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

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

alp

ha

0’al

ph

a 7’

alp

ha

14’

alp

ha

21’

alp

ha

28’

alp

ha

35’

alp

ha

42’

alp

ha

49’

alp

ha

56’

alp

ha

63’

alp

ha

70’

alp

ha

77’

alp

ha

84’

alp

ha

91’

alp

ha

98’

alp

ha

105’

alp

ha

112’

alp

ha

119’

Mcm1/Fkh2/Ndd1

Ace2, Swi5, Mcm1

1 3.5 >5

1/3 1 3

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