Martin Howard

1
Systems Biology A Personal Introduction
Dept of Systems Biology John Innes Centre Norwich

• Martin Howard

2
Systems Biology

• How are we to define systems biology?
• Use of high throughput (omics) technologies?
• Another phrase for theoretical biology?

• Set of approaches and a way of thinking
  rather than a single definition
• Global investigation of how the components of
  a biological system add up to generate its
  behaviour
• Focus mainly on subsystem properties that are
  critical for overall function of system
• Systems Biology approach can be theoretical
  and/or experimental

3
Systems Biology

• Good for physicists
• - once weve learnt the biology (very important
  to do this properly!) this is what weve been
  trained to do
• If approach is theoretical, systems biology
  modelling must be predictive!
• Ideally modelling makes predictions that are
  tested experimentally. New data then informs the
  next round of modelling a virtuous (though
  rarely achieved) cycle
• Precise definition of systems biology probably
  not very important
• No one can agree on a definition anyway!
• Probably best to proceed by giving examples

4
Modelling the Cell Cycle

• Cell Cycle is the process where a cell doubles
  its genetic content and distributes it to 2
  daughter cells
• Subdivided into phases G1 S G2
  M G1 .

Mitosis and Cell Division
DNA replication
Growth
Growth

• Gap phases provide time for the cell to monitor
  extrernal/internal environment to ensure that
  conditions are right for S or M phases to begin
  cell checkpoints
• Individual cell cycle times in a population of
  cells equal to the mass doubling time of the
  population

5
Modelling the Cell Cycle

• How does the cell regulate the progression
  through these phases?
• Complicated regulatory network main components
  cyclin dependent kinases (Cdk) which activate
  cell cycle steps by phosphorylation
• Cdk's are active only if they are bound by a
  cyclin regulatory molecule
• Its the dynamics of these cyclins that drive
  cell cycle
• Most of major steps of cell cycle known to be
  universal in eukaryotic cells

6
Very Cut-Down Cell Cycle Network!
7
Mathematical Model

• Model dynamics using coupled sets of ODEs

• Note the large number of parameters. These need
  to be fitted (or guessed!)
• Probably the biggest problem with large scale
  systems biology models is how to determine the
  parameters

8
How Does a Mathematical Analysis Help?

• Use bifurcation theory to examine properties of
  system
• Examine level of Cdk1-CycB as function of cell
  size

M Cdk1-CycB rise drives cell into mitosis while
subsequent fall is signal for cell
division Tyson, Chen, Novak Curr Opin Cell Biol
15 221-231 (2003)
G2/S
G1
9
How is DNA Properly Distributed to Daughter Cells?

• Elaborate apparatus distributes one copy of each
  chromosome to each daughter cell mitotic spindle
  made up of microtubules and molecular motors

• Microtubules attach to specific location on
  chromosome kinetochore
• When all kinetochores are attached, spindle then
  pulls chromosomes apart

Musacchio Salmon Nature Rev Mol Cell Biol 8
379-393 (2007)
10
Spindle Assembly Checkpoint

• If even a single kinetochore is not attached to
  spindle microtubules then DNA segregation is
  postponed
• Spindle Assembly Checkpoint monitors
  microtubule-kinetochore attachment
• Checkpoint failure leads to improper chromosome
  segregation leading to aneuploidy
• How can such a small object (an unattached
  kinetochore, radius 0.2µm) reliably control
  such an important cell signalling pathway?
• Presumably signal must be amplified
• but checkpoint must still be able to switch
  on/off within minutes
• Need to understand dynamics of kinetochore
  signalling!

11
Dual checkpoint mechanisms
Sear Howard, PNAS 103 16758-16763 (2006)
Sequestration of 106 copies of Cdc20 by Mad2/BubR1

• Example of systems biology modelling where
  almost all the details are stripped out
• Only basic principle is modelled to see whether
  it is feasible

12
Bacterial Chemotaxis

• How do bacteria move towards a source of food?

• Motion achieved through flagellum and motor

Berg Physics Today, Jan 2000
13
Bacterial Chemotaxis

• If motor turns anticlockwise flagella filaments
  rotate in parallel in a bundle generating a run
• If motor turns clockwise flagella filaments
  work independently and bacteria moves erratically
  with little net displacement generating a tumble

• If bacterium is moving up a concentration
  gradient of nutrients
• length of time spent running increased
• probability of tumbling reduced
• Biased random walk!
• But how to measure/remember the local nutrient
  concentration?

14
Bacterial Chemotaxis

• Specialised receptors in the membrane detect
  nutrient concentrations localised at cell poles
• Transmit information based on phosphorylation
  signal that affects flagella rotation
• But nutrient concentrations can be very low
  signal needs to be amplified
• Each receptor can exist in one of two
  conformations, one of which is favoured by the
  binding of a ligand
• Receptor conformations also affected by the
  conformations of the four nearest neighbours in
  the lattice
• Ising model! Close to criticality, amplification!

Duke Bray PNAS 96 10104-10108 (1999)
15
Bacterial Chemotaxis Network

• Che proteins are crucially invovled in the
  chemotaxis signal transduction network
• In addition to detection/signaling a second
  system is at work adaptation
• Functions through methylation of receptors
• Occupancy of binding site reflects current
  conditions
• Level of methylation reflects past conditions
  (memory!)
• Cell can respond appropriately by comparing
  these two indicators

16
Bacterial Chemotaxis Network

• Chemotaxis network is quite complex!
• Many kinetic constants (as usual), but added
  problem of spatial dynamics (diffusion)
• Use available experimental measurements, plus
  models heavily constrained by knock-out mutants
• Packages available to simulate the system e.g.
  Smoldyn

17
Accurate Cell Division Min Oscillations
MinD Oscillations Hale, Meinhardt, de Boer EMBO
J. 20 1563 (2001)

• How does E. coli divide at its middle?!
• MinE stimulates coherent pole to pole
  oscillations of MinCDE
• Centre of cell marked by minimum MinC/MinD
  concentration

18
Model of Min Dynamics
MinD
MinE

• Dynamic instability!
• Systems Biology modelling is essential for
  understanding the dynamics
• Self-organised patterning generated by only a
  few basic properties of Min proteins

Tostevin Howard, Phys. Biol. 3 1-12 (2006)
Average density for MinD
19
Systems Biology Conclusion

• Just scratched the surface of the field!
• Tremendous opportunities for physicists
  (particularly those with stat mech background)
• provided we take the trouble to learn the
  biology
• BUT choose your problems with great care
• - very easy to become too technical
• - or too bogged down in detail
• As the field is so young, try to do the simple
  things first!

20
Position Available!
3 year postdoc position available at The John
Innes Centre, Norwich to work on biological
physics/systems biology If interested send me a
mail martin.howard_at_bbsrc.ac.uk Or talk to me
during the meeting