introduction to systems biology
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Introduction to Systems Biology. Craig Simpson. What is a system?. A collection of components organized to accomplish a specific function of set of functions A group of interacting, interrelated, or interdependent elements or parts that function together as a whole to accomplish a goal. - PowerPoint PPT PresentationTRANSCRIPT
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Introduction to Systems Biology
Craig Simpson
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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
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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
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How does information flow in a cell?
Highly simplified!!!
DNA ProteinRNA Function
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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
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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
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RNA processing
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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
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Codons are the code for which amino acid to use
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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
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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
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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
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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
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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
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Genetics do not dictate function
Function
DNAProtein
RNA
DNA
Protein
RNA
DNA
Protein
RNA
DNA
Protein
RNA
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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
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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
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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
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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
=
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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
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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…