Introduction to Systems Biology

Craig Simpson

What is a system?

1. A collection of components organized to accomplish a specific function of set of functions

2. A group of interacting, interrelated, or interdependent elements or parts that function together as a whole to accomplish a goal

Matthias Heinemann, ETH

What cellular processes are controlled by systems?

• Cell division (mitosis, meiosis)• Cell death (apoptosis,

autophagy, necrosis)• Cell differentiation• Cell movement• Metabolism• Catabolism/anabolism• i.e. every cellular process can

be considered a system or a network

How does information flow in a cell?

Highly simplified!!!

DNA ProteinRNA Function

From DNA to RNA

• Transcription takes place in the nucleus

• RNA is produced from DNA by RNA polymerase– RNA is produced from 1 strand of

DNA– Requires transcription factors

upstream of transcription start site

– Not all genes are transcribed equally

Transcritional regulation

• Promoter region– How accessible is it?

• DNA is tightly coiled• Promoter regions can be modified to shut down transcription

(epigenetic regulation)

• Activators– Enhance interaction between RNA polymerase and

promoter region• Repressors– Bind to regions close to promoter region and prevent RNA

polymerase from binding

RNA processing

RNA to Protein

• Translation takes place on the ribosomes

• Ribosomes read three nucleotide sequences (Codon) from mRNA and add corresponding amino acid to growing peptide chain– Use of tRNA

Codons are the code for which amino acid to use

Regulation of Translation

• mRNA availability• Presence of silencer/inhibitory RNA that binds

to mRNA• Codon usage (abundance of tRNA)• Amino Acids– 20 essential amino Acids

Shape and Structure of Protein

• Chemical bond between two amino acids (peptide bond)

• Composed of multiple peptide bonds between a composition of different amino acids– Chemical properties of the amino acids impart 3D

structure to the protein• Multiple peptides can bind together to form a

complete functional protein

Protein function• Protein’s structure determine its function• All proteins bind to some other molecule

– Tight and long lived interaction– Short and highly energetic reaction– Depends on the amino acid side chains

Metabolites

• End product of protein activity– Anabolic processes– Catabolic processes

• Depends on the context that the cell is in• Everything that is produced in a cell is a

metabolite– Metabolites can be measured

Posttranslational Modifications

• After protein is formed it is chemically modified on the amino acid side chains– Ubiquitylation, sumolation, on lysine– Phosphorylation on tyr, ser, thr– Acetelyation

• Modifications can alter the function of the protein– Mark for destruction– Activate– Change binding partners

Genetics do not dictate function

Function

DNAProtein

RNA

DNA

Protein

RNA

DNA

Protein

RNA

DNA

Protein

RNA

Cellular Process

• Cellular functions and processes are an accumulation of multiple different pathways and signals converging into one complex end point

• Need to understand these processes at a systems level to truly understand the process– Ie need to measure genetic mutations, presence

and levels of mRNA and expression and activity of proteins

Tools we can use to study the cellular system

• Mass Spectrometry– Total protein levels and post translational modificiations– metabolomics

• Sequencing– Genomic and exosome sequence

• Mutations in DNA, RNA

• Arrays– Levels of RNA

• Gene manipulation studies– Knockdown RNA– Overexpress RNA

• IE: Generate a large amount of data

Large amount of Data is meaningless

• Mass Spec: can generate 20-50,000 data points– Absence of protein doesn’t mean its not there

• Sequencing: 22,000 genes– Is a mutation functionally relevant?

• RNA expression: number depends on state of cell– Does a low expression level relate to decreased activity of

protein?• Metabolites: All the small molecules that the cell is

producing– Depends on state and type of cell

What does it all boil down to?

• Biology is governed by chemistry and physics• Chemistry and physics can be mathematically

modeled• Thus… biology can be mathematically

modeled

=

System biology work flowDNA MetabolitesProteinRNA

Modeling of all information (determine regulators of certain function)

Computer driven hypothesis of molecular regulators of function

DNA MetabolitesProteinRNA

Experimental manipulation

Where is system biology relevant?• Disease biology– Cancer– Infections– Diabetes– Any disease is caused by a perturbation to the normal cellular

system• Drug development– Understanding the system behind a disease will allow for

better targeting of disease– Understanding how drugs alter systems

• Many more…