Genomics, Cellular Networks, Preventive Medicine, and Society

Genomics, Cellular Networks, Preventive Medicine, and Society

Guest Lecture to UCSD Medical and Pharmaceutical Students

Genetics in Medicine Course

Amphitheater of the Pharmaceutical Sciences Bldg

December 11, 2009

Dr. Larry Smarr

Director, California Institute for Telecommunications and Information Technology

Harry E. Gruber Professor,

Dept. of Computer Science and Engineering

Jacobs School of Engineering, UCSD

Follow me on Twitter: lsmarr

The Digital Transformation of Health

• Wellness, Biomedical Informatics, and Preventive Medicine– Data-Intensive Biomedical Cyberinfrastructure– Integrating Genomics, Proteomics, System Biology, and Disease States– Individualized Measurements Into Interoperable Informatics Systems– Population Health Systems– Wireless Behavioral Modification– Coupling Engineering and Medicine

– New Generation of Medical Devices– Innovations in MEMS and Nano

Leading Causes of Preventable Deaths in the United States in the year 2000

Mokdad AH, Marks JS, Stroup DF, Gerberding JL (March 2004). "Actual causes of death in the United States, 2000". JAMA 291 (10): 1238–45.

doi:10.1001/jama.291.10.1238. PMID 15010446. www.csdp.org/research/1238.pdf.

1/3 of Deaths

Center for Wireless &Population Health Systems:Program on Research

• Wireless, Clinical, and Home Technologies to Measure and Improve Lifestyle and Other Health-Related Behaviors In:– Healthy Adolescents– Adolescents Recovering from Leukemia– Adolescents Risk for Type 2 Diabetes– Young Adults to Prevent Weight Gain– Overweight and Obese Children and Adults– Depressed Adults – Post-Partum Women to Reduce Weight– Adults with Schizophrenia– Older Adults to Promote Successful Aging– Exposure Biology Research

Center for Wireless &Population Health SystemsCross-Disciplinary Collaborating Investigators

• UCSD School of Medicine– Kevin Patrick, MD, MS, Greg Norman, PhD, Fred Raab, Jacqueline Kerr, PhD

– Jeannie Huang, MD, MPH

• UCSD Jacobs School of Engineering– Bill Griswold, PhD, Ingolf Krueger, PhD, Tajana Simunic Rosing, PhD

• San Diego Supercomputer Center– Chaitan Baru, PhD

• UCSD Department of Political Science– James Fowler, PhD

• SDSU Departments of Psychology & Exercise/Nutrition Science– James Sallis, PhD, Simon Marshall, PhD

• Santech, Inc.– Sheri Thompson, PhD, Jennifer Shapiro, PhD, Ramesh Venkatraman, MS

• PhD students and Post-doctoral Fellows (current)– Barry Demchak, Priti Aghera, Ernesto Ramirez, Laura Pina, Jordan Carlson

http://cwphs.ucsd.edu

Genetic & Biological Factors

Interpersonal & Psychosocial Factors

Environmental/Ecological Factors

Medical & ExerciseSciences

Behavioral& Social Sciences

Environment, Population & Policy Sciences

Center for Wireless &Population Health Systems:Integrative View to Support Interventions

Interpersonal & Psychosocial Factors

NanoTech, Drug Delivery, Sensors, Body Area Networks (BANs)

BAN-to-Mobile-to-Database, SMS/MMS Social networks

Ubicomp, Location-AwareServices, Data Mining, Systems Sciences

Genetic & Biological Factors

Environmental/Ecological Factors

Center for Wireless &Population Health Systems: Developing and Testing Engineering-Based Solutions

Psychological & Social sensors

Biological sensors

Diet & Physical Activity sensors

Air quality (particulate, ozone, etc)Temperature, GPS, Sound, Video,Other devices & embedded sensors

BP, Resp, HR, Blood (e.g. glucose, electrolytes,pharmacological, hormone), Transdermal,Implants

Mood, Social network (peers/family)Attention, voice analysis

Physical activity (PAEE, type), sedentaryPosture/orientation, diet intake (photo/bar code)

Wearable Environmental sensors

Sensor data +Clinical & Personal Health Record Data + Ecological data on determinants of health + Analysis & comparison of parameters in near-real time (normative and ipsative) +Sufficient population-level data to comprehend trends, model them and predict health outcomes +Feedback in near real-time via SMS, audio, haptic or other cues for behavior or change in Rx device

= True Preventive Medicine!

Sensors embedded in the environment

Geocoded data on safety, location of recreation, food, hazards, etc

Center for Wireless &Population Health Systems: Mainly, It’s All About Sensors

Wireless Sensors Allow Your Body to Become an Internet Data Source

• Next Step—Putting You On-Line!– Wireless Internet Transmission

– Key Metabolic and Physical Variables

– Model -- Dozens of 25 Processors and 60 Sensors / Actuators Inside of our Cars

• Post-Genomic Individualized Medicine– Combine

– Genetic Code

– Body Data Flow

– Use Powerful AI Data Mining Techniques

www.bodymedia.com

The Impact on Personal Health from Nutrition, Exercise, Stress Management

Individual Health Requires Measurement of Your Body’s Performance

Measuring Key Molecules in the Blood Provides Longer Term Biofeedback

Source: Ramesh Rao, Calit2

A Mobile Wireless System to Enhance Preventive Healthcare

Source: Paul Blair, Calit2

A Calit2 Prototype of a SmartPhone Based System to Enhance Preventive Healthcare

• Diabetes• Congestive Heart Failure (CHF)• Cardiac• Hypertension• Asthmatics• Congestive Obstructive Pulmonary

Disease(COPD)• Obesity• Infection• …Any chronic illness.

Blood Glucose Body Weight and Blood Pressure EKG / heart rhythms BP (Blood Pressure) Respiration Respiration & Blood Oxygenation Weight & Caloric intake Temperature

Can be Easily Measured / Monitored,and Therefore Controlled

Before Effects are Catastrophic

Source: Paul Blair, Calit2

Calit2 Developed Bluetooth Sensors

NSF RESCUE Strongly Coupled with NIH WIISARD Grant

Wireless Internet Information System for Medical Response in Disasters

First Tier

Mid Tier

Wireless Networks

Triage

Command Center

Reality Flythrough Mobile Video

802.11 pulse ox

Calit2 is Working Closely with the First Responder Community

CitiSense:Air Pollution Case Study

• 158 Million Live in Counties Violating Air Standards– Cancer in Chula Vista, CA Increased 140/Million Residents– Largely Due to Diesel Trucks and Automobiles

– Particulates, Benzene, Sulfur Dioxide, Formaldehyde, etc. • 30% of Public Schools Are Near Highways

– Asthma Rates 50% Higher There– 350,000 – 1,300,000 Respiratory Events in Children Annually

• 5 EPA Monitors in SD Co., 4000 Sq. Mi., 3.1M Residents– But Air Pollution Not Uniformly Distributed in Space or Time– Hourly Updates to Web Page; Annual Reports in PDF Form

• Indoor Air Pollution is Uncharted Territory– Second-hand Smoke is Major Concern – Also Mold, Radon

CitiSense -

CitiSenseCitiSense

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CitiSense TeamPI: Bill Griswold

Ingolf KruegerTajana Simunic Rosing

Sanjoy DasguptaHovav Shacham

Kevin Patrick

C/A

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Intel MSPIntel MSP

LifeChips: the merging of two major industries, the microelectronic chip industry

with the life science industry

LifeChips medical devices

Lifechips--Merging Two Major Industries: Microelectronic Chips & Life Sciences

65 UCI Faculty

Calit2 Brings Computer Scientists and Engineers Together with Biomedical Researchers

• Some Areas of Concentration:– Algorithmic and System Biology

– Bioinformatics

– Metagenomics

– Cancer

– Human Genomic Variation and Disease

– Proteomics

– Mitochondrial Evolution

– Biomedical Instruments

– Multi-Scale Cellular Imaging

– Information Theory and Biological Systems

– Telemedicine

UC Irvine

UC Irvine

Southern California Telemedicine Learning Center (TLC)

National Biomedical Computation Resource an NIH supported resource center

Center for Algorithmic and Systems Biology@Calit2: Bringing World-Class Speakers to Conferences

Building a Genome-Scale Model of E. Coli in Silico

• E. Coli– Has 4300

Genes– Model Has

2000!

Regulatory Actions

Input Signals

Monomers &Energy

Proteins

Genomics

Transcriptomics

Proteomics

Metabolomics

EnvironmentInteractomics

Transcription &Translation

Metabolism

Regulation

E4PX5PGLC

G6P

F6P

FDP

DHAP

3PG

DPG

GA3P

2PG

PEP

PYR

AcCoA

SuccCoA

SUCC

AKG

ICIT

CIT

FUM

MAL

OAA

Ru5P

R5P

S7P

6PGA 6PG

ACTPETH

ATP

NADPHNADH FADH

SUCCxt

pts

pts

pgi

pfkA

fba

tpi

fbp

gapA

pgk

gpmA

eno

pykFppsAaceE

zwfpgl gnd

rpiA

rpe

talAtktA1 tktA2

gltA

acnA icdA

sucA

sucC

sdhA1

frdA

fumA

mdh

adhE

AC

ackA

pta

pckA

ppc

cyoA

pnt1A

sdhA2nuoA

atpA

ACxtETHxt

O2O2xt

CO2 CO2xt

Pi Pixt

O2 trx

CO2 trx

Pi trx

EXTRACELLULARMETABOLITE

reaction/gene name

Map Legend

INTRACELLULARMETABOLITE

GROWTH/BIOMASSPRECURSORS

ETH trxAC trx

SUCC trx

acs

FOR

pflA

FORxt

FOR trx

dld

LAC

LACxtLAC trx

PYRxt PYR trx

glpDgpsA

GL3P

GL glpK

GLxt

GL trx

GLCxtGLC trx

glk

RIB

rbsK

RIBxt

RIB trx

FORfdoH

pnt2A

H+ Qh2

GLX

aceA

aceB

maeB

sfcA

E4PX5PGLC

G6P

F6P

FDP

DHAP

3PG

DPG

GA3P

2PG

PEP

PYR

AcCoA

SuccCoA

SUCC

AKG

ICIT

CIT

FUM

MAL

OAA

Ru5P

R5P

S7P

6PGA 6PG

ACTPETH

ATP

NADPHNADH FADH

SUCCxt

pts

pts

pgi

pfkA

fba

tpi

fbp

gapA

pgk

gpmA

eno

pykFppsAaceE

zwfpgl gnd

rpiA

rpe

talAtktA1 tktA2

gltA

acnA icdA

sucA

sucC

sdhA1

frdA

fumA

mdh

adhE

AC

ackA

pta

pckA

ppc

cyoA

pnt1A

sdhA2nuoA

atpA

ACxtETHxt

O2O2xt

CO2 CO2xt

Pi Pixt

O2 trx

CO2 trx

Pi trx


reaction/gene name

Map Legend



ETH trxAC trx

SUCC trx

acs

FOR

pflA

FORxt

FOR trx

dld

LAC

LACxtLAC trx

PYRxt PYR trx

glpDgpsA

GL3P

GL glpK

GLxt

GL trx

GLCxtGLC trx

glk

RIB

rbsK

RIBxt

RIB trx

FORfdoH

pnt2A

H+ Qh2

GLX

aceA

aceB

maeB

sfcA

E4PX5PGLC

G6P

F6P

FDP

DHAP

3PG

DPG

GA3P

2PG

PEP

PYR

AcCoA

SuccCoA

SUCC

AKG

ICIT

CIT

FUM

MAL

OAA

Ru5P

R5P

S7P

6PGA 6PG

ACTPETH

ATP

NADPHNADH FADH

SUCCxt

pts

pts

pgi

pfkA

fba

tpi

fbp

gapA

pgk

gpmA

eno

pykFppsAaceE

zwfpgl gnd

rpiA

rpe

talAtktA1 tktA2

gltA

acnA icdA

sucA

sucC

sdhA1

frdA

fumA

mdh

adhE

AC

ackA

pta

pckA

ppc

cyoA

pnt1A

sdhA2nuoA

atpA

ACxtETHxt

O2O2xt

CO2 CO2xt

Pi Pixt

O2 trx

CO2 trx

Pi trx


reaction/gene name

Map Legend



ETH trxAC trx

SUCC trx

acs

FOR

pflA

FORxt

FOR trx

dld

LAC

LACxtLAC trx

PYRxt PYR trx

glpDgpsA

GL3P

GL glpK

GLxt

GL trx

GLCxtGLC trx

glk

RIB

rbsK

RIBxt

RIB trx

FORfdoH

pnt2A

H+ Qh2

GLX

aceA

aceB

maeB

sfcA

E4PX5PGLC

G6P

F6P

FDP

DHAP

3PG

DPG

GA3P

2PG

PEP

PYR

AcCoA

SuccCoA

SUCC

AKG

ICIT

CIT

FUM

MAL

OAA

Ru5P

R5P

S7P

6PGA 6PG

ACTPETH

ATP

NADPHNADH FADH

SUCCxt

pts

pts

pgi

pfkA

fba

tpi

fbp

gapA

pgk

gpmA

eno

pykFppsAaceE

zwfpgl gnd

rpiA

rpe

talAtktA1 tktA2

gltA

acnA icdA

sucA

sucC

sdhA1

frdA

fumA

mdh

adhE

AC

ackA

pta

pckA

ppc

cyoA

pnt1A

sdhA2nuoA

atpA

ACxtETHxt

O2O2xt

CO2 CO2xt

Pi Pixt

O2 trx

CO2 trx

Pi trx


reaction/gene name

Map Legend



ETH trxAC trx

SUCC trx

acs

FOR

pflA

FORxt

FOR trx

dld

LAC

LACxtLAC trx

PYRxt PYR trx

glpDgpsA

GL3P

GL glpK

GLxt

GL trx

GLCxtGLC trx

glk

RIB

rbsK

RIBxt

RIB trx

FORfdoH

pnt2A

H+ Qh2

GLX

aceA

aceB

maeB

sfcA

G1 + RNAP G1*

v1

nNTP

mRNA1 nNMPb4

b2

v2

v3=k1[mRNA1]

2aGTP

rib

rib1*

protein1b3

v4 (subject to global max.)

v5

aAA-tRNA

b7

2aGDP + 2aPib8

b5

b1 aAAatRNA

aATP

aAMP

+ 2aPi

b6

v6

2nPi

Pi

b9

G1 + RNAP G1*

v1

nNTP

mRNA1 nNMPb4

b2

v2

v3=k1[mRNA1]

2aGTP

rib

rib1*

protein1b3


v5

aAA-tRNA

b7

2aGDP + 2aPib8

b5

b1 aAAatRNA

aATP

aAMP

+ 2aPi

b6

v6

2nPi2nPi

Pi

b9

Pi

b9

G1 + RNAP G1*

v1

nNTP

mRNA1 nNMPb4

b2

v2

v3=k1[mRNA1]

2aGTP

rib

rib1*

protein1b3


v5

aAA-tRNA

b7

2aGDP + 2aPib8

b5

b1 aAAatRNA

aATP

aAMP

+ 2aPi

b6

v6

2nPi

Pi

b9

G1 + RNAP G1*

v1

nNTP

mRNA1 nNMPb4

b2

v2

v3=k1[mRNA1]

2aGTP

rib

rib1*

protein1b3


v5

aAA-tRNA

b7

2aGDP + 2aPib8

b5

b1 aAAatRNA

aATP

aAMP

+ 2aPi

b6

v6

2nPi2nPi

Pi

b9

Pi

b9

Gc2

tc2

Rc2

Pc2 Carbon2A

Oc2

Carbon1

(indirect)

(-)

If [Carbon1] > 0, tc2 = 0

G2a

t2a

R2a

P2a BC + 2 ATP + 3 NADH

O2a

B(+)

G5

t5

R5

P5 C + 4 NADH

O5

(+)

3 E

If R1 = 0, we say [B] is not in surplus, t2a = t5 = 0

G6a

t6a

R6a

P6aH

O6a

(-)

Hext

If Rh> 0, [H] is in surplus, t6a = 0

Gres

tres

Rres

Pres O2 + NADH

ATP

Ores

O2

(+)

G3b

t3b

R3b

P3bG

O3b

(+)

0.8 C + 2 NADH

If Oxygen = 0, we say [O2] = 0, tres= t3b = 0

G + 1 ATP + 2 NADH

Gc2

tc2

Rc2

Pc2 Carbon2A

Oc2

Carbon1

(indirect)

(-)

If [Carbon1] > 0, tc2 = 0

G2a

t2a

R2a

P2a BC + 2 ATP + 3 NADH

O2a

B(+)

G5

t5

R5

P5 C + 4 NADH

O5

(+)

3 E

If R1 = 0, we say [B] is not in surplus, t2a = t5 = 0

G6a

t6a

R6a

P6aH

O6a

(-)

Hext

If Rh> 0, [H] is in surplus, t6a = 0

Gres

tres

Rres

Pres O2 + NADH

ATP

Ores

O2

(+)

G3b

t3b

R3b

P3bG

O3b

(+)

0.8 C + 2 NADH

If Oxygen = 0, we say [O2] = 0, tres= t3b = 0

G + 1 ATP + 2 NADH

E. coli i2K

Source: Bernhard PalssonUCSD Genetic Circuits Research Group

http://gcrg.ucsd.edu

JTB 2002

JBC 2002

in Silico Organisms Now Available

2007:

•Escherichia coli •Haemophilus influenzae •Helicobacter pylori •Homo sapiens Build 1•Human red blood cell •Human cardiac mitochondria •Methanosarcina barkeri •Mouse Cardiomyocyte •Mycobacterium tuberculosis •Saccharomyces cerevisiae •Staphylococcus aureus

Cytoscape: OPEN SOURCE Java Platform for Integration of Systems Biology Data

• Layout and Query of Interaction Networks (Physical And Genetic)

• Visual and Programmatic Integration of Molecular State Data (Attributes)

• Ultimate Goal is to Provide the Tools to Facilitate All Aspects of Pathway Assembly and Annotation

www.cytoscape.org

Validation of Transcriptional

Interactions With Causal or Functional Links

Network Based Study of Disease

Network Assembly from Genome-Scale

Measurements

Network Evolutionary Comparison / Cross-Species Alignment to

Identify Conserved Modules

Projection of Molecular Profiles on Protein Networks to

Reveal Active Modules

Alignment of Physical and Genetic Networks

Network-Based Rationale Drug

Design

Network-Based Disease Diagnosis /

Prognosis

Moving from Genome-wide Association

Studies (GWAS) to Network-wide

“Pathway” Association (PAS)

Research In The Ideker Lab

Source: Lee Hood, ISB

Use Biology to Drive Technology and Computation. Need to Create a Cross-disciplinary Culture


Disease Arises from Perturbed Cellular Networks:Dynamics of a Prion Perturbed Network in Mice


Increasing Abundance of Protein A for Prion-Infected Blood Samples


Organ-Specific Blood Proteins Will Make the Blood a Window into Health and Disease

• Perhaps 50 Major Organs or Cell Types– Each Secreting Protein Blood Molecular Fingerprint

• The Levels of Each Protein in a Particular Blood Fingerprint Will Report the Status of that Organ – Probably Need Perhaps 50 Organ-Specific Proteins Per Organ

• Will Need to Quantify 2500 Blood Proteins from a Drop of Blood– Use Microfluidic/Nanotechnology Approaches

Key Point: Changes in The Levels Of Organ-Specific Markers Can Assess Virtually All

Diseases Challenges for a Particular Organ


Accelerator: The Perfect Storm-- Convergence of Engineering with Bio, Physics, & IT

2 mm

HP MemorySpot

Nanobioinfotechnology

1000x Magnification

2 micron

DNA-Conjugated Microbeads

Human Adenovirus

400x Magnification

IBM Quantum CorralIron Atoms on Copper

5 nanometers

400,000 x !

The Intersection of Solid State and Biological Information Systems

Snail neuron grown on a CMOS chip with 128x128 Transistors. The electrical activity of the neuron is recorded by the chip.

(Chip fabricated by Infineon Technologies)

www.biochem.mpg.de/en/research/rd/fromherz/publications/03eve/index.html

A-D ResearchFoundation

Nanotrope

Separation SystemsTechnology

ThermopeutiX

Michael J. Sailor Research GroupChemistry and Biochemistry

Nanostructured “Mother Ships” for Delivery of Cancer Therapeutics

Nanodevices for In-vivo Detection & Treatment of Cancerous Tumors

Nano-Structured Porous SiliconApplied to Cancer Treatment

Challenge: What is the Appropriate Data Infrastructure for a 21st Century Data-Intensive BioMedical Campus?

• Needed: a High Performance Biological Data Storage, Analysis, and Dissemination Cyberinfrastructure that Connects: – Genomic and Metagenomic Sequences– MicroArrays– Proteomics– Cellular Pathways– Federated Repositories of Multi-Scale Images

– Full Body to Microscopy

• With Interactive Remote Control of Scientific Instruments• Multi-level Storage and Scalable Computing• Scalable Laboratory Visualization and Analysis Facilities• High Definition Collaboration Facilities

Conceptual Architecture to Physically Connect Campus Resources Using Fiber Optic Networks

UCSD Storage

OptIPortalResearch Cluster

Digital Collections Manager

PetaScale Data Analysis

Facility

HPC System

Cluster Condo

UC Grid Pilot

Research Instrument

N x 10Gbps

Source:Phil Papadopoulos, SDSC/Calit2

DNA Arrays, Mass Spec.,

Microscopes, Genome

Sequencers

UCSD Planned Optical NetworkedBiomedical Researchers and Instruments

Cellular & Molecular Medicine West

National Center for

Microscopy & Imaging

Biomedical Research

Center for Molecular Genetics Pharmaceutical

Sciences Building

Cellular & Molecular Medicine East

CryoElectron Microscopy Facility

Radiology Imaging Lab

Bioengineering

Calit2@UCSD

San Diego Supercomputer

Center

• Connects at 10 Gbps :– Microarrays

– Genome Sequencers

– Mass Spectrometry

– Light and Electron Microscopes

– Whole Body Imagers

– Computing

– Storage

UCSD Research Park

Natural Sciences Building

Creates Campus–Wide“Data Utility”

Calit2 Microbial Metagenomics Cluster-Next Generation Optically Linked Science Data Server

512 Processors ~5 Teraflops

~ 200 Terabytes Storage 1GbE and

10GbESwitched/ Routed

Core

~200TB Sun

X4500 Storage

10GbE

Source: Phil Papadopoulos, SDSC, Calit2

CAMERA’s Global Microbial Metagenomics CyberCommunity

Over 3200 Registered Users From Over 70 Countries

http://camera.calit2.net

The Human Microbiome is the Next Large NIH Drive to Understand Human Health and Disease

• “A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms.”

• “We discovered significant inter-subject variability.” • “Characterization of this immensely diverse ecosystem is the first step in

elucidating its role in health and disease.”

“Diversity of the Human Intestinal Microbial Flora” Paul B. Eckburg, et al Science (10 June 2005)

395 Phylotypes

The Human Gut is a Microbial Environment Which is Being Metagenomically Sampled

Business

Genomics, Cellular Networks, Preventive Medicine, and Society