# Presentation: 579600

## Understanding the Genome: How Close are We to a Star Trek Medical Diagnosis?

**Understanding the Genome:**** ****How Close are We to a Star Trek Medical Diagnosis?**

**Bruce E. Shapiro**
**Exploration Systems Autonomy Section 367**
**bshapiro@jpl.nasa.gov**

- Background Image: Pilot Kevin  Kregal draws blood from Mission Specialist Chuck Brady on STS 78 (June 20, 1996). http://lsda.jsc.nasa.gov

**CL#03-0455**

## Star Trek Medicine - The Concept

- Crewman gets ill
- Doctor sequences alien pathogen
- Pathogenic activity and mechanism of action is inferred from knowledge of the genome
- “Antidote” is manufactured
- Patient is cured

## “Smart” Medicine

- Unknown Pathogen
- Proteomics
- Genomics
- Modeling
- Design Generic Intervention

- Sequence & Identify Pathogen

- Symptoms

- Sequence Patient

- Design Individually Tailored Intervention

**“****Smart” Medicine**

- http://www.ornl.gov/hgmis/education/images.html

## At JPL

- We are working on a number of projects that have developed tools that could be utilized/redirected to “smart” medicine:
**Functional Genomics**
**Micro-array data analysis**
**Cell Signaling**
**Biological Modeling**

## Roadmap 

**Motivation & Background**
- Research Priorities
- Genomes in form and function
- Signal Transduction Networks
- Tools and Techniques
- Projects

## Space Biology Research Priorities

- Understanding and ameliorating problems that may limit astronauts' ability to survive and/or function during prolonged spaceflight.
- Fundamental biological processes in which gravity is known to play a direct role.

- http://www.nas.edu/ssb/csbmes.htm

- Space Studies Board
- National Research Council
- National Academy of the Sciences

## Cell Biology
Developmental Biology
Space Horticulture
Plant Gravitropism 
Sensorimotor Integration
Bone Physiology
Skeletal Muscle
Cardiovascular/Pulmonary
Endocrinology
Immunology

**Cell Biology**
**Developmental Biology**
**Space Horticulture**
- Plant Gravitropism
- Sensorimotor Integration
**Bone Physiology**
**Skeletal Muscle**
- Cardiovascular/Pulmonary
- Endocrinology
- Immunology

**Bone & Muscle Loss**
- Vestibular Function
- Return to Earth
**Radiation Hazards**
- Physiological Stress
- Psychosocial Issues
- Graviperception
- Reproduction & **development**
- Gravitropism

**High Priority Disciplines**

**Cross-Cutting **
**Research Priorities**

- Background image of Mars us MGS MOLA and MOC data  http://ltpwww.gsfc.nasa.gov/tharsis/ngs.gif

## OBPR Research Priorities

**Assure human survival in space:**** **space medicine; low-gravity adaptation; cosmic rays; optimize psychosocial environment
- Understand effect of space on life
**Identify cellular, genetic, and systemic changes**
**Developmental and life-cycle biology in space**
- Facilitate appropriate new technology
- quantum/bio/nano-tech; complex systems; material science
- http://spaceresearch.nasa.gov/research_projects/resplans.html

## Roadmap 

- Roadmap

**Motivation & Background**
- Research Priorities
- Genomes in form and function
- Signal Transduction Networks
- Tools and Techniques
- Projects

## Genomes are being sequenced at an exponential Rate

- Images: _[http://www.sciencemag.com, ](http://www.ncbi.nlm.nih.gov/entrez)__http://www.nature.com_

**Genomes are being sequenced at an exponential Rate**

## What is a genome?

- genomes

- chromosomes

- long strings of DNA

- genes

- regulatory sequences

- ????

- The human genome has 23 pairs of chromosomes

## Chromosomal Structure

## Base Pairs = Barbells

- Adenine

- Thymine

- Guanine

- Cytosine

**A**

**T**

**C**

**G**

**A**

**T**

**G**

**C**

**A-T   T-A**
**C-G   G-C**

**“****hydrogen bonds”**

**4 flavors**

## Put one barbell on each spoke of a ladder

**Put one barbell on each spoke of a ladder**

**... then twist the ladder**

## ... and you get the “Double Helix”

**DNA =deoxyribonucleic acid**

## The SEQUENCE of the Human Genome

- 23 chromosome pairs
- 2.91 Giga Base Pairs
- 691 MB (at 2 bits/Base Pair)
- 39,114 genes: functional units
- 26,383 “known” function
- Average gene ≈27 kBP
- Genes ≈ 1/3 of genome

- GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAACATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAAATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGAGAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGGAAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAATGGGCCGGGATGGGATAGCGCAAACTGCCC...

- 4592 miles
- 364,000 pages
- (12 point font)
- (100x80 char/page)

## Individual genomic differences occur one every approximately 1000 base pairs
≈1,000,000 significant points of difference between any two individuals
Not all the same locations in everyone
differences in drug metabolism, disease sensitivity, eye color, ...
Yet we are 99.9% 
    _x0008__x0008_the same!

- ≈1,000,000 significant points of difference between any two individuals
- Not all the same locations in everyone
- differences in drug metabolism, disease sensitivity, eye color, ...
- Yet we are 99.9%
-     _x0008__x0008_the same!

- Genomic Variation

- http://creative.gettyimages.com

## If you stretched out the DNA in your body it would be HOW long?

- If you stretched out the DNA in your body it would be HOW long?

- http://www.ornl.gov/hgmis/education/images.html

## “Gene Products”

**“****Gene Products”**

- http://www.ornl.gov/hgmis/graphics/slides/sciblkmachine.html

## Total Amount of Genomic Information

**Total Amount of Genomic Information**

- Database Size - Base Pairs

## Sequencing is Automated

- http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v421/n6921/full/nature01410_fs.html

_**1986**_
- 250 base pairs/day:
- 32,000 years
_**2003**_
- 1,500,000 base pairs/ day: 5.3 years

- 2.9 Giga Base Pairs

## The SEQUENCE of the genome

- Tells us
- What the genome is
- 	MADE OUT OF
- We can DEDUCE gene
- 	products (proteins) from the GENETIC CODE
- What it doesn’t tell us
- Function of the genes and gene products
- local function: what does a gene (product) DO?
- global function: how does what a gene (product) does relate to the function of the cell (organsim) as a whole?

- www.startreknemesis.com

## Local Protein Function

## Roadmap 

**Motivation & Background**
- Research Priorities
- Genomes in form and function
- Signal Transduction Networks
- Tools and Techniques
- Projects

## Tetanus Genome

*Proc Natl Acad Sci ***100**(3):1316-1321 (Feb 4, 2003)

**One of the many **
**signal transduction **
**networks in this organism**

**Global Function: Network**

**transporters**
**Local Function**
**signalling molecules**

**cell membrane**

**Sequence**

**This Picture is very complicated**

## Networks are composed of Functional Modules

**example:****MAPK* Cascade**3-stages  1-2 levels of activation at each stagefully activated stage i activates stage i+1

**MAPK=Mitogen Activated Protein Kinase**

- Shapiro, Levchenko, Mjolsness, _Automatic model generation with applications to MAP-Kinase Pathways_, in *Foundations of Systems Biology*, MIT Press, 2002

## MAPK modules have many functions

**Cell Growth and Survival**

**Heat Shock, Radiation, Chemical, Inflamatory  Stress**

- lab of Jim Woodget, http://kinase.uhnres.utoronto.ca/

## Online network databases exist

## Database entry for MKK1

## Roadmap 

- Motivation & Background
**Tools and Techniques**
- Microarrays and Data Clustering
- Network Extraction
- Modeling and Simulation
- Biological Reaction Database
- Systems Biology Workbench
- Systems Biology Markup Language
- Projects

## Network Inference

- Genome (DNA)

- RNA

- Protein

- Structure

- Transcription Factor

- Signaling

- Signaling

- Functional Proteomics:
- network inference
- from protein expression

- Functional Genomics:
- network inference
- from RNA expression

## Micro-array Experiment 

## Clustering

## Data clusters in two dimensions

*x*

*y*

## Data clusters in two dimensions

*x*

*y*

## Roadmap 

- Motivation & Background
**Tools and Techniques**
- Microarrays and Data Clustering
- Network Extraction
- Modeling and Simulation
- Biological Reaction Database
- Systems Biology Workbench
- Systems Biology Markup Language
- Projects

## Signal Transduction Network

**Clusters correspond to functional modules**

**4:**** Input**

**0: ****Output**

**1**

**2**

**3**

## Stripe Formation in the Fruit Fly

- J Exp Zoology 271:47-56

- Patterson, JT Studies in the genetics of drosophila, University of Texas Press (1943);            http://flybase.bio.indiana.edu:82/anatomy/Drosophila

## Roadmap 

- Motivation & Background
**Tools and Techniques**
- Microarrays and Data Clustering
- Network Extraction
- Modeling and Simulation
- Biological Reaction Database
- Systems Biology Workbench
- Systems Biology Markup Language
- Projects

## MAPK Cascade ModelMAPK=Mitogen Activated Protein Kinase

**MAPK Cascade Model****MAPK=Mitogen Activated Protein Kinase**

## Model Representations

**As chemical reactions**

**As a cascade**

**As differential equations**

## Models: Predictions

**Differential equations**

## Modeling: Cellerator

## http://www-aig.jpl.nasa.gov/

- _[http://www-aig.jpl.nasa.gov/](http://www.ncbi.nlm.nih.gov/entrez)_
- _[public/](http://www.ncbi.nlm.nih.gov/entrez)__[mls](http://www.ncbi.nlm.nih.gov/entrez)__[/](http://www.ncbi.nlm.nih.gov/entrez)__[cellerator](http://www.ncbi.nlm.nih.gov/entrez)_

- Shapiro *et al*, Cellerator: extending
- a computer algebra system to include
- biochemical arrows for signal
- transduction simulations, *Bioinformatics*, in press (2003)

## Roadmap 

- Motivation & Background
**Tools and Techniques**
- Microarrays and Data Clustering
- Network Extraction
- Modeling and Simulation
- Biological Reaction Database
- Systems Biology Workbench
- Systems Biology Markup Language
- Projects

## Sigmoid

- Database of:
- Biological Reactions
- Reaction Kinetics
- Reaction Networks
- Citation Links

- Multi-platform support
- Multi-language support
- Web-compatible
- SBW/SBML compatible (next slides)

- Prototype (Reduced) UML for Reactions
- and Citations

## Systems Biology Workbench (SBW)

- A

- B

- C

- Application

- Application

- Application

- Application

- Application

- http://www.sbw-sbml.org

- libraries allow applications to talk to one another via remote procedure call

- SBW broker starts applications as needed and coordinates communcation

- Core applications:
- clipboard
- generic GUI
- generic plotter
- CORBA gateway
- readers
- translators SBML/Matlab/Simulink
- stochastic simulator

## SBML

- A language for different programs to share data and models
- Based on XML (extensible markup language: http://www.w3.org/XML/
- model & data exchange
- standardization
- portable
- databases
- models remain when s/w upgraded or replaced
- machine readable

- Systems Biology Markup Language

- Hucka *et al* (42 authors, 4 from JPL), The systems biology markup language: a medium for representation and exchange of biochemical network
- models,  *Bioinformatics*, in press, March 2003

## Roadmap 

- Motivation & Background
- Tools and Techniques
**Projects**
- Shoot Apical Meristem
- Secondary Leukemia
- Muscle Atrophy during Space Flight

## Shoot Apical Meristem

- Provide:
- most of our food and fiber
-  all of our paper, cellulose, rayon
-  pharmaceuticals
-  feed stock
-  waxes
-  perfumes

- growing tip of a plant

- Image courtesy of E. M. Meyerowitz, Caltech Division of Biology

## SHOOT

**APICAL**
**MERISTEM**

- Image courtesy of E. M. Meyerowitz, Caltech Division of Biology

## Simulation of Meristem Growth

## Ongoing Clinical StudyCity of Hope National Medical Center, Duarte, CA

- Remove Bone Marrow Cells**

- Intensive Chemo/radiotherapy
- kills tumor AND healthy stem cells

- Extract and Freeze
- Healthy Stem Cells

- Thaw and Transplant**

- Remission of
- Primary Cancer

- Secondary Cancer, Leukemia (MDS/AML*)

- 2-5 years later

- 1/5 of all AML* cases

- *t-MDS/AML= treatment related myelodysplasia and acute myeloid leukemia

- **aPBSCT=Autologous peripheral blood stem cell transplant (aPBSCT)

- 50,000 New Lymphoma Cases/Yr
- (USA)

- USA:10,000 AML/year
- 2,000 t-AML/year

- Over 600,000 Americans Currently have some form of Leukemia or Lymphoma

## Ongoing Clinical StudyCity of Hope National Medical Center, Duarte, CA

- 2 are symptomatic after 2 years
- Derive kinetic models from micro-array data of
- changes due to treatment
- changes over course of primary cancer (lymphoma)
- changes due to secondary cancer (leukemia)
- changes that may predict secondary leukemia

- Ongoing Clinical StudyCity of Hope National Medical Center, Duarte, CA

## Bone and Muscle Loss in Space

- Problems:
- Bone loss ≈1%/month
- Muscle atrophy, weakness, fatigue, soreness
- Changed in motor patterns
- Unstable locomotion on return
- Goals of study:
- Determine signal transduction networks involved
- Use terrestrial models
- bed rest patients
- animal model

- after one week in space

- terrestrial rat muscle fibers

## Hind Limb Unloading

- Three-way collaboration
- experiments: Johnson SC
- array data: Caltech
- analysis: JPL
- Goals of Funded Study
- Observe changes  gene expression due to atrophy & regeneration
- Statistical correlation between changes and other variables (gender, age, cell-type, treatments)
- Extract pathways
- Suggest future in-orbit experiments

## “Smart” Medicine

- Unknown Pathogen
- Proteomics
- Genomics
- Modeling
- Design Generic Intervention

- Sequence & Identify Pathogen

- Symptoms

- Sequence Patient

- Design Individually Tailored Intervention

**“****Smart” Medicine**

## Smart Medicine - The Reality -

- We are a long way away from an emergency medical hologram

- NASA Astronaut Jerry Linenger on Mir station (Jan - May 1997)
- http://lsda.jsc.nasa.gov

## Acknowledgements

**Sponsors**
- NASA/NCI Biological Physics Research Program
- NASA Office of Biological and Physical Research
- NASA Advanced Concepts Program
- Children’s Hospital of Los Angeles
- Burroughs-Wellcome Fund
- Kitano Symbiotic Systems
- Office of Naval Research
- Caltech President’s Fund
- Whittier Foundation

**Academic/NASA Collaborators**
- Eric Mjolsness, UC, Irvine
- Andre Levchenko, Johns Hopkins
- Dan Feeback, Johnson Space Center
- Henrik Jönsson, Lund University
- Ruye Wang, Harvey Mudd College
- Barbara Wold, Caltech
- Brian Williams, Chris Hart, Wold Lab
- Elliot Meyerowitz, Caltech

**SBW/SBML Team**
- Hamid Bolouri, Inst. for Systems Biology
- Andrew Finney, Univ. Hertfordshire
- Mike Hucka, Caltech
- Herbert Sauro, Keck Graduate Institute
- Maria Schilstra, Univ. Hertfordshire
- John Doyle, Caltech PI

**JPL**
- Ben Bornstein
- Becky Castaño
- Dennis Decoste
- Victoria Gor
- Dominic Mazzoni
- Joe Roden
- Lucas Scharenbroich
- Tim Stough

**For More Information:**
**Bruce E. Shapiro**
**bshapiro@jpl.nasa.gov**