studies.
3D culture
ORGANOID MODELS
Image: Ranga et al. (2014) Advanced Drug Delivery Reviews. 70:19–28 56

MODEL ORGANISMS ON ISS NL 2014-2015
Worms (C. elegans; D. japonica):
“Micro 5” (SpX-5, NASA)
Studies infection and survival of C. elegans with Salmonella
typhimurium on orbit. (immune)
“Nematode Muscle” (SpX-6, JAXA)
Studies mechanisms of muscle atrophy
in C. elegans (muscle).
“Flatworm Regeneration” (SpX-4, ISSNL CASIS) Studies cell
signaling during tissue regeneration of D. japonica in microgravity.
(muscle; wound healing)
Rodents:
Rodent Research-1 (SpX-4, ISSNL CASIS)
Study of muscle atrophy
in mice lacking the MuRF-1
(Muscle Ring Finger 1) which
labels proteins for degradation.
Rodent Research-2 (SpX-6, ISSNL CASIS)
Longitudinal study of bone remodeling with on-orbit measures of
bone mineral density loss with longer exposure to microgravity.
Plants (Arabidopsis):
“CARA” Characterizing Arabidopsis Root Attractions 1&2
(SpX-3, ISSNL CASIS)
Studies mechanisms of root
growth in microgravity at the
molecular and genetic level.
Plant Gravity Sensing 1&2 (SpX-4, -6 NASA) Studies the
structures involved in Ca++ signaling required for optimal growth in
microgravity.
Fruit Flies (Drosophila):
Fruit Fly Lab-01 (SpX-5, NASA)
Planned study of microbial interaction,
microgravity, and radiation on fruit flies on ISS; hardware
failure, re-flight planned in replacement hardware.
(immune)
Studying model organisms in space contributes to understanding basic processes that can also be applied
on Earth, such as treatments for disease, improvements for aging populations, and innovative agricultural
processes.
57

CASIS RFI 2015-3
This RFI seeks to capture the trends in organs-on-chips that are beyond the state of the art and recapitulate the microarchitecture and
functions of living organs using human cells in microphysiological systems that may either be adapted for use in microgravity on the
International Space Station National Lab or used on Earth for hypothesis-driven research designed to accelerate discovery and/or
translation of the system for tissue engineering and regenerative medicine. In-vitro models of bone and cartilage, skeletal muscle,
brain, gastrointestinal tract, lung, liver, microvasculature, skin, and other tissues are of primary interest, and any process of generating
spatially-controlled cell patterns using microfluidics or 3D printing technologies are welcomed.
CASIS
http://www.iss-casis.org/Opportunities/Solicitations/RFIOrgansOnChipsResearch2015.aspx#sthash.bUb13mOo.dpuf
NASA NSPIRES
http://nspires.nasaprs.com/external/
RFI Issued on June 15, 2015 RFI Closes on September 8, 2015
58

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