prof mathias uhlen department of biotechnology royal institute of technology (kth)
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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). - PowerPoint PPT PresentationTRANSCRIPT
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Prof Mathias UhlenDepartment of Biotechnology
Royal Institute of Technology (KTH) Stockholm, Sweden
Vision for future biotech applications
Stockholm, August 24, 2004
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The Double Helix Model of DNA
25 April, 1953
James Watson and Francis Crick
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• 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)
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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.
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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
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Gene
Transcription/translation
ProteinProtein
Chromosome
Central dogma - from DNA to protein
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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
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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
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• 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
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The use of biological systems and biologicalknowledge to produce or refine products
Agriculture(food)
Biotechnology
NewmaterialsPharmaceuticals
Environment
Forestry
Biotechnology
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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
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Genome-based pharmaceutical development
Personalized medicine
Gene therapy
Stem cell therapy
Biomaterials
Nanotechnology sensors (environment, bioterroism)
Agriculture and forestry
Biotech companiesNew biotech applications
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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
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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
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• 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)
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Genomics
Genes
Target discovery(New Chemical Entities)
DNA-diagnosticsGene therapy
BiotherapeuticsVaccines ProteinsProteins
Genome-based pharmaceutical development
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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
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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
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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
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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)
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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
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Less than six months from outbreak to sequence of the
genome
SARS
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“The Beijing Genomics Institute…plans to produce a “working draft” of the (rice) genome within 2 years…” Science April 21, 2000
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Sequencing the rice genome. A contribution to science and mankind by China. Published in Science April 2002.
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……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!
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• Mankind: approximately 10,000 generations
• Difference between two individuals: <1/1000
• Responsible for all heriditary traits
Genetic variability
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Genetic
Environment
Age
Stochastic (random events)
Biotech companiesPersonal traits
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To study life (and our heritage)
Disease understanding (genetic epidemiology)
Genetic predisposition
Predictive medicine (personalized)
Forensics
Biotech companiesThe use of genetic information
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“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
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Genetic variation
Estimated frequency of variation: 1 variation (SNP)/562 bp
48 people will be sequenced: multiethnic
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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
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• Safety (GMOs, bioterrorism)
• Ethical (stem cells, gene therapy, ”patenting life”)
• Personal integrity (personalized medicine, forensics)
Issues (new biotech applications)
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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