Bioinformatics – Discovering the “Bio-Logic” of Nature Robert Cormia Foothill College

Transducing the Genome 50 years after Watson and Crick deduced the structure of DNA… The information molecules of nature now reside as data bits inside computers But what does it all mean? We have ~15 GBytes of genomic data And only just beginning to unravel it

50 years after Watson and Crick deduced the structure of DNA…

The information molecules of nature now reside as data bits inside computers

But what does it all mean?

We have ~15 GBytes of genomic data

And only just beginning to unravel it

‘ Energy Systems’ Before ‘Life’ “ Life” arose on earth almost 4 billion years ago, 1 billion years before cells Long chains of molecules harvesting energy, probably deep below the sea Before DNA, RNA and the sophisticated proteins that we know today There were plenty of sources of energy, but no “choreographed metabolism”

“ Life” arose on earth almost 4 billion years ago, 1 billion years before cells

Long chains of molecules harvesting energy, probably deep below the sea

Before DNA, RNA and the sophisticated proteins that we know today

There were plenty of sources of energy, but no “choreographed metabolism”

Energy Metabolism

“ In the Beginning” Rock, heat, and some water Early molecules of life Energy moved from rock into sea Molecular networks played in the path Capturing a memory of that process was probably the key to life today

Rock, heat, and some water

Early molecules of life

Energy moved from rock into sea

Molecular networks played in the path

Capturing a memory of that process was probably the key to life today

Life on the Sea Floor?

RNA Busy Before Cellular Life

The RNA World There is no way to know how the molecules of life really formed… Amino acids and ribonucleotides have formed in “pre-biotic” experiments RNA molecules, which appear to be both catalysts and templates, are thought to have formed energy networks

There is no way to know how the molecules of life really formed…

Amino acids and ribonucleotides have formed in “pre-biotic” experiments

RNA molecules, which appear to be both catalysts and templates, are thought to have formed energy networks

RNA Codons and Catalysts

RNA and DNA A, T, C, G, and U A = Adenine T = Thymine C = Cytosine G = Guanine U = Uracil A-T and C-G in DNA A-U and C-G in RNA

A, T, C, G, and U

A = Adenine

T = Thymine

C = Cytosine

G = Guanine

U = Uracil

A-T and C-G in DNA

A-U and C-G in RNA

Central Dogma of Life

The Genome DNA – D eoxyribo N ucleic A cid is the prominent molecule of the genome Genes are formed of lengths of DNA polymers which code for proteins Exons and introns exist in DNA Regulatory regions control transcription and the formation of every protein and enzyme. It is the key to metabolism.

DNA – D eoxyribo N ucleic A cid is the prominent molecule of the genome

Genes are formed of lengths of DNA polymers which code for proteins

Exons and introns exist in DNA

Regulatory regions control transcription and the formation of every protein and enzyme. It is the key to metabolism.

DNA at Transcription

The Proteome Proteins form cellular structure and enzymes, which function in metabolism Over 100,000 proteins exist in humans DNA is not enough to run metabolism Proteins have a “run-time” knowledge Proteins control the transcription of DNA and DNA controls formation of proteins

Proteins form cellular structure and enzymes, which function in metabolism

Over 100,000 proteins exist in humans

DNA is not enough to run metabolism

Proteins have a “run-time” knowledge

Proteins control the transcription of DNA and DNA controls formation of proteins

Rubisco Protein – Photosynthesis

RAD Protein Complex

Number of Genes vs. Time

What is Bioinformatics? Molecular biology Ability to sequence DNA Internet databases To store and transmit data Mathematical algorithms To model and solve biological problems Analysis Using the I2I Technology Model

Molecular biology

Ability to sequence DNA

Internet databases

To store and transmit data

Mathematical algorithms

To model and solve biological problems

Analysis Using the I2I Technology Model

Internet Technologies CPU Networking Data Storage Data Mining Grid Computing Storage Area Networks

Bioinformatics Technologies Informatics IT / Networking Molecular Biology Data Modeling Computational Biology Genomic Databases

A Tool for Biotechnology Bioinformatics creates a set of tools for understanding the mountain of new data In biotechnology, these tools are used to discover how genes and proteins work Computers are used to both analyze and “mine” new data for hidden relationships Discovering the “bio-logic” of nature

Bioinformatics creates a set of tools for understanding the mountain of new data

In biotechnology, these tools are used to discover how genes and proteins work

Computers are used to both analyze and “mine” new data for hidden relationships

Discovering the “bio-logic” of nature

From Data to Knowledge

DNA Sequencing

DNA Sequencing Chemical sequencing Molecular sequencing Now about $0.01 per base Human Genome took 10 years Celera sequenced in 3 years Moore’s law applies to biotechnology too In 2010 a single human genome in ~7 days

Chemical sequencing

Molecular sequencing

Now about $0.01 per base

Human Genome took 10 years

Celera sequenced in 3 years

Moore’s law applies to biotechnology too

In 2010 a single human genome in ~7 days

DNA Sequencing http://www.accessexcellence.org

Gel Enhanced Staining

DNA Micro Arrays Used to monitor gene expression Which genes are active? What are the “co-expressed patterns”? Compare healthy and diseased tissue Extract “expressed” mRNA in cytoplasm Convert mRNA to cDNA Discover relationships of proteins to disease states, and function / location of genes Is becoming the first step in “drug-discovery”

Used to monitor gene expression

Which genes are active?

What are the “co-expressed patterns”?

Compare healthy and diseased tissue

Extract “expressed” mRNA in cytoplasm

Convert mRNA to cDNA

Discover relationships of proteins to disease states, and function / location of genes

Is becoming the first step in “drug-discovery”

Microarray Output Screen

Microarray Output

Partnering with Pharma Bioinformatics is an industry of tools Biotech is a consumer / user of these tools Pharma needs more “innovation engines” Less than 2 drugs per firm in the ‘pipeline’ Drug discovery creates a new value chain bioinformatics > biotech > ‘big pharma’ Convergence is the modality of innovation

Bioinformatics is an industry of tools

Biotech is a consumer / user of these tools

Pharma needs more “innovation engines”

Less than 2 drugs per firm in the ‘pipeline’

Drug discovery creates a new value chain

bioinformatics > biotech > ‘big pharma’

Convergence is the modality of innovation

Pharma and Biotech

Drug Discovery Target discovery Target validation Protein interactions Rapid screening The long haul… $800 million / year is spent on drug discovery Over 75% of drug compounds will never work

Target discovery

Target validation

Protein interactions

Rapid screening

The long haul…

$800 million / year is spent on drug discovery

Over 75% of drug compounds will never work

Drug Development Process

Drug Discovery

“ Pharmaco Genomics” Individualized medicine Looking at SNPs along drug targets What makes each of us – us? 1 million SNPs, about one per intron In the future, each of us will have our genome “insilico” (genome on a chip) Data mining against 6 billion genomes!

Individualized medicine

Looking at SNPs along drug targets

What makes each of us – us?

1 million SNPs, about one per intron

In the future, each of us will have our genome “insilico” (genome on a chip)

Data mining against 6 billion genomes!

Pharmaco Genomics

One Genome There are three very different ways to look at genomic diversity – and all are equally valid! A “collective” human genome 3 billion base pairs – called the ‘golden path’ Each one of us is a unique genome “ I am a genome of one”, my SNPS make me - ‘me’ The Genome on planet earth A collective metabolic evolution and speciation

There are three very different ways to look at genomic diversity – and all are equally valid!

A “collective” human genome

3 billion base pairs – called the ‘golden path’

Each one of us is a unique genome

“ I am a genome of one”, my SNPS make me - ‘me’

The Genome on planet earth

A collective metabolic evolution and speciation

Terra Genoma

Molecular Networks Genome or Proteome? Proteome of Genome? Wait a minute… What if it’s both? Now what would that look like?

Genome or Proteome?

Proteome of Genome?

Wait a minute…

What if it’s both?

Now what would that look like?

Gene Regulatory Networks

Pathway Kinetics

Gene Regulatory Network

Bioinformatics Tools NCBI BLAST, 12 million records, SNP databases ExPASy Swiss-Prot, EMBL, Swiss-Model PIR – Protein Information Resource PDB – Protein Data Bank Pfam – Protein families

NCBI

BLAST, 12 million records, SNP databases

ExPASy

Swiss-Prot, EMBL, Swiss-Model

PIR – Protein Information Resource

PDB – Protein Data Bank

Pfam – Protein families

NCBI National Center for Biotechnology Information, part of NIH and NLM Funded by US – open to all GenBank and GenPept 13 million entries, 12 billion base pairs Resources include oncology, retroviruses, SNP databases, and much more Sequin submission of raw sequence data

National Center for Biotechnology Information, part of NIH and NLM

Funded by US – open to all

GenBank and GenPept

13 million entries, 12 billion base pairs

Resources include oncology, retroviruses, SNP databases, and much more

Sequin submission of raw sequence data

NCBI Resources

Retroviruses

BLAST Basic Local Alignment Search Tool Used as a “genomic search engine” Compare your target sequence to the “non-redundant” database of 13B bps. Can search the genomes of species Human, mouse, fly, E.coli etc. ‘ Hits’ return inks to GenBank and GenPept

Basic Local Alignment Search Tool

Used as a “genomic search engine”

Compare your target sequence to the “non-redundant” database of 13B bps.

Can search the genomes of species

Human, mouse, fly, E.coli etc.

‘ Hits’ return inks to GenBank and GenPept

Swiss-Prot Swiss - protein annotated database Protein resource Minimal redundancy, reasonably current protein annotated / integrated database Links to protein structures and properties Links back into GenBank, EMBL, DDBJ Literature resources for submissions

Swiss - protein annotated database

Protein resource

Minimal redundancy, reasonably current

protein annotated / integrated database

Links to protein structures and properties

Links back into GenBank, EMBL, DDBJ

Literature resources for submissions

ExPASy The ExPASy ( Ex pert P rotein A nalysis Sy stem) Proteomics server of the Swiss Institute of Bioinformatics (SIB) is dedicated to analysis of protein sequences and structures Swiss-Prot and PROSITE Links to SWISS-MODEL

The ExPASy ( Ex pert P rotein A nalysis Sy stem)

Proteomics server of the Swiss Institute of Bioinformatics (SIB) is dedicated to analysis of protein sequences and structures

Swiss-Prot and PROSITE

Links to SWISS-MODEL

PROSITE - Database of Protein Families and Domains

Structure Analysis

Protein Data Bank SWISS-MODEL Protein Data Bank Archive of .pdb files Structures determined by X-ray, NMR Theoretical Structure Search Features a “Molecule of the Month” http://www.rcsb.org/pdb/

SWISS-MODEL

Protein Data Bank

Archive of .pdb files

Structures determined by X-ray, NMR

Theoretical Structure Search

Features a “Molecule of the Month”

http://www.rcsb.org/pdb/

PIR Protein Information Resource i ProClass and PRI-NREF PIR-PSD, Swiss-Prot, TrEMBL, RefSeq, GenPept, and PDB http://pir.georgetown.edu/ Integrated public resource of protein informatics Supports genomic and proteomic research and scientific discovery - i ProClass and PRI-NREF

Protein Information Resource

i ProClass and PRI-NREF

PIR-PSD, Swiss-Prot, TrEMBL, RefSeq, GenPept, and PDB

http://pir.georgetown.edu/

Integrated public resource of protein informatics

Supports genomic and proteomic research and scientific discovery - i ProClass and PRI-NREF

Pfam Protein family comparisons Look at multiple alignments View protein domain architectures Examine species distribution Follow links to other databases View known protein structures Follow ‘conserved domains’ from BLASTp searches of protein databases

Protein family comparisons

Look at multiple alignments

View protein domain architectures

Examine species distribution

Follow links to other databases

View known protein structures

Follow ‘conserved domains’ from BLASTp searches of protein databases

The Grand Challenge

The Technology Roadmap Genomics 1995 to 2005 Proteomics 2000 to 2010 Systems biology 2005 to 2015 Genetic remodeling / re-engineering 2010 to 2020 Generation Phi Children born in 2025 may never know disease

Genomics

1995 to 2005

Proteomics

2000 to 2010

Systems biology

2005 to 2015

Genetic remodeling / re-engineering

2010 to 2020

Generation Phi

Children born in 2025 may never know disease

Convergence of Biotech & Pharma Genomics Proteomics Systems biology Pharmaco genomics Genetic engineering

Genomics

Proteomics

Systems biology

Pharmaco genomics

Genetic engineering

Mouse Genome

Gene Therapy Somatic Gene Therapy Therapeutic Gene Therapy Incorporate “missing genes” Remove cells from host organism Amplify target cells Insert gene using (viral) vector Return target cells into host organism Insulin gene was one of the first trials

Somatic Gene Therapy

Therapeutic Gene Therapy

Incorporate “missing genes”

Remove cells from host organism

Amplify target cells

Insert gene using (viral) vector

Return target cells into host organism

Insulin gene was one of the first trials

Labeling Active Genes Along Chromosomes

Transgenic Species

Designer Flies – Is Blue Cool?

Your Own Private Genome

Surfing the Genome Internet technologies Connecting users, tools, and data Molecular biology Racing forward a top Moore’s Law Informatics Mathematical interrogation of nature’s secrets Surfing the Genome! Discovering the “bio-logic” of Nature http://www.SurfingTheGenome.us/ Spring 2003

Internet technologies

Connecting users, tools, and data

Molecular biology

Racing forward a top Moore’s Law

Informatics

Mathematical interrogation of nature’s secrets

Surfing the Genome!

Discovering the “bio-logic” of Nature

http://www.SurfingTheGenome.us/ Spring 2003

Contact Information Robert D. Cormia Foothill College [email_address] http://www.informaticus.org/ 650 747 1588 Surfing the Genome – Spring 2003

Robert D. Cormia

Foothill College

[email_address]

http://www.informaticus.org/

650 747 1588

Surfing the Genome – Spring 2003