What I cannot create I do not understand

Richard Feynman’s last board

A multi-scale data problem

Scale

Whole brain data (20 um

microscopic MRI)

Mosiac LM images (1 GB+)

Conventional LM images

Individual cell morphologies

EM volumes & reconstructions

Solved molecular structures

Reverse-engineering?

A system whose mechanisms are obscured

What is reverse-engineering?

System whose mechanisms are obscured

Individual components andan explanation of how they fit together

What is reverse-engineering?

Provide a framework of parts ready to be snapped together

Put the parts back together

A multi-scale synthesis problem

Simulation-based research Challenging intuition via predictive models Construction of models requires deep

organization of understanding of a system Forces you to fill in gaps Observing unexpected behaviors produced

by the models Able to look across multiple variables at the

same time Can do experiments that would otherwise

be impossible to do in a real biological system

Enter the worm: c. elegans

What’s up, baby?

Virtual physical organisms in a computer simulation

In search of nature’s design principles via simulation

• How can a humble worm regulate itself?– Reproduces– Avoids predators– Survives in different chemical and temperature

environments– Seeks and finds food sources in an ever

changing landscape– Distributes nutrients across its own cells– Manages waste and eliminates it

– If we can’t understand genes to behavior here, why would we expect to understand it anywhere?

Enter the worm: c. elegans

I’ve only got 1000 cells in

my whole body… please simulate me!

A complete simulation of the worm’s brain, body and environment

SimulatedWorld

Detailed simulation of worm body

Detailed simulation of cellular activity

The goal: understanding a faithfully simulated organism end to end

Extracting mathematical principles from biological systems is necessary if we are going to understand and reconstruct the much larger system of the human.

Outreach: put the model online and let the world play with it

•Sex: Hermaphrodite•Interested in: Escaping my worm Matrix•Relationship status: Its complicated.

Worm biology ~1000 cells / 95 muscles Neuroscience:

302 neurons 15k synapses

Shares cellular and molecular structures with higher organisms Membrane bound organelles; DNA complexed into chromatin and organized into discreet chromosomes Control pathways

Genome size: (9.7 x 107 base pairs or 97 Megabases), vs human: 3 billion base pairs (3 X 109 bp or 3000 Megabases).

C. elegans homologues identified for 60-80% of human genes (Kaletta & Hangartner, 2006)

C. Elegans disease models

Kaletta & Hengartner, 2006

Can present drugs

Kaletta & Hengartner, 2006

Entire cell lineage mapped

Entire cell lineage mapped

Entire cell lineage mapped

Entire cell lineage mapped

Full connectome

Varshney, Chen, Paniaqua, Hall and Chklovskii, 2011

P. Sauvage et al. / Journal of Biomechanics 2011

Biomechanics

Interrogation of Behavior

Core platform: Open Worm project

One core hooks together multiple simulation engines addressing diverse biological behavior

Estimates of computational complexity Mechanical model

~5 Tflops Muscle / Neuronal

conductance model~240 Gflops

One Amazon GPU cluster provides 2 Tflops Source: http://csgillespie.wordpress.com/2011/01/25/cpu-and-gpu-trends-over-time/

Mechanical model

Palayanov, Khayrulin, Dibert (submitted)

3D body plan

Christian Grove, Wormbase

Team – A brief history

Collaboration technologies used

Jan – Sept 2011

Architecture

Neuronal model

GPU Performance Testing: 302 Hodgkin-Huxley neurons for 140 ms (dt = 0.01ms)

Architecture proof of concept using Hodgkin-Huxley neurons

ms

Worm Browser

http://www.youtube.com/watch?v=nAd9rMey-_0

Physics: SPH

Smoothed particle hydrodynamics (SPH) algorithm for soft-body / liquid finite element interactions

Soft-body & fluid mechanics

Finite element modeling

C.elegans neuron models in NeuroML

Mendeley group has 234 references

Presented poster at Neuroinformatics 2011

OpenWorm links:

Project page: http://code.google.com/p/openworm/

Twitter: @openworm

Mailing List: http://groups.google.com/group/openworm

Sept 2011 – March 2012

Muscle cell with “arms”

Cell Body

5 arms, 10 compartments

each, passive currents

Cell body, 1 compartment, active

currents

Boyle & Cohen, 2007

Case study: locomotion

Gao et al, 2011

Conductance model of c. elegans muscle cell

Boyle & Cohen, 2007

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Cell

Body

Quadrant 1 Quadrant 2

Quadrants of muscle cells

Genetic Algorithms and Parameter optimization

Achard, De Schutter, 2006

Gaming and crowdfunding