Luca Cardelli Microsoft Research Cambridge UK http://www.luca.demon.co.uk/BioComputing.htm http://research.microsoft.com/bioinfo

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Luca CardelliMicrosoft ResearchCambridge
UKhttp//www.luca.demon.co.uk/BioComputing.htmh
ttp//research.microsoft.com/bioinfo
Languages for Systems Biology
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Structural Architecture
Nuclear membrane
EukaryoticCell (10100 trillion in human body)
Mitochondria
Membranes everywhere
Golgi
Vesicles
E.R.
Plasma membrane (lt10 of all membranes)
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Functional Architecture
Regulation
Abstract Machines of Molecular Biology
GeneMachine
Biochemical Networks - The Protein
MachineGene Regulatory Networks - The Gene
MachineTransport Networks - The Membrane
Machine
Nucleotides
Makes proteins,where/when/howmuch
Holds genome(s),confines regulators
Directs membrane construction and protein
embedding
Signals conditions and events
Model Integration Different time and space scales
Holds receptors, actuators hosts reactions
ProteinMachine
Machine
Membrane
Implements fusion, fission
Aminoacids
Phospholipids
Phospholipids
Metabolism, PropulsionSignal ProcessingMolecular
Transport
ConfinementStorageBulk Transport
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1 The Protein Machine
Pretty close to the atoms.
cf. BioCalculus KitanoNagasaki, k-calculus
DanosLaneve
On/Off switches
Each protein has a structure of binary switches
and binding sites. But not all may be always
accessible.
Inaccessible
Protein
Inaccessible
Binding Sites
Switching of accessible switches. - May cause
other switches and binding sites to become
(in)accessible. - May be triggered or inhibited
by nearby specific proteins in specific states.

• Binding on accessible sites.
• May cause other switches and binding sites to
  become (in)accessible.
• - May be triggered or inhibited by nearby
  specific proteins in specific states.

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Molecular Interaction Maps
http//www.cds.caltech.edu/hsauro/index.htm
The p53-Mdm2 and DNA Repair Regulatory Network
JDesigner
Taken from Kurt W. Kohn
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2. The Gene Machine
Pretty far from the atoms.
cf. Hybrid Petri Nets Matsuno, Doi, Nagasaki,
Miyano
Positive Regulation
Transcription
Negative Regulation
Input
Output
Coding region
Gene(Stretch of DNA)
External Choice The phage lambda switch
Regulatory region
Regulation of a gene (positive and negative)
influences transcription. The regulatory region
has precise DNA sequences, but not meant for
coding proteins meant for binding
regulators. Transcription produces molecules (RNA
or, through RNA, proteins) that bind to
regulatory region of other genes (or that are
end-products).
Human (and mammalian) Genome Size3Gbp (Giga base
pairs) 750MB _at_ 4bp/Byte (CD) Non-repetitive
1Gbp 250MB In genes 320Mbp 80MB Coding
160Mbp 40MB Protein-coding genes
30,000-40,000 M.Genitalium (smallest true
organism) 580,073bp 145KB (eBook)E.Coli
(bacteria) 4Mbp 1MB (floppy)Yeast (eukarya)
12Mbp 3MB (MP3 song)Wheat 17Gbp 4.25GB (DVD)
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Gene Regulatory Networks
http//strc.herts.ac.uk/bio/maria/NetBuilder/
NetBuilder
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The Membrane Machine
Very far from the atoms.
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Membrane Transport Algorithms
LDL-Cholesterol Degradation
Protein Production and Secretion
Viral Replication
Taken from MCB p.730
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Equations gt Notations gt Languages

• How to model a system
• Mathematical modeling
• Formal (e.g. differential equations).
• Dynamic (but increasingly difficult to analyze).
• Non scalable. Non visual.
• gt Alterantive notations in biology
• Too informal. Too static. Non scalable.
• Exceeding capabilities of traditional
  mathematical modeling.
• gt Programming languages for biology
• Formal, Dynamic
• Scalable, Analyzable
• Visual (with some effort).

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Road Ahead

• Identifying the architecture
• Physics, Chemistry, Biology, InformaticsPrincipl
  es of Operation
• Modeling the system
• Scalable, compositional, integrated descriptions
• A common framework (stochastic process calculi)
• Analyzing the model
• Exploiting techniques unique to computing
• Perturbing, predicting, engineering

Model Integration
The data are accumulating and the computers are
humming, what we are lacking are the words, the
grammar and the syntax of a new language D.
Bray (TIBS 22(9)325-326, 1997)
Although the road ahead is long and winding, it
leads to a future where biology and medicine are
transformed into precision engineering. Hiroaki
Kitano.