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

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) : DNA arrays introduced (Fodor, Brown, Davis) 1995: first complete genome sequences for organisms 2001: first draft of human genome sequence reported

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

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

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

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

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

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

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

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

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

Yeast cell cycle DNA replication Sister chromatid separation Budding Growth

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’ Mbp1/Swi6 Swi4/Swi6 Mcm1/Fkh2/Ndd1 Ace2, Swi5, Mcm >5 1/3 1 3 Yeast Cell Cycle Gene Expression Program Spellman et al. and Cho et al., Genes Affymetrix Microarray

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 Cell Cycle Regulatory Network Target Gene Key: Activators Cyclins Yeast genome regulation

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

History of Selected Human Diseases 2000BC1000BC 1000AD 2000AD smallpox plague tuberculosis malaria AIDS measles

World Mortality WHO 2000 Communicable diseases 17,380,000 Acute lower respiratory3,963,000 HIV/AIDS2,673,000 Diarrhoeal diseases2,213,000 Tuberculosis1,669,000 Malaria1,086,000 Measles 875,000 Tetanus 377,000 Pertussis 295,000 Meningitis 171,000 Syphilis 153,000

Communicable Disease: Selected Human Pathogens HIV-1 Influenza Virus Echovirus Herpes Virus Viral S. typhimiriumM. tuberculosis L. monocytogenesS. aureus Bacterial

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

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

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

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

Genetics Biochemistry Molecular Biology Cell Biology Genomics Proteomics

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

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

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

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