biological dynamics

1
biological dynamics

• Dynamics how systems change/evolve with time
• Why are dynamics important to biological systems?
• Temporal behavior of proteins, cells, organisms
• metabolism, cell growth, development, protein
  production, aging, death, species evolution all
  are time dependant processes
• Inherent complexity in biological systems both in
  time and space
• temporal patterns are related to structural ones

2
traditional biological framework

• tend to think in terms of single point
  equilibrium processes
• a stable and constant steady state

time ----
time ----
3
biological dynamics can be complex

• as time goes to infinity response doesnt 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)!
4
Oscillations / Rhythms Occur in NatureAt all
time scales

• Predator Prey Population Cycles (years)
• Circadian Rhythms (24 hours)
• sleep wake cycles
• Biochemical Oscillations (1 20 min)
• metabolites oscillate
• Cardiac Rhythms (1 s)
• Neuronal Oscillations (ms s)
• Hormonal Oscillations (10 min - 24 hour)
• Communication in Animal and Cell Populations
• fireflies can synchronize their flashing
• bacteria can synchronize in a population

5
Biological Clocks

• Why do you think that you sleep at night and are
  awake during the day?
• External or Internal Cues?
• What do you think would happen if you were in a
  cave, in complete darkness?
• 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?
• i.e. 1 wake sleep 1 day 24 hours?

6
Internal Clock

• Humans w/o Input or External Cues
• 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
• nocturnal (active at night)
• constant darkness ?23 hour clock period (hours)
• wake up a little earlier each day
• constant light lengthens the period

time of day
Day
7
Circadian Rhythms Everywhere!

• actually more rare for a biological factor to not
  change through-out the 24 hour day
• temperature
• cognition
• learning
• memory
• motor performance
• perception

all cycle through-out the day
8
The Circadian Clock
Defined By

• 1. Period of 24 hours
• 2. synchronized by the environment
• 3. temperature independent
• 4. self-sustained (--- therefore inherent)

9
Clock Definitions

• Period (T) time for the rhythm to repeat

T
10
Clock Definitions - Phase Shifts

• Phase Advance Phase Delay

Period (T) remains the same External cues can
shift the phase
11
Basis of the Clock?

• Self-sustained rhythm
• Inherent Period
• must be some inherent mechanism
• cells proteins genes??
• Light Dark Pattern
• modulates the Phase
• sets the clock
• (and period slightly)

What is the cellular mechanism? How does light
interact?
12
Entrainment

• Entrainment Causing a gradual phase shift so
  that the oscillation becomes synchronized with
  the entraining rhythm or signal
• Zeitgeber entrainment signal
• German for time giver
• Light ZeitgeberSleep / Wake Circadian Rhythm
  entrains primarily to light
• You know this
• phase shift - adjust to traveling overseas
• Direction and time of day you fly makes a
  difference
• light therapy strategies for jet lag

13
Zeitgeber
All light inputs in mammals come in through the
photosystem
14
Genes?

• Drosophila (fruit flies)
• convenient for genetics
• mutation behavior genetic screens
• Screened for flies with altered circadian rhythms
• some too short
• some too long
• some arrhythmic (no repeating pattern at all)
• What genes are mutated?

15
Seymour Benzer

• 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
• mutating drosophila
• Sort for specific behavior changes or deficits
• Search for the underlying gene mutation
• became the father of neurogenetics
• Discovered genes underlying circadian rhythms

16
Time, Love Memory By Jonathan Weiner
17
Genes Involved?

• one of them period (per)
• 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?
18
Mathematical Model

• Based on biochemical, cellular, and gene data
• Can Period support its own oscillations?

hypothesis negative feedback knew this existed
from experimental data question? can this
system alone oscillate? answered this with
modeling yes
19
Feedback Mechanism
phosphorylated protein inhibits mRNA production
make mRNA
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
20
Other genes?

• timeless (tim)
• timeless mutations were arhythmic
• Timeless affected Period
• Per location
• Per level
• Per protein oscillations
• Per phosphorylation

How does Period and Timeless interact? How does
light interact?
21
Drosophila PER TIM Model
Goldbeter NATURE VOL 420 14 NOVEMBER 2002
Ahhh!! Light induces TIM degradation
Leloup Goldbeter, J . theor . Biol . (1999)
198, 445459
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.
22
Leloup Goldbeter, J . theor . Biol . (1999)
198, 445459
23
example of simulation output
protein oscillations
mRNA oscillations
PER TIM complex oscillations
Leloup Goldbeter, J . theor . Biol . (1999)
198, 445459
24
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
25
More complete known Per / Tim Feedback Loop in
Drosophila
26
Humans - Free Running Clock (FRP)

• 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

27
Suprachiasmatic Nucleus (SCN)
Wang et al. BMC Developmental Biology 2001 19
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
28
(No Transcript)
29
Circadian rhythm of firing activity of SCN neurons
30
Dissociated neurons, however, are not in phase
31
Block the cells for days And the firing rhythm
emerges again with the same phase
The circadian rhythm firing is an inherent
property of individual neurons
32
Clock Genes Vs. Clock Controlled Genes
Such as Temperature Blood pressure Cognitive Horm
ones
Clock genes
Clock controlled genes
33
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)

34
Clock Phathologies

• A type of dynamic disorder
• Appears to live 25 hour day on average despite
  light dark cues
• Not properly entrained
• Has a weak zeitgeber response
• Man suffers from severe depression

35
Human Pathologies

• Advanced Sleep Phase Syndrome
• Delayed Sleep Phase Syndrome
• Light Entrainment
• Impacts some blind individuals