1. Languages for Systems Biology
Luca Cardelli Microsoft Research Cambridge UK
Languages for Systems Biology

2. Structural Architecture
Eukaryotic Cell
(10~100 trillion in human body)
Nuclear
membrane
Mitochondria
Membranes
everywhere
Golgi
Vesicles
E.R.
Plasma
membrane
(<10% of all membranes)
2/19/2019

3. Functional Architecture
Regulation
Abstract Machines of Molecular Biology
Gene Machine
Biochemical Networks - The Protein Machine Gene Regulatory Networks
- The Gene Machine Transport Networks
- The Membrane Machine
Nucleotides
Makes proteins, where/when/howmuch
Holds genome(s), confines regulators
Signals conditions and events
Directs membrane construction and protein embedding
Model Integration
Different time and space scales P Q
Holds receptors, actuators hosts reactions
Protein Machine
Machine
Membrane
Implements fusion, fission
Aminoacids
Phospholipids
Phospholipids
Metabolism, Propulsion Signal Processing Molecular Transport
Confinement Storage Bulk Transport
2/19/2019

4. 1: The Protein Machine Pretty close to the atoms. On/Off switches
cf. BioCalculus [Kitano&Nagasaki], k-calculus [Danos&Laneve]
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.
2/19/2019

5. Molecular Interaction Maps
The p53-Mdm2 and DNA Repair Regulatory Network
JDesigner
Taken from
Kurt W. Kohn
2/19/2019

6. “External Choice” The phage lambda switch
2. The Gene Machine
Pretty far from the atoms.
cf. Hybrid Petri Nets [Matsuno, Doi, Nagasaki, Miyano]
Positive Regulation
Negative Regulation
Transcription
Input
Output1
Output2
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 Size 3Gbp (Giga base pairs) 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) ,073bp 145KB (eBook) E.Coli (bacteria): 4Mbp 1MB (floppy) Yeast (eukarya): 12Mbp 3MB (MP3 song) Wheat 17Gbp 4.25GB (DVD)
2/19/2019

7. Gene Regulatory Networks
Taken from
Eric H Davidson Or
And
Gate
Amplify
Sum
DNA
Begin coding region
NetBuilder
2/19/2019

8. The Membrane Machine P Q P Q Very far from the atoms. Drip Mate Mito
Bud R
One case
Arbitrary subsystem
Mate
Mito
Zero case
Fusion
Fission
Mito:
special
cases P
Pino
Phago R
Arbitrary subsystem
Zero case
One case
Exo
Endo Q
Endo:
special
cases
Fusion
Fission
2/19/2019

9. Membrane Transport Algorithms
LDL-Cholesterol Degradation
Protein Production and Secretion
Viral Replication
Taken from
MCB p.730
2/19/2019

10. Equations => Notations => Languages
How to model a system
Mathematical modeling:
Formal (e.g. differential equations).
Dynamic (but increasingly difficult to analyze).
Non scalable. Non “visual”.
=> Alterantive notations in biology:
Too informal. Too static. Non scalable.
Exceeding capabilities of traditional mathematical modeling.
=> “Programming” languages for biology:
Formal, Dynamic
Scalable, Analyzable
Visual (with some effort).
2/19/2019

11. Road Ahead Identifying the architecture Modeling the system
Physics, Chemistry, Biology, Informatics: Principles 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): , 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.
2/19/2019