Prof Mathias Uhlen Department of Biotechnology Royal Institute of Technology (KTH)

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 TheDouble Helix Model of DNA

3. 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

4. Decoding the Book of Life A Milestone for Humanity White Hourse Science Event 10:19 am EST / June 26 ，2000THE 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 • DNA • Proteins • Organism • 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 Gene Transcription/translation 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 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

12. New biotech applications Biotech companies • Genome-based pharmaceutical development • Personalized medicine • Gene therapy • Stem cell therapy • Biomaterials • Nanotechnology sensors (environment, bioterroism) • Agriculture and forestry

13. Genome-based biotechnlogy The post-genomic era Genomics Transgenetics Bioproducts Animals Plants Biotherapeutics Vaccines Gene therapy Stem cell therapy Functional biology (proteins) Diagnostics Pharmacogenomics Molecular diagnostics Traditional diagnostics Therapeutics Target discovery Drug development Understanding cell biology Understanding diseases 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 Gene therapy Genes DNA-diagnostics Vaccines Proteins Biotherapeutics 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. Status genomics H. sapiens A. thaliana S. cerevisae D. melanogaster H. influenzae M. musculus C. elegans 1995 1996 1998 1999 2000 2002 2001(03) 1,8 Mbp 13,5 Mbp 100 Mbp 140 Mbp 120 Mbp 3000 Mbp 3000 Mbp ~3000 genes ~6000 genes ~13 500 genes ~19 000 genes ~25 000 genes ~30 000 genes ~30 000 genes The Human Genome Project • 200 complete genomes • Present rate: >100 new genes every day • DNA sequence in public databases doubles every 10 months

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 Institute…plans 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. Thechallenge 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: <1/1000 • Responsible for all heriditary traits

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

28. The use of genetic information Biotech companies • 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 China’s 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. 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