Prof Mathias UhlenDepartment of Biotechnology

Royal Institute of Technology (KTH) Stockholm, Sweden

Vision for future biotech applications

Stockholm, August 24, 2004

The Double Helix Model of DNA

25 April, 1953

James Watson and Francis Crick

• Restriction enzymes Nobel prize

• Recombinant DNA-technology Nobel prize

• DNA sequencing Nobel prize

• DNA synthesis Nobel prize

• In vitro mutagenesis Nobel prize

• DNA amplification (PCR) Nobel prize

• Hybridomas (Mab) Nobel prize

Gene technologies (70:ies and 80:ies)

Decoding the Book of Life A Milestone for Humanity

White Hourse Science Event 10:19 am EST / June 26 ， 2000

THE PRESIDENT: Good morning. I want to, first of all, acknowledge Prime Minister Blair, who will join us by satellite in just a moment from London. I want to welcome here the Ambassadors from the United Kingdom, Japan, Germany, France. And I'd also like to acknowledge the contributions not only that their scientists, but also scientists from China, made to the vast international consortium that is the Human Genome Project.

OrganismProteinsDNA

ACAGTTAC

TGTCAATG

Basis

Molecule Information Function Building block

DNA “Digital” Memory 4 basis

Protein “Analogue” Chemistry of life 20 amino acids

Building blocks of life

Gene

Transcription/translation

ProteinProtein

Chromosome

Central dogma - from DNA to protein

Knowledge about proteins structure and function ...Knowledge about proteins structure and function ...

…facilitates the development of treatment to disease…facilitates the development of treatment to disease

Proteins - chemistry of lifeProteins - chemistry of life

EnzymesEnzymes Hormones /Receptors

Hormones /Receptors

CollagenCollagen DNA-binding proteins

DNA-binding proteins

AntibodyAntibody

Catalysis Catalysis SignalingSignaling StructureStructure RegulationRegulation ProtectionProtection

• June 2000 (”draft” sequence) - 141, 821 gaps

• February 2001 (”finished” sequence)

• April 2003 (”complete” sequence)

• August 2004 (”more complete sequence”) - 341 gaps

• Number of genes: 22,787

The status of the human genome

The use of biological systems and biologicalknowledge to produce or refine products

Agriculture(food)

Biotechnology

NewmaterialsPharmaceuticals

Environment

Forestry

Biotechnology

1. Pharmaceuticals Development of medical drugs

2. Medical technology Instrument (devices) for hospitals

3. Diagnostics Analytical methods, primarily for medicine

4. Functional food Food (probiotics) using biotechnology

5. Agro-biotech Development of improved crops

6. Environmental Biologically related environmental methods

Biotech companiesBiotech applications today

Genome-based pharmaceutical development

Personalized medicine

Gene therapy

Stem cell therapy

Biomaterials

Nanotechnology sensors (environment, bioterroism)

Agriculture and forestry

Biotech companiesNew biotech applications

Functionalbiology

(proteins)

Genomics

Bioproducts

Diagnostics

Understanding diseases

BiotherapeuticsVaccinesGene therapyStem cell therapy

Infectious: HIV, HepatitisGenetic: Cancer, CFOther: Alzheimer

Transgenetics

AnimalsPlants

Understanding cell biology

Signal transductionDifferentiationCell death

TherapeuticsTarget discoveryDrug development

PharmacogenomicsMolecular diagnosticsTraditional diagnostics

The post-genomic eraGenome-based biotechnlogy

INDA

Phase I,II,III

NDA

New chemical entityNew chemical entity (NCE)(NCE)

Approval for Approval for clinical trialclinical trial

Marketing Marketing approvalapproval Target discovery Target discovery

Target decisionTarget decision

Motif decisionMotif decision

Lead CompoundLead Compound

Pharmaceutical development

Average cost for a new approved drug: 600 - 800 MUSD

• 4th leading cause of death in US

• 106,000 deaths in 1994 (US)

• 2.2 million ADRs in 1994 (US)

• Cost: approximately 77 billion USD

Source: Scrip PJB Publications

Adverse drug reaction (ADR)

Genomics

Genes

Target discovery(New Chemical Entities)

DNA-diagnosticsGene therapy

BiotherapeuticsVaccines ProteinsProteins

Genome-based pharmaceutical development

Human Proteome Resource (HPR)

”The Swedish Human Proteome Resource” program (July 1, 2003)

Funding (non-profit) from the Wallenberg Foundation (four years)

Analyze 6,000 human proteins (25% of the human proteins)

All data will be publically available

More information: www.hpr.se

The Human Genome Project

H. influenzae

1995

~3000genes

1,8 Mbp

C. elegans

~13 500genes

100 Mbp

1998

S. cerevisae

~6000genes

13,5 Mbp

1996

D. melanogaster

~19 000genes

140 Mbp

1999

A. thaliana

~25 000genes

120 Mbp

2000

M. musculus

~30 000genes

3000 Mbp

2002

H. sapiens

~30 000genes

3000 Mbp

2001(03)

Status genomics

200 complete genomes Present rate: >100 new genes every day DNA sequence in public databases doubles every 10 months

Organisms proposed to be sequenced in USARound Organism Ranking

2/10/02 Chicken (Gallus gallus) Proposal (PDF file) High Priority

2/10/02 Chimpanzee (Pan troglodytes) Proposal #1 (PDF file), Proposal #2 High Priority

6/10/02 Cow (Bos taurus) Proposal (PDF file) High Priority

6/10/02 Dog (Canis familiaris) Proposal (PDF file) High Priority

2/10/02Fungi Proposal (PDF file)

Cryptococcus neoformans, Serotype A

The entire proposal to sequence fifteen fungal species was given High Priority. GRASPP encouraged additional thought regarding the specific choices of species. The first seven species in this list were suggested for sequencing by the panel. However, the final choice is left to the submitters of the proposal.

Pneumocystis carinii (human and mouse)

Magnaporthe grisea

Aspergillus nidulans

Fusarium graminearum

Coprinus cinereus

Ustilago maydis

Coccidiodes posadasii

Trichophyton rubrum

Rhizopus oryzae

Aspergillus flavus

Aspergillus terreus

Neurospora discreta

Batrachochytrium dendrobatidis

Paxillus involutus

2/10/02 Honey Bee (Apis mellifera) Proposal (PDF file) High Priority

6/10/02Oxytricha trifallax (macronucleus + equivalent micronucleus sequences) (ciliate) Proposal (PDF file)

High Priority

2/10/02 Sea Urchin (Strongylocentrotus purpuratus) Proposal (PDF file) High Priority

2/10/02 Tetrahymena thermophila macronucleus Proposal (PDF file) High Priority

6/10/02 Trichoplax adhaerens (lower metazoan) Proposal (PDF file) Moderate Priority

2/10/02 Rhesus Macaque (Macaca mulatta) Proposal (PDF file) Moderate Priority

Ex. MalariaEx. Malaria

Mosquito genome(2002)

Mosquito genome(2002)

Parasite genome(2002)

Parasite genome(2002)

Human genome(2001)

Human genome(2001)

New ways to treat diseases (knowledge-based)New ways to treat diseases (knowledge-based)

Vaccine development

• Mycoplasma mycoides

• Genome determined at KTH• A-list WHO

• Effects cattle (primarily in third world)

• 1,060 genes (public available)

• Facilitates vaccine development

Less than six months from outbreak to sequence of the

genome

SARS

“The Beijing Genomics Institute…plans to produce a “working draft” of the (rice) genome within 2 years…” Science April 21, 2000

Sequencing the rice genome. A contribution to science and mankind by China. Published in Science April 2002.

……most biotechnology research is now carried out in the industrialized world, and is primarily market-driven. This is ethically unacceptable. Dr. Gro Harlem Brundtland, Former Director-General, WHO

The challenge is not only technology, but also humanity!

• Mankind: approximately 10,000 generations

• Difference between two individuals: <1/1000

• Responsible for all heriditary traits

Genetic variability

Genetic

Environment

Age

Stochastic (random events)

Biotech companiesPersonal traits

To study life (and our heritage)

Disease understanding (genetic epidemiology)

Genetic predisposition

Predictive medicine (personalized)

Forensics

Biotech companiesThe use of genetic information

“The HapMap project will create a powerful tool for linking differences in the genome to differences in health, including increased risk for common diseases,” said Huanming Yang, director of a genetic institute in Beijing and leader of China’s contribution to the project.

- The Washington Post, Oct. 30, 2002

Gentic variation in people

Genetic variation

Estimated frequency of variation: 1 variation (SNP)/562 bp

48 people will be sequenced: multiethnic

1. Therapeutic failure

2. Appropriate drug response

3. Adverse reaction

Pharmacogenomics

Linking individual genetic variations to drug responses

”The right drug to the right patient”

Personalized medicine

• Safety (GMOs, bioterrorism)

• Ethical (stem cells, gene therapy, ”patenting life”)

• Personal integrity (personalized medicine, forensics)

Issues (new biotech applications)

The building blocks (genes) of Homo sapiens have been defined

The general knowledge-based is rapidly expanding

The genetic variability systematically analyzed

We are entering a new era of post-genomics

DNA diagnostics technically easy

New therapies not yet proven (gene therapy, stem cells etc)

Personalized medicine (fact or fiction)

Relatively few applications outside the fields of medicine,

veterinary, food, forestry and environmental monitoring

Biotech companiesConclusions