not a keynote, but a footnote on molecular biology and computation for rocky 1 the biology of...
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not a keynote, but a footnote on molecular biology and computation
for Rocky 1
The Biology of Information
Walter Fontana (SFI)walter@santafe.edu
www.santafe.edu/~walter
1. What can computation do for biology?
The computer as…
The computer as…
…theater: simulation, modeling
The computer as…
…theater: simulation, modeling
…library: organization of data
The computer as…
…theater: simulation, modeling
…library: organization of data
…instrument: component of experiment
The computer as…
…theater: simulation, modeling
…library: organization of data
…instrument: component of experiment
…mathematical structure: formalism, concept
. . . ( , ) ( )u eu e x e x x
1. What can computation do for biology?
1. What can computation do for biology?
Nothing.
1. What can computation do for biology?
A lot.
1. What can computation do for biology?
2. What can biology do for computation?
…but this business is not well understood on both sides…
molecular biology and computer science are in the same conceptual business
molecular biology and computer science are in the same conceptual business
at the very minimum,both are about structure-behavior relations,
i.e. configuring systems to engender specific behaviors(both are “programming” disciplines)
a self-printing program in C
a self-printing program in C
now imagine these expressions…
… decaying… moving around… combining into imprecise meanings… acting in parallel & asynchronously
a self-printing program
now imagine these expressions…
… decaying… moving around… combining into imprecise meanings… acting in parallel & asynchronously
molecular components…
…turn over (from minutes to days)…are stochastic (wrt reliability, number, recognition)…move around (passively or actively) in a structured medium…communicate through physical contact…control each other’s state and production…are often multipurpose…need (lots of) energy for communication…operate concurrently
turn-over of components:persistence of identitymemory of state
stochasticity (in number and recognition):error-correction
massive concurrency:emergence of determinismcoordination & conflicts
communication by contact:energy transportcontrol of space
…which entails a suite of issues, such as:
plasticityreconfigurabilitycompressibilityevolvability (neutrality, modularity)autonomyselfrobustness
biological architectures emphasize systemic capacities, e.g.
all these features are desirable but absent in present daycomputer architectures
+
in biological systems, there is no “software running on something” !
IS NOT
in (theoretical) computer science…
…physical hardware is distinct from software.(in CS, “machine” is a software notion)
in biology…
…physical hardware is software
• dynamics
• stochasticity
• effective potentials
• combinatorial trajectories & path-dependency
• discrete events & concurrency
• object syntax and action
• generative interactions
physics
logic
digital
analog
A few vignettes where the gap between computation and molecular biology is widest
enzyme kinetics 101
Who is the “s
ignal”??
phosphorylation chain
phosphorylation chain
multiple phosphorylation in proteins (phosphobase*)
* A. Kreegipuu, N. Blom, S. Brunak. Nucleic Acids Research (1998/1999)
W.Fontana & D.Krakauer (in progress)
0
1
( / )J i
iQ S
phosphorylation chain and hypersensitivity
generalized signaling cascades
shifting the threshold by positioning P-chains of different width at various depths in a cascade
pulse filter
multiple phosphorylation as pulse filter
W.Fontana & D.Krakauer (in progress)
multiple phosphorylation as pulse filter
W.Fontana & D.Krakauer (in preparation)
memory and “checkpoints”
phosphorylation chain
phosphorylation chain with positive feedback
phosphorylation chain with symmetric feedback
phosphorylation chain with symmetric feedback
|rela
tive a
vera
ge d
iff o
f end s
tate
s|
n/signal
large J:Bose-Einstein
small J:Curie-Weiss
S.Krishnamurty,E.Smith,D.Krakauer,W.Fontana
Phys.Rev.Lett., submitted
stochastic treatment of a P-chain with symmetric feedback
second order phase-transition
stochastic master equation
introduce operator algebra familiar from many-body physics
obtain equivalent equation,now approachable by techniques
from many-body physics
effective potentials
idea by M.Sasai & P.Wolynes:
Sasai & Wolynes: “Stochastic gene expression as a many-body problem”,PNAS, 100, 2374–2379 (2003).
the landscape concept made formally preciseby techniques from statistical mechanics
“programming” becomes sculpting an appropriate landscape.
But how?(cf. neural networks, spin glasses…)
the landscape metaphor: from energy landscapes in proteins to epigenetic landscapes a la Waddington
reconfigurable molecular networks, plasticity
Milan N Stojanovic, Darko Stefanovic. Nature Biotechnology, 21, 1069 - 1074 (2003)
allostericRNA gates
Why do we need the formalisms of computation and logic?
a pragmatic answer: more tools get us to more places.
a deeper answer: because we need a theory of (molecular) objects.Why?
Because the pressing (and recalcitrant) question for biology is not only to describe the behavior of a particular system, but to understand that system in the context of the possible, i.e. of what is evolutionarily
accessible to it.
Stated differently: we must eventually be able to reason about novelty.We never can do so within the confines of dynamical systems,
because dynamical systems do not represent the objects they are made of.(Remember chemistry.)
we need an abstraction of chemistryin which
molecules are interacting computational agents
the grand challenge:
describe a system with an expression that is at the same time
a program to “run” that systemAND
a formula to reason about it abstractly.
A brief coda where the gap between computation and molecular biology is closing
(at the formal language end)
inputoutput
function
no interaction with the “environment”
Old notion of computation
semantics: input-output relation
process
semantics: potential sequences of interaction events
interaction with the “environment”
New notion of computation
function
closed system
process
open system
computation:
analogy in physics:
equilibrium normal form
organizationmain concern:
Theory of concurrency, Process algebra
Robin Milner, Communicating and Mobile Systems: the -calculus, Cambridge (1999)
The -calculus (Milner, Walker and Parrow 1989)
• a program specifies a network of interacting processes
• processes are defined by their potential communication activities
• communication occurs on complementary channels, identified by names
• message content: channel name
Aviv Regev, Ehud Shapiro, Corrado Priami, and others:application of concurrency / process algebras
to molecular signal transduction
A.Regev & E.Shapiro, Nature, 419, 343 (2000), Concepts
concurrency theory, what for?
• tool for agent-based simulation based on a theory of the agents
• tool for agent-based simulation
at worst:
at its most hopeful:
molecular biology
nanotechnology &molecular information systems
distributed OS design
concurrency
a lingua franca?
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