Vision for future biotech applications
Stockholm, August 24, 2004
Prof Mathias Uhlen
Department of Biotechnology
Royal Institute of Technology (KTH)
Stockholm, Sweden
25 April, 1953
James Watson and Francis Crick
The Double Helix Model of DNA
Gene technologies (70:ies and 80:ies)
• 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
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.
Building blocks of life
A
C
A
G
T
T
A
C
T
G
T
C
A
A
T
G
DNA
Basis
Proteins
Organism
Molecule
Information
Function
Building block
DNA
“Digital”
Memory
4 basis
Protein
“Analogue”
Chemistry of life
20 amino acids
Central dogma - from DNA to protein
Gene
Transcription/translation
Protein
Chromosome
Knowledge about proteins structure and function ...
…facilitates the development of treatment to disease
Proteins - chemistry of life
Catalysis
Signaling
Structure
Regulation
Protection
Enzymes
Hormones /
Receptors
Collagen
DNA-binding
proteins
Antibody
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
Biotechnology
The use of biological systems and biological
knowledge to produce or refine products
Environment
Agriculture
(food)
Forestry
Biotechnology
Pharmaceuticals
New
materials
Biotech
applications
today
Biotech
companies
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
New
biotech
applications
Biotech
companies
 Genome-based pharmaceutical development
 Personalized medicine
 Gene therapy
 Stem cell therapy
 Biomaterials
 Nanotechnology sensors (environment, bioterroism)
 Agriculture and forestry
The post-genomic
era
Genome-based
biotechnlogy
Genomics
Transgenetics
Bioproducts
Animals
Plants
Diagnostics
Pharmacogenomics
Molecular diagnostics
Traditional diagnostics
Understanding cell biology
Signal transduction
Differentiation
Cell death
Functional
biology
(proteins)
Biotherapeutics
Vaccines
Gene therapy
Stem cell therapy
Therapeutics
Target discovery
Drug development
Understanding diseases
Infectious: HIV, Hepatitis
Genetic: Cancer, CF
Other: Alzheimer
Pharmaceutical development
Marketing
approval
Target discovery
NDA
Phase I,II,III
Approval for
clinical trial
Target decision
INDA
New chemical entity
(NCE)
Motif decision
Lead Compound
Average cost for a new approved drug: 600 - 800 MUSD
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
Genome-based pharmaceutical development
Genomics
Gene therapy
Vaccines
Genes
Proteins
Target discovery
(New Chemical Entities)
DNA-diagnostics
Biotherapeutics
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
Status
genomics Project
The Human
Genome
S. cerevisae
D. melanogaster
C. elegans
H. influenzae
1995
1996
1,8 Mbp
~3000
genes
H. sapiens
A. thaliana
M. musculus
1998
1999
2000
2002
2001(03)
13,5 Mbp
100 Mbp
140 Mbp
120 Mbp
3000 Mbp
3000 Mbp
~6000
genes
~13 500
genes
~19 000
genes
~25 000
genes
~30 000
genes
~30 000
genes
 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 USA
Round
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
Cryptococcus neoformans, Serotype A
Pneumocystis carinii (human and mouse)
Magnaporthe grisea
Aspergillus nidulans
Fusarium graminearum
Coprinus cinereus
2/10/02
Fungi
Proposal
(PDF file)
Ustilago maydis
Coccidiodes posadasii
Trichophyton rubrum
Rhizopus oryzae
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.
Aspergillus terreus
Neurospora discreta
Batrachochytrium dendrobatidis
Paxillus involutus
2/10/02
Honey Bee (Apis mellifera) Proposal (PDF file)
High Priority
6/10/02
Oxytricha 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
New ways to treat diseases (knowledge-based)
Ex. Malaria
Mosquito genome
(2002)
Parasite genome
(2002)
Human genome
(2001)
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
SARS
Less than six months
from outbreak to
sequence of the
genome
“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.
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
Genetic variability
• Mankind: approximately 10,000 generations
• Difference between two individuals: <1/1000
• Responsible for all heriditary traits
Personal
traits
Biotech
companies
 Genetic
 Environment
 Age
 Stochastic (random events)
TheBiotech
use of genetic
information
companies
 To study life (and our heritage)
 Disease understanding (genetic epidemiology)
 Genetic predisposition
 Predictive medicine (personalized)
 Forensics
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
China’s contribution to the project.
- The Washington Post, Oct. 30, 2002
Genetic variation
48 people will be sequenced: multiethnic
Estimated frequency of variation:
1 variation (SNP)/562 bp
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”
Issues (new biotech applications)
• Safety (GMOs, bioterrorism)
• Ethical (stem cells, gene therapy, ”patenting life”)
• Personal integrity (personalized medicine, forensics)
Conclusions
Biotech
companies
 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