Download biological dynamics

biological dynamics
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Dynamics = how systems change/evolve with time
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Why are dynamics important to biological systems?
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Temporal behavior of proteins, cells, organisms
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metabolism, cell growth, development, protein production,
aging, death, species evolution … all are time dependant
processes
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Inherent complexity in biological systems both in time and
space
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temporal patterns are related to structural ones
traditional biological framework
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tend to think in terms of single point equilibrium
processes
time ---->
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time ---->
a stable and constant steady state
biological dynamics can be complex
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as time goes to infinity … response doesn’t have to go to a
single constant value
could for example have oscillations that
would go on forever unless perturbed
time --->
can even have aperiodic
behavior that goes on forever
but never repeats (chaotic)!
Oscillations / Rhythms Occur in Nature
At all time scales
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Predator Prey Population Cycles (years)
Circadian Rhythms (24 hours)
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Biochemical Oscillations (1 – 20 min)
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sleep wake cycles
metabolites oscillate
Cardiac Rhythms (1 s)
Neuronal Oscillations (ms – s)
Hormonal Oscillations (10 min - 24 hour)
Communication in Animal and Cell Populations
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fireflies can synchronize their flashing
bacteria can synchronize in a population
Biological Clocks
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Why do you think that you sleep at night and are
awake during the day?
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External or Internal Cues?
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What do you think would happen if you were in a
cave, in complete darkness?
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If you were in a cave .. Could you track the days
you were there by the number of times you fell
asleep and woke up?
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i.e. 1 wake – sleep = 1 day = 24 hours?
Internal Clock
Humans w/o Input or External Cues
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diurnal (active at day
constant darkness  ~25 hour clock (>24 hours)
wake up about 1 hour later each day
constant light shortens the period
Rodents
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nocturnal (active at night)
constant darkness ~23 hour clock period (<24 hours)
time of day
wake up a little earlier each day
constant light lengthens the period
Day
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Circadian Rhythms Everywhere!
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actually more rare for a biological factor to
not change through-out the 24 hour day
temperature
 cognition
 learning
 memory
 motor performance
 perception
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all cycle through-out the day
The Circadian Clock
Defined By:
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1. Period of ~24 hours
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2. synchronized by the environment
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3. temperature independent
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4. self-sustained (--- therefore inherent)
Clock Definitions
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Period (T)– time for the rhythm to repeat
T
Clock Definitions - Phase Shifts
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Phase Advance
Period (T) remains the same
External cues can shift the phase
Phase Delay
Basis of the Clock?
Self-sustained rhythm
 Inherent Period
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must be some inherent mechanism
cells … proteins … genes??
Light Dark Pattern
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modulates the Phase
“sets” the clock
(and period slightly)
What is the cellular mechanism? How does light interact?
Entrainment
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Entrainment: Causing a gradual phase shift so that the
oscillation becomes synchronized with the entraining rhythm or
signal
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Zeitgeber: entrainment signal
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German for “time” “giver”
Light Zeitgeber”:Sleep / Wake Circadian Rhythm entrains primarily
to light
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You know this
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phase shift - adjust to traveling overseas
Direction and time of day you fly makes a difference
light therapy strategies for jet lag
Zeitgeber
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All light inputs in mammals come in through the photosystem
Genes?
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Drosophila (fruit flies)
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Screened for flies with altered circadian rhythms
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convenient for genetics
mutation – behavior genetic screens
some too short
some too long
some arrhythmic (no repeating pattern at all)
What genes are mutated?
Seymour Benzer
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Purdue Physicist.
PhD from Purdue in 1947
Important role in the invention of the transistor
Cal Tech.
• became interested in genes and behavior
• highly original experiments
1. mutating drosophila
2. Sort for specific behavior changes or deficits
3. Search for the underlying gene mutation
• became the father of neurogenetics
• Discovered genes underlying circadian rhythms
Time, Love & Memory
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By Jonathan Weiner
Genes Involved?
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one of them period (per)*
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found point mutations in period
some delayed, some advanced, some
arrhythmic
found that Period (PER) levels oscillates in
single cells with period of 24 hours!
Clocks in single cells??
Are the oscillations inherent to Period?
Or does another gene / protein interact to create the oscillations?
Mathematical Model
Based on biochemical, cellular, and gene
data
 Can Period support its own oscillations?
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hypothesis:
negative feedback
knew this existed from
experimental data
question?:
can this system alone oscillate?
answered this with modeling
yes
Feedback Mechanism
make mRNA
phosphorylated protein
inhibits mRNA production
mRNA transport
into cytosol
phosphorylated protein
travels into nucleus
make protein
protein phosphorylation (2Xs)
This model can in fact support 24 hours oscillation of Per protein levels
But no mechanism for entrainment!! How does light interact?
Model … incomplete???
Goldbeter NATURE VOL 420 14 NOVEMBER 2002
Other genes?
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timeless (tim)
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timeless mutations were arhythmic
Timeless affected Period
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Per
Per
Per
Per
location
level
protein oscillations
phosphorylation
How does Period and Timeless interact?
How does light interact?
Drosophila PER TIM Model
Goldbeter NATURE VOL 420 14 NOVEMBER 2002
Leloup & Goldbeter, J . theor . Biol . (1999) 198, 445–459
Ahhh!!
Light induces TIM
degradation
fully phosphorylated
PER and TIM
form a complex
that inhibits expression
of both
Can this model simulate the experimental observations of effects of light?
Answer … most of them!! … but still a few things missing … other genes etc.
Leloup & Goldbeter, J . theor . Biol . (1999) 198, 445–459
example of simulation output
protein
oscillations
mRNA
oscillations
PER TIM
complex
oscillations
Leloup & Goldbeter, J . theor . Biol . (1999) 198, 445–459
Entrainment
Light Destroys TIM
When tim RNA is high … it delays the clock (phase delay)
Because mRNA is ready to quickly replace the destroyed TIM
When tim RNA is low … it advances the clock (phase advance)
Because mRNA is not ready to quickly replace the destoyed TIM
So effect of light depends on the tim mRNA levels
protein
oscillations
mRNA
oscillations
PER TIM
complex
oscillations
More complete known Per / Tim Feedback Loop in Drosophila
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Humans - Free Running Clock (FRP)
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Actually variation in FRPs in humans
Can be longer or shorter than 24 hrs
Entrainment depends on the FRP of the clock and the light cycle
People who like to go to bed early and get up early often have FRP <24 and
vice versa
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Suprachiasmatic Nucleus (SCN)
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Wang et al. BMC Developmental Biology 2001 1:9
A symmetric pair of nuclei
In the hypothalamus
Just behind the nose
Near the crossing of the optic nerves
Is the “master circadian clock” in the brains of humans
Circadian rhythm of firing activity of SCN neurons
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Dissociated neurons, however,
are not in phase
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Block the cells for days
And the firing rhythm emerges again with the same phase
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The circadian rhythm firing is an inherent property of individual neurons
Clock Genes Vs. Clock Controlled Genes
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Clock
genes
Clock
controlled
genes
Such as:
Temperature
Blood pressure
Cognitive
Hormones
Output Rhythms
• Secondary Oscillations in Body
• Isolated organs and cell from other part of body also display
circadian oscillations in gene expression
• Phased slightly later than the SCN “pacemaker”
• Will generally dampen out (not sustain) after isolation
• Physiological Outputs
• Blood pressure (lowest just after midnight)
• Cognitive Performance (best in mid afternoon)
• Hormones
• Cortisol (highest in morning)
• Melatonin (highest at night)
Clock Phathologies
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A type of dynamic disorder
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Appears to live 25 hour day on
average despite light dark cues
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Not properly entrained
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Has a weak zeitgeber response
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Man suffers from severe
depression
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Human Pathologies
Advanced Sleep Phase Syndrome
 Delayed Sleep Phase Syndrome
 Light Entrainment
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Impacts some blind individuals