Anda di halaman 1dari 13

SYSTEMS BIOLOGY AN INTRODUCTION

James Gomes
Department of Biochemical Engineering & Biotechnology Indian Institute of Technology Delhi

What is Systems Biology?


Currently no generally accepted definition of Systems Biology exists From time to time researchers have tried to propose a definition; some are listed here
Systems biology is a comprehensive quantitative analysis of the manner in which all the components of a biological system interact functionally over time (Alan Aderem, Cell, Vol 121, 611613, 2005. Institute of Systems Biology, Seattle). Systems biology is the study of the behavior of complex biological organization and processes in terms of the molecular constituents (Marc W. Kirschner, Cell, Vol 121, 503-504, 2005. Department of Systems Biology, Harvard Medical School).

J Gomes, IITD

What is Systems Biology?


Systems biology can be described as Integrative Biology with the ultimate goal of being able to predict de novo biological outcomes given the list of components involved (Edison T. Liu, Cell, Vol 121, 505-506, 2005. Genome Institute of Singapore). Systems biology aims at a quantitative understanding of biological systems to an extent that one is able to predict systemic features (Peer Bork and Luis Serrano, Cell, Vol 121, 507-509, 2005. EMBL Germany).

J Gomes, IITD

New Field?
Network Mathematics was established in the 19th century A school of thought exists that systems biology of the living cells has its origin in the expansion of molecular biology to genomewide analyses. The first regulatory circuits were mapped out over 40 years ago The feedback inhibition of amino acid biosynthetic pathways was discovered in 1957 Restriction enzymes and cloning were a maor breakthrough in the 1970s Scale-up of fundamental experimental approaches of molecular biology began in the 1980s Automated DNA sequences reached genome scale sequences in the 1990s

J Gomes, IITD

A Historical Perspective
Two lines of inquiry led from the approximate onset of molecular biological thinking to present-day systems biology. The top timeline represents the root of systems biology in mainstream molecular biology, with its emphasis on individual macromolecules. Scaled-up versions of this effort then induced systems biology as a way to look at all those molecules simultaneously, and consider their interactions. The lower timeline represents the lesserknown effort that constantly focused on the formal analysis of new functional states that arise when multiple molecules interact simultaneously. Erin Boyle

Hans V Westerhoff & Bernhard O Palsson, Nature Biotechnology Vol 22 No 10 Oct 2004

J Gomes, IITD

Evolution of Systems Biology


Molecular Self Organization Large-scale models Metabolic Control Analysis Convergence of many concepts of engineering, mathematics, nonlinear thermodynamics and molecular biology

J Gomes, IITD

Molecular Self Organization


The integration of multiple molecular processes is fundamental to the living cell. Biochemical processes create an increase in entropy (chaos). The paradox how to explain the progressive ordering that occurs in biological systems by self-organization while entropy increases.
Two opposing effects play a role one that produces order (selforganization) and the other produces entropy (chaos) The problem is to understand how structures, oscillations and waves occur in biological systems Discover general principles rather than provide descriptions Establish the link be different molecular mechansims

J Gomes, IITD

Building Large Scale Models


Following the discovery of the genetic regulation, mathematical models were written to simulate the functions of regulatory circuits. Cell-scale flux models of he human red cells were published in 1980s The single cell model was proposed by Shuler and Domach in the 1980s Now models for evolution of life itself is being tested; these have be written based on principles of systems biology
J Gomes, IITD 8

Metabolic Control Analysis


Developed in the early 1970s, presented a key approach to characterize properties of biochemical reaction networks MCA resolved the paradox that multiple rate limiting steps could exist in large reaction networks Defining parameters such elasticity coefficients and flux-control coefficients quantified the performance of biosynthetic pathways Connectivity laws proven by MCA pinpointed the distribution of control related to network structure and kinetic properties of all network coponents simultaneously.
J Gomes, IITD 9

Convergence
Engineering Principles Nonlinear systems analysis Network theory Abstract mathematics representation theory, group theory and graph theory Nonlinear Thermodynamics Physics Molecular biology
J Gomes, IITD 10

Systems Biology Cycle for Strain Improvement


Gregory Stephanopoulos, Hal Alper and Joel Moxley, Nature Biotechnology, Vol 22 No 10 Oct 2004

Iterative perturbations and systematic phenotype characterization yield system insight through integration of large data sets

J Gomes, IITD

11

Exploiting Complexities in Metabolic Networks


Wild type cells are engineered to overexpress the enzyme E3 with the aim of increasing the yield of Y. However, because of network interactions, overexpression of E3 has minimal effect on yield of Y. To increase Y multiple steps of the pathway will have to be targeted.

Gregory Stephanopoulos, Hal Alper and Joel Moxley, Nature Biotechnology, Vol 22 No 10 Oct 2004

J Gomes, IITD

12

Integrating Physiological and Transcriptional Data


Various pattern models and data analysis techniques can be used for linking data sets. For example statistical correlations can be used to link microarray data with phenotype. Models of increased complexity require more data but are also able to provide deeper insight.
Gregory Stephanopoulos, Hal Alper and Joel Moxley, Nature Biotechnology, Vol 22 No 10 Oct 2004

J Gomes, IITD

13