overview of biological problems history human disease key biology research areas model organisms...
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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)1994-95: DNA arrays introduced (Fodor, Brown, Davis)1995: first complete genome sequences for organisms2001: 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 sequenceEvolution
Gene expressionRegulation
Cell biologyCancer is loss of cell growth control
Development 1 cell -> 1013 cells
Immunity ~10% cells
Neurobiology Cognition
Human Biology
Genome sequenceEvolution
Gene expressionRegulation
Cell biologyCancer is loss of cell growth control
Development 1 cell -> 1013 cells
Immunity ~10% cells
Neurobiology Cognition
TFIIB
RNAPII
TFIIATFIID
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 programis controlled by transcriptional regulators across the genome
Transcriptional Regulatory Networks
Transcription factors implicated in human disease
CancerAML1, p53, PLZF, PML, Rb, WT1
Developmental DefectsGATA1, VDR, CRX, CBP, MeCP2
DiabetesIPF1, HNF4a, TCF/HNF1, TCF2
Immunological DefectsRFX5, WHN
ObesityPPARgamma, SIM1
HypertensionNR3C2, GCCR
Jimenez-Sanchez et al, Nature, Feb. 2001
Human Biology
Genome sequenceEvolution
Gene expressionRegulation
Cell biologyCancer is loss of cell growth control
Development 1 cell -> 1013 cells
Immunity ~10% cells
Neurobiology Cognition
Yeast cell cycle
DNAreplication
Sister chromatid separation
Budding
Growth
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Mcm1/Fkh2/Ndd1
Ace2, Swi5, Mcm1
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Yeast Cell Cycle Gene Expression Program
Spellman et al. and Cho et al., 1998
800 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 expressionRegulation
Cell biologyCancer is loss of cell growth control
Development 1 cell -> 1013 cells
Immunity ~10% cells
Neurobiology Cognition
Evolution Genomics
History of Selected Human Diseases
2000BC 1000BC 1000AD 2000AD
smallpox
plague
tuberculosis
malaria
AIDS
measles
World MortalityWHO 2000
Communicable diseases 17,380,000
Acute lower respiratory 3,963,000 HIV/AIDS 2,673,000Diarrhoeal diseases 2,213,000Tuberculosis 1,669,000 Malaria 1,086,000Measles 875,000Tetanus 377,000Pertussis 295,000 Meningitis 171,000 Syphilis 153,000
Communicable Disease: Selected Human Pathogens
HIV-1
Influenza Virus
Echovirus
Herpes Virus
Viral
S. typhimirium M. tuberculosis
L. monocytogenesS. aureus
Bacterial
Host Immunity
CD4+
CD8+
APC
YY
Y
Y B cell
cytokines
CTL
YY
Y YY
Y
Dendritic cellsMacrophages
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 advantagesfor studying specific biological problems
Overview of Biological Problems
History
Human disease
Key biology research areas
Model organisms
Research methods in biology
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 programis controlled by transcriptional regulators across the genome
Transcriptional Regulatory Networks
Activators
Genome-wide Gene Expression (mRNA) can be Measured with DNA Microarrays
GeneRNAPIITFIIH
Transcription apparatus
mRNA
mRNAlabel
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 analysisAnalysis tools and methods