New Frontiers in Systems Biology John J Tyson

New Frontiers in Systems Biology John J. Tyson Department of Biology and Virginia Bioinformatics Institute Virginia Polytechnic Institute and State University Blacksburg, Virginia

Systems Science …the use of mathematics to study how the parts of a complex system fit together to function in ways that transcend the properties of the individual parts.

Norbert Weiner (1948) Cybernetics: Control & Communication in the Animal and the Machine Systems Science is the flip-side of Reductionist Science. reductionist science (parts) systems science (whole)

Outline Weather Forecasting Traditional Systems Biology “New” Systems Biology

Weather Forecasting The map is a snapshot of the highs and lows at one instant; weather is a dynamic process…the movement of air masses in time across the continent.

Weather Forecasting Navier-Stokes Equations Modern weather prediction is based on accurate computer “simulations” of moving air masses.

Weather Forecasting Accurate weather forecasting is essential to modern… Transportation industry Military planning Civil defense

Biological Systems Ecosystems Odum, Mac. Arthur, Wilson, May, … Infectious disease

Biological Systems Ecosystems Organ systems Entelos: math model of human digestive system— diabetes, obesity

Biological Systems Organ systems Ecosystems Animal cell “Systems-level” thinking has been slow to catch on because…

… the “parts list” was missing 1985 -2000: The era of reductionist molecular biology; discovery of the parts list (proteins and the genes that encode them); culminating in the complete sequence of the human genome.

New Systems Biology …the use of mathematics to study how genes and proteins interact to produce the complex behaviors of a living cell… movement energy supply signaling growth division death

Cell signaling External signals Growth Development Death Information Processing System Division Reproduction Hanahan & Weinberg (2000)

Cell signaling Division Reproduction Hanahan & Weinberg (2000)

The Budding Yeast Cell Cycle budding DNA synthesis growth newborn cell division mitosis

Esp 1 Pds 1 Esp 1 Cell division unaligned chromosomes Cdh 1 SBF Pds 1 Mcm 1 Cdc 20 PPX Net 1 P Cdc 15/MEN growth APC-P Mcm 1 Cln 3 Clb 2 Cdc 14 Swi 5 and Sic 1 Bck 2 Cdh 1 RENT MBF SBF Clb 5 unaligned chromosomes Cdc 20 Cdh 1 Inactive trimer APC CDKs PP Sic 1 Inactive trimer Clb 5 DNA synthesis Clb 2 Cln 2 Clb 2 Mad 2 Cdc 14 ? Bub 2 Cdc 14 Cdc 20 Mitosis Lte 1 Tem 1 -GTP Net 1 Mcm 1 Tem 1 -GDP Cln 2 Budding SCF

The mathematical model synthesis degradation activation binding inactivation

mass CKI Cln 2 G 1 Cdh 1 S/M Clb 2 Cdc 20 Time (min)

46, 000 Full Details: http: //mpf. biol. vt. edu

Esp 1 Pds 1 Esp 1 Sister chromatid separation unaligned chromosomes Cdh 1 SBF Pds 1 Mcm 1 Cdc 20 PPX Net 1 P Mutants Mcm 1 Clb 2 Cdc 14 Swi 5 and Sic 1 Bck 2 Cdh 1 RENT MBF SBF Clb 5 unaligned chromosomes Cdc 20 Cdh 1 Inactive trimer APC CDKs PP Sic 1 Inactive trimer Clb 5 DNA synthesis Clb 2 Cln 2 Clb 2 Mad 2 Cdc 14 ? Bub 2 Cdc 14 Cdc 20 APC-P Lte 1 Tem 1 -GTP Net 1 Mitosis growth Cln 3 Cdc 15/MEN Tem 1 -GDP Cln 2 Budding SCF

Accurate account of the properties of >100 mutant cells; correctly predicts properties of new mutant combinations

What use is the new systems biology? Designer Drugs Taxol Cancer Information Processing System Hanahan & Weinberg (2000)

The impact of the new systems biology on biomedicine, pharmaceuticals and homeland security may, some day, be as great as the impact of modern weather prediction on transportation, military preparedness and civil defense.