ROBUSTNESS in Biological Systems

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ROBUSTNESS in Biological Systems

• Are Biochemical networks delicately balanced?

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Robustness in Biological Systems

• Common issues
• How is it achieved?
• How does it evolve within various aspects of
  biological systems?
• def. Systems that are robust maintain their
  state and function against external and internal
  perturbations.

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Robustness in Biological Systems

• Robustness is an essential feature of biological
  systems
• Robust systems are insensitive to internal
  parameter changes
• Able to adapt to changes in the environment
• Even damage may just produce minor alterations

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Properties of Highly Robust Systems

• Feedback
• Bacteria Chemotaxis
• P53-based cell-cycle arrest
• Modularity
• Spatial Localization of biochemical networks
• Redundancy
• Circadian Oscillator
• Structural Stability
• Archetypal genetic switch (the lambda phage
  decision circuit)
• Drosophila embryogenesis

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I. Bacterial Chemotaxis

• Robustness thru feedback.

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Bio-organisms are Responsive

• Networks of interacting proteins demonstrate the
  responsiveness of living cells to a variety of
  external stimuli.
• But if living cells are so responsive, does that
  make them (including us) too sensitive to slight
  changes in the stimuli?
• For example, an abrupt change in chemical signals.

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Two Possibilities

• Either nature is designed to be very sensitive to
  inputs (which is consistent with its
  responsiveness), OR
• It is actually very robust, and is in fact very
  insensitive to the precise values of its
  parameters or inputs!

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Bacteria Chemotaxis

• chemotaxis -
• cell movement caused by chemical
  stimulus movement or change in the position of a
  cell or organism in response to the presence of a
  chemical agent

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Bacteria Chemotaxis

• In this case, changes in the stimuli do not
  hamper an organisms performance.
• It actually helps the organism survive.
• Bacteria such as E. Coli bias their swimming
  motion towards specific attractants, and away
  from repellents.

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Information about the chemical environment is
transduced into the cells by chemoreceptors. INPU
T chemical environment. FEEDBACK or OUTPUT
tumbling motions to swim towards or away the
stimulus
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II. The Circadian Oscillator

• From the Latin circa about, and dies day
• Circadian rhythm is a periodicity of about 24
  hours this is exhibited by biological organisms
• Contained within cells which contain a particular
  molecular clockwork

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The Circadian Oscillator

• Such cells use molecular loops that are sealed
  within the cell itself it cannot therefore be
  affected by external factors
• Consequently, circadian clock cells dont need
  cell-to-cell or cell-to-environment interactions
  to keep time

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The Circadian Oscillator

• The best known examples
• eyes of some marine mollusks
• retina of amphibians
• mammalian suprachiasmatic nucleus
• pineal gland of nonmammalian vertebrates,
  particularly those of birds.
• Example pineal glands removed from sparrows
  (MPRCO)

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Core Model (simplistic)
nuclear Gene transcription protein (Pn)
nRNA (Mp)
Protein (Po)
P2
P1
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How it works

• The model incorporates gene transcription,
  transport of mRNA (MP) into the cytosol where it
  is translated into the clock protein (Po) and
  degraded. The clock protein can be reversibly
  phos-phorylated from the form P0 into the forms
  P1 and P2, successively.

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But theres Molecular Noise

• As the number of molecules decreases, ? the above
  system fluctuates in its timing
• Noise produced is proportional to 1/sqrt(N),
  where N is the no. of molecules

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Circadian Robustness

• Robustness increases in proportion to the number
  of molecules in the system.
• With few molecules, the standard deviation in the
  oscillation is much greater, but
• With many molecules, the average oscillations
  approach the circadian value, or the correct
  frequency

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III. The ? Phage circuit

• Paramecium bursaria chlorella virus 1 (PBCV-1)
  negatively stained with uranyl acetate. The
  smaller particles are lambda phage.

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Gene Regulatory Circuits

• Regulatory Circuits are also called Decision
  Circuits.
• These often persist in alternative stable states
• These are switches in the sense that they can
  move from one stable state to another
• if the input signals reach a certain threshold.

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Is ? Phage Robust?

• A bigger question is, Are Biochemical networks
  delicately balanced?
• Independent experiments on the ? Phage decision
  circuit altered what were thought to be
  essential components.
• A complex site called the OR region contains many
  of the events believed to control most of the
  regulatory behaviors.

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Section A is a map of the OR region. Note that 3
sub regions are OR1, OR2, and OR3. PR promoter
that transcribes cI PRM promoter that
transcribes cro
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? Phage Experiment

• Binding of cI is tight to OR1, weak to OR3, and
  cooperative to OR2.
• Cro binds equally well to OR1 and OR3.
• To test robustness, the binding patterns of cro
  and cI were disrupted, and the resulting circuit
  regulation was studied
• Results demonstrate that the qualitative pattern
  of ? gene regulation persists despite these
  changes.

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? Experiment Conclusion

• Biochemical networks are not delicately balanced,
  but can continue to function over a range of
  parameters.
• Despite assuming the crucial role of differential
  repressor binding (in the OR region), this turns
  out to be non-essential in ?-regulation.

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? Experiment Conclusion

• It may be that the OR region is likely a
  fine-tuning of the circuitry for optimal
  behavior.
• Its stable switching action arises from the
  structure of its network, rather than the
  specific affinities of its binding site Kitano