Overview of Biological Problems

1. Overview of Biological Problems History Human disease Key biology research areas Model organisms Research methods in biology

2. A brief history of biological discovery 1838: modern cell biology begins with cell theory (Schleiden and Schwann) 1865: modern genetics begins with basic laws of heredity (Mendel) 1875: evolutionary theory (Darwin) 1953: structure of DNA determined (Watson and Crick) 1960: first crystal structure of protein (Kendrew and Perutz) 1972: first recombinant DNA molecules (Berg, Cohen, Boyer) 1977: rapid sequencing techniques (Gilbert and Sanger) 1994-95: DNA arrays introduced (Fodor, Brown, Davis) 1995: first complete genome sequences for organisms 2001: first draft of human genome sequence reported

3. Overview of Biological Problems History Human disease Key biology research areas Model organisms Research methods in biology

4. Human disease • Inherited disease (Cystic fibrosis) • Somatic disease (Cancer: 17m deaths) • Communicable disease (AIDS, etc: 20m deaths)*

5. Overview of Biological Problems History Human disease Key biology research areas Model organisms Research methods in biology

6. Human Biology • Genome sequence • Evolution • Gene expression • Regulation • Cell biology • Cancer is loss of cell growth control • Development • 1 cell -> 1013 cells • Immunity • ~10% cells • Neurobiology • Cognition

7. Human Biology • Genome sequence • Evolution • Gene expression • Regulation • Cell biology • Cancer is loss of cell growth control • Development • 1 cell -> 1013 cells • Immunity • ~10% cells • Neurobiology • Cognition

8. How are Genes Regulated? DNA-binding Activators Are Key To Specific Gene Expression Mediator RNAPII TFIIH TFIIF TFIIE TFIIB TFIIA TFIID Chromatin modification complexes Transcription initiation apparatus Activators Gene

9. Transcriptional Regulatory Networks Transcriptional regulatory networks describe how a gene expression program is controlled by transcriptional regulators across the genome

10. Transcription factors implicated in human disease Cancer AML1, p53, PLZF, PML, Rb, WT1 Immunological Defects RFX5, WHN Developmental Defects GATA1, VDR, CRX, CBP, MeCP2 Obesity PPARgamma, SIM1 Diabetes IPF1, HNF4a, TCF/HNF1, TCF2 Hypertension NR3C2, GCCR Jimenez-Sanchez et al, Nature, Feb. 2001

11. Human Biology • Genome sequence • Evolution • Gene expression • Regulation • Cell biology • Cancer is loss of cell growth control • Development • 1 cell -> 1013 cells • Immunity • ~10% cells • Neurobiology • Cognition

12. Yeast cell cycle Growth Sister chromatid separation DNA replication Budding

13. alpha 0’ alpha 7’ alpha 14’ alpha 21’ alpha 28’ alpha 35’ alpha 42’ alpha 49’ alpha 56’ alpha 63’ alpha 70’ alpha 77’ alpha 84’ alpha 91’ alpha 98’ alpha 105’ alpha 112’ alpha 119’ Yeast Cell Cycle Gene Expression Program Mbp1/Swi6 Swi4/Swi6 800 Genes Mcm1/Fkh2/Ndd1 Ace2, Swi5, Mcm1 Affymetrix Microarray 1/3 1 3 Spellman et al. and Cho et al., 1998 1 3.5 >5

14. Cell Cycle Regulatory Network Target Gene Key: Activators Cyclins Activators that function during one stage of the cell cycle regulate activators that function during the next stage This serial regulation of transcriptional activators forms a connected, circular regulatory network Yeast genome regulation

15. Human Biology • Gene expression • Regulation • Cell biology • Cancer is loss of cell growth control • Development • 1 cell -> 1013 cells • Immunity • ~10% cells • Neurobiology • Cognition • Evolution • Genomics

16. History of Selected Human Diseases tuberculosis measles smallpox malaria plague AIDS 2000BC 1000BC 2000AD 1000AD

17. World Mortality WHO 2000 Communicable diseases 17,380,000 Acute lower respiratory 3,963,000 HIV/AIDS 2,673,000 Diarrhoeal diseases 2,213,000 Tuberculosis 1,669,000 Malaria 1,086,000 Measles 875,000 Tetanus 377,000 Pertussis 295,000 Meningitis 171,000 Syphilis 153,000

18. Communicable Disease: Selected Human Pathogens Bacterial Viral S. typhimirium M. tuberculosis Echovirus HIV-1 S. aureus L. monocytogenes Herpes Virus Influenza Virus

19. Y Y Y Y Y Y Y B cell Y Y Y CD4+ cytokines APC CTL CD8+ Host Immunity Dendritic cells Macrophages

20. Overview of Biological Problems History Human disease Key biology research areas Model organisms Research methods in biology

21. Model Organisms Baker’s yeast (S. cerevisiae) Nematode (C. elegans) Fruit fly (Drosophila) Mouse Non-human primates Each model organism has distinct advantages for studying specific biological problems

22. Overview of Biological Problems History Human disease Key biology research areas Model organisms Research methods in biology

23. Research methods in biology Genetics Biochemistry Molecular Biology Cell Biology Genomics Proteomics

24. Overview of Biological Problems History Human disease Key biology research areas Model organisms Research methods in biology

25. Transcriptional Regulatory Networks Transcriptional regulatory networks describe how a gene expression program is controlled by transcriptional regulators across the genome

26. Genome-wide Gene Expression (mRNA) can be Measured with DNA Microarrays Transcription apparatus mRNA Gene RNAPII TFIIH Activators ATGC TACG hybridization label mRNA

27. Functional Genomics High-throughput technology DNA sequence (automated sequencers) RNA expression (DNA microarrays) Protein content (2-D gels/mass spectrometry, other arrays) Protein location (DNA-bound, microscopic visualization) Protein-protein interaction (2-hybrid, IP-mass spectrometry, FRET) Protein structure (Protein structure initiative, prototypical structures) Analysis and information technology Databases for data sharing and analysis Analysis tools and methods