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Can we Verify an Elephant?. David Harel The Weizmann Institute of Science. Surprisingly many parts of this were influenced by Amir Pnueli. In recent years he became very interested in biological modeling, and actively participated in some of the projects.

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slide1

Can we Verify an Elephant?

David Harel

The Weizmann Institute of Science

slide2

Surprisingly many parts of this were influenced by Amir Pnueli

In recent years he became very interested in biological modeling, and actively participated in some of the projects

slide7

Unexplained demos

Just to get us in the mood….

slide8

Why do we do computerized modeling?

What and how should we model?

What makes models “valid”, “complete”, and how do we verify this?

Such questions become especially acute when we try to model Nature

slide9

BiologyasReactivity

Biological artifacts are really reactive systems(Harel & Pnueli, 1986) on all levels: the molecular and the cellular, and all the way up to organs and full organisms

slide10

Biological systems can be modeled and analyzed as reactive systems, using languages/tools developed for constructing computerized systems

A thesis follows:

Put simply:Let’s reverse-engineer an elephant rather than engineer an F-15…

what to model
What to model?

Be comprehensiveThat is, do the whole thing...

but what is the whole thing horizontal delineation
An entire cell

An entire organ or organism

An entire population?

But what isthe whole thing? (horizontal delineation)
on or up to what level of detail vertical delineation
Inter-cellular

Intra-cellular (inter-molecular)

Probably also genomic/proteomic

Maybe biochemistry & even physics (particles, quantum mechanics, string theory…)??

On (or up to) what level of detail? (vertical delineation)
slide14

Crucial point:Comprehensive modeling entails capturingeverything that is known about the system, and doing everything else any which way…

slide15

WOP: Whole Organism Project

A Grand Challenge for Comprehensive Modeling (H, 2003)

To construct a “full”, true-to-all-known-facts, 4-dimensional model of a multi-cellular organism

Which animal would be a good choice? Later (but it’s not an elephant…)

slide16

Another crucial point

(otherwise we’re wasting our time):

The model should make researchers excited, enabling them to observe, analyze and understand the organism ― development and behavior ― in ways not otherwise possible; e.g., to predict

slide17

Additional potential gains are enormous

  • Help uncover gaps, correct errors, form theories and explanations
  • Suggest new experiments, and help predict unobserved phenomena
  • Help discover emergent properties
  • Verifybiological theories against laboratory observations
  • Pave the way for in silico experimentation, and possibly synthesis, drug construction,…
how to model
How to model?

Be realisticThat is, make it look good…

project i thymus with s efroni and i cohen 03
T-cell (thymocyte) behavior in the thymus.

Many cells, complex internal behavior, interaction and geometric movement.

Enormous amount of biological knowledge assimilated and modeled (~ 400 papers).

Project I (thymus)(with S. Efroni and I. Cohen, ‘03 )
statechart outline for a single t cell
Statechart outline for a single T-cell

Interaction

Receptors

Migration

Receptorsdecisions

Entry to thymus

Cell phase

slide22

Straight run

Interaction, etc.

Pre-recorded demos

slide23

Competition change:

The model reveals emergent properties(with Efroni and Cohen, ‘07)

project ii pancreas with y setty y dor and i cohen 2007
Embryonic development of the pancreas (very different characteristics).

Here we use 3D animation and are interested in organ formation.

Project II (pancreas)(with Y. Setty, Y. Dor and I. Cohen; 2007)
slide26

Pre-recorded demos

Normal growth:

Cell count results:

slide28

Wild “playing” yielded insights into the role of blood vessel density into organ development

Experimental confirmation in progress!

slide29

Project III (C. elegans)

(with N. Kam, M. Stern, J. Hubbard, J. Fisher, H. Kugler, A. Pnueli; 2001−7)

  • Vulval precursor cell (VPC) fate determination in the C. elegans nematode
  • Few cells, lateral and inductive signaling with subtle timing; many mutation-driven variants.
slide31

Development

Behavior

slide32

Proposal:

Meet the Grand Challenge by modeling the C. elegans nematode

Or some comparable creature

slide33

anchor cell

P7.p

P6.p

P5.p

P4.p

ayIs4;e1282;lin-15(n309)

slide35
Carry out multi-level modeling, with different abstraction levels modeled with different languages and methods

Then combine all to yield a smoothly zoomable & executable model

Central CS problem to be solved:

Vertical linkage

(hierarchy, abstraction and levels)

a modest step forward biocharts with h kugler and a larjo 2009
A compound, fully executable 2-tier language for modeling biology

Upper level captured using Statecharts

Lower level captures networks, pathways, etc.; e.g., with semantics-rich biological diagrams.

A modest step forward: Biocharts(with H. Kugler and A. Larjo, 2009)
when are we done
When are we done?

Aha! The $64m question…

slide38

But,… comprehensive modeling is about understanding a whole thing

You really and truly understand a thing when you can build an interactive simulation that does exactly what the original thing does on its own.

Q:How do you tell when you’ve managed to achieve that?

slide39

A: We want prediction-making taken to the utmost limit; the key to this is to fool an expert.

Hence, for comprehensive modeling,I propose a Turing-like test, but with a Popperian twist

slide40

A Turing-like test for modeling (H’ 2005)

We are done when a team of biologists, “well versed” in the relevant field, won’t be able to tell the difference between the model and the real thing

slide41

This is not a test for the weak-hearted, or for the impatient…

And it’s probably not realizable at all…

But as the ultimate mechanism for prediction-confirming, it can serve as a lofty, end-of-the-day, goal for the WOP Grand Challenge