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Prof Mathias Uhlen

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Title: Prof Mathias Uhlen


1
Vision for future biotech applications
Stockholm, August 24, 2004
Prof Mathias Uhlen Department of
Biotechnology Royal Institute of Technology (KTH)
Stockholm, Sweden
2
25 April, 1953
James Watson and Francis Crick
The Double Helix Model of DNA
3
Gene technologies (70ies and 80ies)
  • 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

4
Decoding the Book of Life A
Milestone for Humanity
White Hourse Science Event

1019 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.
5
Building blocks of life
A
T
C
G
A
T
G
C
T
A
T
A
A
T
C
G
Organism
Proteins
DNA
Basis
Molecule Information Function Building
block DNA Digital Memory 4
basis Protein Analogue Chemistry of life
20 amino acids
6
Central dogma - from DNA to protein
Protein
Chromosome
7
Knowledge about proteins structure and function
...
facilitates the development of treatment to
disease
8
Proteins - chemistry of life
Catalysis
Signaling
Structure
Regulation
Protection
Enzymes
Hormones /Receptors
Collagen
DNA-binding proteins
Antibody
9
The status of the human genome
  • 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

10
Biotechnology
The use of biological systems and
biological knowledge to produce or refine products
Environment
Agriculture (food)
Forestry
Biotechnology
New materials
Pharmaceuticals
11
Biotech companies
Biotech applications today
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
12
Biotech companies
New biotech applications
  • Genome-based pharmaceutical development
  • Personalized medicine
  • Gene therapy
  • Stem cell therapy
  • Biomaterials
  • Nanotechnology sensors (environment,
    bioterroism)
  • Agriculture and forestry

13
The post-genomic era
Genome-based biotechnlogy
Genomics
Bioproducts
Transgenetics

Biotherapeutics Vaccines Gene therapy Stem cell
therapy
Animals Plants
Functional biology (proteins)
Diagnostics
Pharmacogenomics Molecular diagnostics Traditional
diagnostics
Therapeutics
Target discovery Drug development
Understanding diseases
Understanding cell biology
Infectious HIV, Hepatitis
Signal transduction
Genetic Cancer, CF Other Alzheimer
Differentiation
Cell death
14
Pharmaceutical development
Marketing approval
Target discovery
NDA
Phase I,II,III
Approval for clinical trial
Target decision
INDA
Motif decision
New chemical entity (NCE)
Lead Compound
Average cost for a new approved drug 600 - 800
MUSD
15
Adverse drug reaction (ADR)
  • 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
16
Genome-based pharmaceutical development
  • Genomics

Genes
DNA-diagnostics
Gene therapy
Biotherapeutics
Vaccines
Proteins
Target discovery (New Chemical Entities)
17
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

18
The Human Genome Project
Status genomics
  • 200 complete genomes
  • Present rate gt100 new genes every day
  • DNA sequence in public databases doubles every
    10 months

19
Organisms proposed to be sequenced in USA Organisms proposed to be sequenced in USA Organisms proposed to be sequenced in USA Organisms proposed to be sequenced in USA
Round Organism Organism Ranking
2/10/02 Chicken (Gallus gallus) Proposal (PDF file) Chicken (Gallus gallus) Proposal (PDF file) High Priority
2/10/02 Chimpanzee (Pan troglodytes) Proposal 1 (PDF file), Proposal 2 Chimpanzee (Pan troglodytes) Proposal 1 (PDF file), Proposal 2 High Priority
6/10/02 Cow (Bos taurus) Proposal (PDF file) Cow (Bos taurus) Proposal (PDF file) High Priority
6/10/02 Dog (Canis familiaris) Proposal (PDF file) Dog (Canis familiaris) Proposal (PDF file) High Priority
2/10/02 Fungi 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.
2/10/02 Fungi Proposal (PDF file) Pneumocystis carinii (human and mouse) 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.
2/10/02 Fungi Proposal (PDF file) Magnaporthe grisea 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.
2/10/02 Fungi Proposal (PDF file) Aspergillus nidulans 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.
2/10/02 Fungi Proposal (PDF file) Fusarium graminearum 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.
2/10/02 Fungi Proposal (PDF file) Coprinus cinereus 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.
2/10/02 Fungi Proposal (PDF file) Ustilago maydis 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.
2/10/02 Fungi Proposal (PDF file) Coccidiodes posadasii 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.
2/10/02 Fungi Proposal (PDF file) Trichophyton rubrum 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.
2/10/02 Fungi Proposal (PDF file) Rhizopus oryzae 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.
2/10/02 Fungi Proposal (PDF file) Aspergillus flavus 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.
2/10/02 Fungi Proposal (PDF file) Aspergillus terreus 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.
2/10/02 Fungi Proposal (PDF file) Neurospora discreta 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.
2/10/02 Fungi Proposal (PDF file) Batrachochytrium dendrobatidis 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.
2/10/02 Fungi Proposal (PDF file) Paxillus involutus 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.
2/10/02 Honey Bee (Apis mellifera) Proposal (PDF file) Honey Bee (Apis mellifera) Proposal (PDF file) High Priority
6/10/02 Oxytricha trifallax (macronucleus equivalent micronucleus sequences) (ciliate) Proposal (PDF file) Oxytricha trifallax (macronucleus equivalent micronucleus sequences) (ciliate) Proposal (PDF file) High Priority
2/10/02 Sea Urchin (Strongylocentrotus purpuratus) Proposal (PDF file) Sea Urchin (Strongylocentrotus purpuratus) Proposal (PDF file) High Priority
2/10/02 Tetrahymena thermophila macronucleus Proposal (PDF file) Tetrahymena thermophila macronucleus Proposal (PDF file) High Priority
6/10/02 Trichoplax adhaerens (lower metazoan) Proposal (PDF file) Trichoplax adhaerens (lower metazoan) Proposal (PDF file) Moderate Priority
2/10/02 Rhesus Macaque (Macaca mulatta) Proposal (PDF file) Rhesus Macaque (Macaca mulatta) Proposal (PDF file) Moderate Priority
20
New ways to treat diseases (knowledge-based)
Ex. Malaria
Mosquito genome(2002)
Parasite genome (2002)
Human genome (2001)
21
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

22
SARS
Less than six months from outbreak to sequence
of the genome
23
The Beijing Genomics Instituteplans to
produce a working draft of the (rice) genome
within 2 years
Science April 21, 2000
24
Sequencing the rice genome. A contribution to
science and mankind by China. Published in
Science April 2002.
25
The challenge is not only technology, but also
humanity!
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
26
Genetic variability
  • Mankind approximately 10,000 generations
  • Difference between two individuals lt1/1000
  • Responsible for all heriditary traits

27
Biotech companies
Personal traits
  • Genetic
  • Environment
  • Age
  • Stochastic (random events)

28
Biotech companies
The use of genetic information
  • To study life (and our heritage)
  • Disease understanding (genetic epidemiology)
  • Genetic predisposition
  • Predictive medicine (personalized)
  • Forensics

29
Gentic variation in people
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 Chinas
contribution to the project. - The
Washington Post, Oct. 30, 2002
30
Genetic variation
48 people will be sequenced multiethnic
Estimated frequency of variation 1 variation
(SNP)/562 bp
31
Personalized medicine
Pharmacogenomics
Linking individual genetic variations to drug
responses
1. Therapeutic failure 2. Appropriate drug
response 3. Adverse reaction
The right drug to the right patient
32
Issues (new biotech applications)
  • Safety (GMOs, bioterrorism)
  • Ethical (stem cells, gene therapy, patenting
    life)
  • Personal integrity (personalized medicine,
    forensics)

33
Biotech companies
Conclusions
  • 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
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