lecture03-cell-physiology
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Transcript lecture03-cell-physiology
Cellular Participation
In Physiology
Jim Pierce
Bi 145a
Lecture 3, 2009-2010
Cellular Physiology
There is more to cells than just performing basal
functions.
Cellular Physiology is the study of how cells
perform both basal and tissue specific functions.
It is the bridge between molecular biology and
tissue function.
Cellular Physiology
General Cellular Physiology
The study of inputs, metabolism, and outputs.
Our goal for this lecture is to look at examples of
inputs and outputs.
Cellular Physiology
Specific Cellular Physiology
This is the study of specific aspects of cellular
function.
Our goal in this lecture is to discuss some of the
common functions: membrane function, cellular
structure, cellular motors, and secretion.
General Cell Physiology
Homeostasis versus Active Function
Often, we want to do more than
“cruise along” at status quo.
This means doing stuff
Homeostasis
What is homeostasis?
It is central to understanding physiology, and makes
metabolism much easier.
It is the property of a system to try to maintain
constancy in the face of external perturbations.
Homeostasis
Regulation
When a system maintains some variable despite
internal or external perturbation.
Control
When a force adjusts the output of a system over
time.
Refrigerator Thermostat
Glycogen in a Myocyte
Homeostasis
Figuring out the Refrigerator is easy
The thermostat controls
The “dial” indicates the set point
A circuit in the Refrigerator regulates.
It compares the actual temperature to
the thermostat’s set point
It heats or cools accordingly
Refrigerator
Cooling
Homeostasis
Glycogen is not so easy.
What controls glycogen levels?
There is no thermostat.
The myocyte does not receive a specific
“glycogen level signal.”
Homeostasis
What controls glycogen levels?
There are external signals that inform the myocyte of the
state of the body.
There are internal signals that inform the myocyte of the
state of the cell.
The cell must integrate these signals to make that
decision.
Homeostasis
The way a cell integrates these signals to
make that decision is called
A Control Structure
Homeostasis
How is glycogen level regulated?
Because there is no thermostat,
it is not a simple “compare” like the fridge
Instead the pathway “pays attention” to every
reaction, intermediate, and final product
This is called a
Regulatory Structure
Homeostasis
How is glycogen level regulated?
The Regulatory Structure is affected by
the Control Structure.
It is through those interactions that
the Regulatory Structure obeys the
Control Structure
Homeostasis
What makes up these structures?
Cells Do Chemistry.
(they do physics, too, but I don’t like physics so I won’t
talk about it)
Chemical Compounds (stuff)
Processes Involving Chemical Compounds (a way
to change stuff)
Homeostasis
Structures are composed of reactions
AB
CD
EF
Metabolism
Xsource
supply
demand
-->
M -->
(in a nutshell)
Xsink
Regulatory Network
Xsource
supply
demand
-->
M -->
(in a nutshell)
Xsink
Control Network
Xsource
supply
demand
-->
M -->
(in a nutshell)
Xsink
Why is this confusing?
The final product has the greatest effect on
the flux through metabolism
So the USE of the final product
exerts CONTROL
Regulation versus Control
So certain Regulatory structures give
“Control” to the end product
This is probably why biologists use
“regulate” and “control” interchangeably
Just remember, like precision and accuracy,
control and regulation are different!
Metabolism and its Control
So how do we describe these things?
We start with a Model of the system
Metabolic Pathway
A B C D
A set of metabolites and reactions involving those metabolites.
(note that a metabolic pathway can be described by graph theory)
Generalized Linear Metabolic
Pathway
A B C D
Generalized Branched
Metabolic Pathway
Generalized Substrate Cycle
Metabolic Network
Control and Regulation
We can then describe how any given thing
(enzyme, molecule, extrinsic parameter)
affects any other given thing
This gives a bunch of variables
This allows a mathematical model
Control in Dynamical Systems
Models That Exist:
Linear Systems
Linear Models
Non-Linear Systems
Non-Linear Models
Linear Models
Metabolism
There is more to metabolism than just the graph of
the reactions
Location of the reactions
Cytosolic, Membrane Bound, Nuclear
Job in “the bigger picture”
Anabolism versus Catabolism
Control by Supply
Feedforward Control:
1) Can achieve high control of flux
2) High control of flux forces us to have low
control of metabolites!
(That means AMPLIFICATION)
Control By Demand
Feedback Control
1) Can achieve high control of flux
2) High control of flux forces us to have high
control of metabolites!
Metabolic Control Analysis
We can prove that:
1) Feedback is the way we get control of both
flux and concentration.
2) Feedforward is the way we get control of flux
and amplification.
Internal State
The first consideration in “doing stuff”
is the Internal State of the Cell
The set of DNA, RNA, and protein (especially
“transcription factors”)
Organelles and Compartmentalization
Membrane and its Potential
Secondary messengers
Internal State
Sometimes, the decision to Activate
is the Internal State
The best studied example is Cell Cycle
There is an internal clock
(multiple, actually)
In many cases, the ticking of the clock alone is
the largest stimulus for cell division
Internal State
A closely related (and more interesting) example is
Early Development
Much of the earliest patterning results from internal
state
Distribution of Bicoid mRNA (Drosophila)
Distribution of Vg-1 protein (Xenopus)
Random Genetic and Positional Noise
(Chick rotates with gravity,
Mouse random based on position in ICM)
(Bi 182 for more info!)
Internal State
Other basal functions include:
Basal secretion in glands
Basal membrane potential patterns
Anabolism and Catabolism
for Housekeeping
Internal State
In the case of cell cycle,
the output includes:
Replicating DNA and organelles
Nuclear Division
Cytosol Division
A huge number of checkpoints
Lots of error correcting
Internal State
In the case of early development
the output consists of:
Spacial and Temporal Patterning
of space (intra and extracellular)
Interpreting “Internal state” into
Cellular Phenotype
General Cell Physiology
Obviously, though, internal state cannot be
the only cue!
In a complex organism, even making ATP
depends on the state of the organism!
(a fat cell should never steal glucose
from a starving brain cell)
General Cell Physiology
Types of Inputs:
Small Molecules
Neurotransmitters, Steroids, Peptides
Non steroid, non peptide hormones
General Cell Physiology
Types of Inputs:
Large Molecules
ICAMs, Selectins, Integrins
Lipoproteins
Other Immunoglobulins
Other Glycoproteins
Small Molecules
Why Small Molecules?
They are very versatile
They can carry information (in both
concentration and concentration gradient)
They can diffuse or be transported.
Small Molecules
Why Small Molecules?
They are very efficient
The earliest “computation” on small molecules
was probably bacterial chemotaxis
Food (i.e. reduced molecules) was transduced
into swimming behavior
Small Molecules
Why Small Molecules?
They are very efficient
This system can be harnessed by using specific
small molecules as a signal
Ever notice that many neurotransmitters are
decarboxylated amino acids?
Small Molecules
Examples of Small Molecules
Addition / Integration
Two inhibitory cells both release GABA onto the
same dendrite, increasing hyperpolarization
Each parathyroid cell releases hormone into the
blood, and response is a function of “total
hormone” levels.
Small Molecules
Retention
Insulin binds to its receptor and is internalized,
providing continued signaling.
Degredation
Serum Catecholamine-O-Methyl-Transferase has
different rates of catecholamine removal than
neuronal reuptake machinery
Small Molecules
Gradient
Retinoic Acid (vitamin A) and HOX genes
DPP in certain non-mammal animals
Target
Autocrine – stimulates self
Paracrine – stimulates neighbor
Neurocrine – neural synapse
Endocrine – stimulates distant cell via blood
Neuroendocrine – neural secretion into blood
Large Molecules
Why Large Molecules?
They can “mark” an area of extracellular space.
(i.e. they stay put)
They convey information about tissue structure
(both cell-cell and cell-ECM).
Large Molecules
Consider Neural Crest Cells
Early development “encodes” space with a set of
small molecules, gradients, and large molecules.
Neural crest cells migrate through this space, using
the cellular computer to respond to spacial
differences
Large Molecules
Consider a skin injury…
The cells at the edge of the injury lose the
suppressing signal from cell-cell adhesion
receptors.
…But they cannot grow without the stimulating
signal from the basement membrane.
Large Molecules
Thus, these large signals are key to tissue
functioning.
We spend so much time thinking about the
small signals (Bi/CNS 150) that we
sometimes forget how much information is
encoded in these large molecules.
Large Molecules
Every time two cells stick together, they are
communicating
Every time a cell sits in the extracellular
matrix, it is listening to its surroundings
General Cell Physiology
Also remember: a huge portion of the signals
are suppressive.
In the brain…
On the basement membrane…
In the glands...
General Cell Physiology
Secondary Messengers
yuk.
Secondary Messengers
Words of advice about these guys:
Anything can function as a secondary
messenger if it can convey information, such
as small molecules, assembled structures,
and even the membrane itself.
Secondary Messengers
Always think about the cellular compartment where
the secondary messenger is located; different
compartments have different properties.
The surface of the membrane is two dimensional, and
therefore is better for diffusion.
Cytosolic messengers can overcome three dimension
diffusion by assembly.
On the flip side, cytosolic messengers can also change
compartments and locations in the cell.
Secondary Messengers
Do not fall into the trap of thinking of certain
messengers as “activating” or “suppressing.”
cAMP
cGMP
Ca++
Secondary Messengers
“Secondary messengers” only get their name
because they're supposedly restricted to the
cell itself.
Some hormones (steroids) compute like
secondary messengers
Some secondary messengers (nitric oxide) can
change cells like hormones.
General Cell Physiology
Concept Questions?
Cancer
We talked about:
Homeostasis
Regulation versus Control
How one could actually study it
Now:
Cancer
Cancer
Tumor
Tumere – “swelling”
What can cause swelling?
Too Many Cells
Too Much Extracellular Matrix
Too Much Fluid
Neoplasm
Neo – “new” Plasm – “growth”
Too Many Cells
Cancer
Neoplasm
Benign – Cells stay where they are
Malignant – Cells invade somewhere new
Often benign ends in –oma (lipoma)
Often malignant ends in
-carcinoma = malignant from epithelium
-sarcoma
= malignant from meso/endothelium
Cancer
Is benign “benign?”
A benign fatty growth that squishes the trachea
and suffocates the patient
Is malignant “malignant?”
A slow growing skin cancer that never causes
any symptoms and the patient
dies 20 years later of a heart attack
Cancer
Cancer
Multi-Hit Theory
Cancer doesn’t develop overnight
After “watching” many different tumors, one
begins to notice a progression.
Over time, the tumor gets uglier, bigger,
grows faster, and grows in new places.
Multi Hit Theory
The multi-hit theory was proposed simply by
watching the DNA
The older or more severe the tumor…
… the more DNA mutations that
could be found.
Multi Hit Theory
So it was hypothesized that cancer develops
by sequential epigenetic mutations
In that case, a predisposition to cancer occurs
from germ line mutations, which is how
many important genes were found
Multi Hit Theory
Further Support arrived with the
identification of viruses that induce cancer
These viruses contained mutated genes
v-myc (v-genes in general) = Viral myc
c-myc (c-genes) = Cellular myc
Multi Hit Theory
These viral genes were called
Oncogenes – (onko (greek) – mass )
Their corresponding cellular genes were called
“proto-oncogenes” (proto – first)
They behave (generally) as
gain-of-function phenotype
Multi Hit Theory
Another class of genes were described that
provided “resistance” to carcinogenesis
from viruses
These genes were called
Tumor Suppressor Factors
They behaved (generally) like
loss of function phenotype
Multi Hit Theory
So the multi-hit theory is the idea that cancer
arises through a series of steps
Each one corresponds to a “gain of function” or
“loss of function” mutation
in a specific gene
Thus explaining what surgeons had been
observing since Brahman period medicine in early
India
Multi Hit Theory
But that implies that cancer is
“Growth out of control”
Uncontrolled Cell Cycle, which accelerates
and accelerates.
Cancer
So why is it so difficult to grow
cancer cells in a dish?
Cancer
Primary Cultures
Died if they weren’t attached to a surface
Died if there were too many
Died if there were too few
Died without serum or growth factors
Died with too much serum or growth factors
…And often just died anyway
Cancer
HeLa cells
1951 – Johns Hopkins Medical School
Henrietta Lacks, mother of four
Cervical Cancer cells were cultured by George
Gay, MD without permission.
They grew “horrifically”
Cancer
Prior to HeLa cells, primary cultures
of human cells had a “finite” lifespan
Just to keep them alive for a week took the
addition of “serum” with its panoply of
unknown factors.
Cancer
So how could cancer be so awful,
if it won’t even grown in a dish?
The answer lies in “phenotypes”
Cancer is better thought of as a
“Disease of Gain-of-Phenotype”
Cancer
There are many different phenotypes:
Needs
basement membrane
neighboring cells
growth factors
Abilities
Secretion, Absorption
Metabolism
Cell Cycle
Computation
Cancer
These include “new” or “unusual”
phenotypes:
Invasion through basement membrane
Ability to migrate
Ability to live in a new milieu
Blood
Lymph Nodes
Other Tissues
Cancer
Evasion of Immune System
Resistance to killing (similar to viruses)
Resistance to Aging
Telomeres
DNA Damage
Cancer
Secretion of Hormones
Autocrine Stimulation
Growth Factors
Recruitment of “support” (angiogenesis)
Cancer
So every tumor is a different combination of
“phenotypes”
Disease progression is sequential addition of
new phenotypes, each which result from
mutations
Cancer
External / Internal signals for survival
Gaining proliferative phenotype
Losing apoptotic / senescent phenotype
Gaining metastatic phenotypes
Avoiding immune respone
Angiogenesis and other novel phenotypes
Cancer
These mutations often make the cell appear
less differentiated and more multipotent.
So in many ways, understanding Cancer is
very similar to understanding Stem Cells
(and their differentiation phenotypes)
Cancer
For more on Clinical Aspects of Cancer
Try out my brand new Bi 23, Winter 09-10
Cancer Examples
Esophageal Adenocarcinoma
Fastest Rising Western Cancer
(~500% in the last 30 years)
Normal Esophageal Mucosa
Normal Layers
Esophageal Cancer
Chronic gastroesophageal reflux
Leads to Acid and Bile Exposure
The cells
will try to
protect
themselves
Barrett’s Esophagus
With Esophagitis
Esophageal Cancer
To defend itself, the cell “gains” the
phenotype of “mucous secretion”
Normal
Barrett’s
Esophageal Cancer
This is called “metaplasia”
- Metaplasia is when one tissue type changes to
another tissue type that “naturally” occurs in the
body in a different location
Metaplasia requires that the cell respond to
stimuli and change phenotype
Esophageal Cancer
The mechanisms of metaplasia depend on
the tissue and stimulus, but often involve
DNA damage
In the case of Esophageal Cancer, bile acids
are carcinogenic
Skin Cancer – UV light
Lung Cancer – Smoking
Cervical Cancer – HPV
Esophageal Cancer
Not surprisingly, continued acid exposure
allows progressive accumulation of DNA
damage
It becomes carcinoma when:
It grows without regard to neighbors
It is able to cross the basement membrane
Esophageal Cancer
Barrett’s
Adenocarcinoma
Adenocarcinoma
Cancer Progression
What we see is:
Primary Injury (bile)
Progressive DNA damage
Gain of Phenotypes
“Pre-Cancer” – not yet across the
Basement Membrane
“Cancer” – crossed over
Metastasis – gone somewhere else
Good Cancer / Bad Cancer
Why focus on cell cycle and apoptosis?
Removing checkpoints and error correcting
facilitates gain-of-phenotype
Apoptosis is the solution for excessive DNA
damage, broken apoptosis leads to proliferation
despite severe damage.
Questions?