Systems biology course 2018 Uri Alon - Lecture 8 A - Dynamic Compensation
Summary
TLDRThis lecture covers dynamic compensation in physiological circuits, focusing on robustness in biological systems. It explores how biological circuits maintain stable function despite natural variations, such as organ size control, glucose regulation, and resistance to mutations. The discussion moves from cell-level circuits to organ-level communication, particularly focusing on the glucose-insulin circuit. The lecture emphasizes how organs maintain their size despite continuous cell turnover, and how insulin sensitivity and resistance play a key role in glucose regulation. Real-life examples, such as diabetes and pregnancy-induced insulin resistance, are used to demonstrate these principles.
Takeaways
- 📚 The lecture focuses on dynamic compensation in physiological circuits, emphasizing the robustness of biological systems to natural variations.
- 🔬 Robustness in biological circuits is defined as the insensitivity to naturally occurring variations, which is crucial for precise functioning.
- 🐕 The lecture welcomes all species, highlighting the universal presence of physiological circuits in different organisms.
- 🧬 The discussion transitions from cellular to physiological levels, examining how organs communicate through hormones like insulin to maintain homeostasis.
- 🩸 Glucose homeostasis is critical for health, with the body striving to maintain blood glucose levels within a narrow range for optimal brain function.
- 💉 Insulin, produced by the pancreas, is central to glucose regulation, prompting cells to take up glucose and lower blood sugar levels.
- 🏋️♀️ Insulin sensitivity varies and can be influenced by factors like exercise, infection, and obesity, affecting how effectively insulin works.
- 📉 The body can compensate for changes in insulin sensitivity, maintaining glucose dynamics despite significant variations in this parameter.
- 🤰 Insulin resistance is a common issue, especially in Western societies, and can be influenced by factors like obesity, lack of exercise, and aging.
- 📊 The classic glucose tolerance test is used to measure how the body handles glucose, providing insights into insulin sensitivity and glucose regulation.
Q & A
What is the main topic of the lecture?
-The main topic of the lecture is dynamic compensation in physiological circuits, focusing on robustness in biological systems and how it applies to the communication between organs in our body.
What is meant by robustness in the context of biological circuits?
-Robustness in biological circuits refers to the property where these systems remain functional and maintain their performance despite naturally occurring variations.
What is the concept of 'network motifs' mentioned in the lecture?
-Network motifs are recurring circuit elements that carry out different computational functions within biological networks.
How does the concept of exact adaptation apply to bacterial chemotaxis?
-Exact adaptation in bacterial chemotaxis refers to the ability of bacteria to maintain a constant tumbling frequency despite changes in their environment, such as the presence or absence of food.
What is the role of insulin in the body as discussed in the lecture?
-Insulin is a hormone that stimulates the uptake of glucose from the blood by cells like muscles, fat, and liver, thereby helping to regulate blood sugar levels.
What is insulin sensitivity and why is it significant?
-Insulin sensitivity refers to the effectiveness of insulin in promoting glucose uptake by cells. It is significant because it can vary under different physiological conditions and is a key factor in glucose homeostasis.
How does the body maintain a stable organ size despite cells constantly dividing and dying?
-The body maintains stable organ size through a balance between cell division and cell death, ensuring that the overall size of organs remains constant throughout adulthood.
What is the glucose tolerance test and why is it important?
-The glucose tolerance test is a procedure used to determine how well the body processes glucose. It is important for diagnosing conditions like diabetes and understanding how the body handles glucose after a meal.
What are some factors that can influence insulin resistance?
-Factors that can influence insulin resistance include obesity, lack of exercise, aging, infections, and certain hormonal changes such as those that occur during pregnancy.
How does the body compensate for changes in insulin sensitivity?
-The body compensates for changes in insulin sensitivity by adjusting the amount of insulin produced and secreted by the pancreas, as well as by tuning the sensitivity of cells to insulin.
What is the minimal model for glucose-insulin dynamics mentioned in the lecture?
-The minimal model for glucose-insulin dynamics is a mathematical model that describes how glucose levels in the blood change over time in response to insulin and other factors, such as meal intake.
Outlines
🧬 Introduction to Dynamic Compensation in Physiological Circuits
The lecture begins with a focus on dynamic compensation within physiological circuits, emphasizing the concept of robustness in biological systems. Robustness is defined as the insensitivity of biological circuits to naturally occurring variations. The lecture builds upon the previously discussed principle of network motifs, which are recurring circuit elements that perform different computational functions. The speaker highlights the challenges that biological circuits face due to the inherent problems in biological materials and aims to explore how these circuits maintain precise operations despite these challenges. The lecture also introduces the idea of moving up a level of organization from individual proteins within cells to entire organs that communicate with each other through hormones and other signaling mechanisms.
🌡️ Exploring Robustness in Hormonal Communication
This section delves into the robustness of hormonal communication between organs, using the example of glucose and insulin regulation. The speaker discusses the importance of maintaining proper glucose levels in the bloodstream, as both high and low levels can be detrimental to health. The lecture explains how the body uses insulin, produced by the pancreas, to regulate glucose uptake by muscles, fat, and liver. The concept of insulin sensitivity is introduced, which refers to the effectiveness of insulin in promoting glucose uptake by tissues. The speaker also touches on how insulin sensitivity can vary under different physiological conditions, such as exercise, infection, and pregnancy, and how these variations are managed by the body to maintain glucose homeostasis.
🩺 The Glucose-Insulin Feedback System
The paragraph explains the feedback mechanism between glucose and insulin in the body. When blood glucose levels rise, such as after a meal, the pancreas releases insulin. Insulin then signals cells in muscles, fat, and liver to take up glucose, thereby reducing blood glucose levels. The speaker simplifies the complex physiological process into a mathematical model to illustrate how the body can maintain a stable glucose level despite variations in insulin sensitivity. The model is a differential equation that represents the balance between glucose input from food and glucose removal by tissues, modulated by insulin sensitivity. The lecture aims to demonstrate how such a model can help understand the body's ability to compensate for changes in insulin sensitivity and maintain glucose levels within a healthy range.
🏋️♀️ Impact of Insulin Sensitivity on Glucose Dynamics
This section discusses how insulin sensitivity impacts glucose dynamics in the body. The speaker explores the physiological mechanisms behind insulin resistance, which can occur due to various factors such as obesity, lack of exercise, and aging. The lecture explains that insulin resistance is a significant health issue, particularly in Western societies, and is associated with conditions like type 2 diabetes. The speaker also addresses the question of why the body would evolve a system that includes insulin resistance, suggesting that it serves a purpose in resource allocation during different physiological states, such as during exercise or infection. The lecture emphasizes the importance of understanding not just the 'what' and 'how' but also the 'why' behind biological processes.
📚 Mathematical Model of Glucose and Insulin Dynamics
The speaker introduces a mathematical model of glucose and insulin dynamics, which is crucial for understanding how the body maintains glucose homeostasis. The model is a differential equation that describes the change in glucose levels over time, influenced by meal intake and glucose removal by tissues. The removal rate is determined by insulin sensitivity (s), the amount of insulin (I), and the effectiveness of insulin in promoting glucose uptake. The speaker highlights that while this model is widely used in clinical settings to interpret glucose tolerance tests, it does not fully explain the body's ability to compensate for changes in insulin sensitivity. The lecture encourages students to think critically about the models and to consider the broader implications of parameter changes in biological systems.
🔍 Measuring Insulin Sensitivity and Its Clinical Relevance
In this part, the speaker discusses how insulin sensitivity can be measured clinically and its importance in understanding an individual's response to insulin. The measurement involves injecting a unit of insulin and observing the subsequent decrease in blood glucose levels. This method provides a quantitative measure of s, the insulin sensitivity parameter. The speaker emphasizes that understanding insulin sensitivity is crucial for managing conditions like diabetes and for personalizing treatment strategies. The lecture also touches on the dynamic nature of insulin sensitivity, which can change rapidly in response to physiological needs, such as during exercise or infection, and how these changes are clinically relevant.
Mindmap
Keywords
💡Dynamic Compensation
💡Physiological Circuits
💡Robustness
💡Network Motifs
💡Bacterial Chemotaxis
💡Insulin
💡Glucose Tolerance Test
💡Insulin Resistance
💡Hormones
💡Cytokines
Highlights
Introduction to dynamic compensation in physiological circuits and the concept of robustness in biological systems.
Review of network motifs as recurring circuit elements carrying out different computational functions.
Discussion on how biological circuits maintain precise function despite naturally occurring variations.
Explanation of robust input-output relationships in phosphorylation circuits.
Introduction to bacterial chemotaxis as an example of robustness in biological systems.
Concept of exact adaptation and integral feedback in maintaining steady state in biological circuits.
Shift in focus from cellular to physiological level, examining organs and their communication through hormones.
Importance of maintaining organ size despite constant cell turnover.
Challenges in inter-organ communication due to variations in parameters and the need for robustness.
Addressing the issue of mutations in cells and their impact on robustness.
Overview of the hormone circuit for glucose and insulin as a well-characterized example.
Role of insulin in glucose uptake by muscles, fat, and liver, and its regulation by insulin sensitivity.
Function of the pancreas and beta cells in insulin production in response to blood glucose levels.
Variability in insulin sensitivity and its impact on glucose dynamics.
Physiological mechanisms behind changes in insulin sensitivity, such as during infection or exercise.
Discussion on insulin resistance, its causes, and its implications in society and health.
Exploration of how the body compensates for changes in insulin sensitivity to maintain glucose homeostasis.
Introduction to the minimal model for glucose and insulin dynamics and its limitations.
Invitation for feedback on the course material for the development of a textbook.
Transcripts
everyone welcome to our lecture on
dynamic compensation in physiological
circuits we're gonna turn off the music
and but as always let's invite you to
take a nice deep sigh of relief I love
the way the class is getting better and
better at letting out a you know I want
a ridiculous sound because that's when
you're really relaxed and it's review
and of course you know we finished the
the first part which was about principle
of network motifs the recurring circuit
elements that carry of different
computational functions and now we're in
the second part of the course about
robustness robustness is a property of
biological circuits where they're a
central feature is insensitive to
naturally occurring variations so we're
learning more and more about the
problems in biological material the
problems which circuits have to overcome
in order to work precisely and so far
we've been a nice deep sigh of relief
welcome there's even a dog it's great
great another sigh of relief for the dog
what's his name - Lee classic yeah yeah
all species are welcome another
really because all species actually have
all these physiological circuits we'll
talk about today about the hormones
stuff super and actually dogs played a
big role you know and so we talked about
so we said that robustness of what of a
feature with respect to a variation that
occurs naturally so we talked about for
example how to have a robust
input-output relationships in a circuit
a circuit phosphorylation circuit it's
saying by having these by functional
components and then if you vary the
concentration of the proteins you don't
get input output to change and we talked
about bacterial chemotaxis have material
sense and food and they change your
tumbling frequency the tumbling
frequency and has some level and then
when if they sense food it goes back to
the same level so this is the property
of exact adapt ation and how we can
build circuits that have exact
temptations basically differential
equations where they where the output
appears the only way to get a zero is
for the output to be at its steady state
level that's we call that integral
feedback they'll play a role today too
so I'll review it if you don't worry and
we talked about full change detection
which is the ability of systems to
respond to fold change there's a
relative changes is to normalize out if
you give them an input a constant and
multiplies that input we talked about
these forms of robustness and we all so
far we talked in this course about
basically about cells like bacteria and
about the cell we started the cell is
the level of organization that we worked
on how to cell sensor the environment
how it computes how it responds and
today what I want to show you is that
you can take very similar equations and
ways of thinking and go up a level of
organization so now instead of proteins
inside cells that make a circuit we're
going to talk about cells that
communicate with each other making each
other / etc
and the context we'll talk about is
organs in our body so we're going to
move to the physiological level our
body's made of organs brain liver
pancreas muscles etc and these organs
talk to each other a lot of times
through the bloodstream by secreted
hormones for example send messages to
each other in order to keep us in a good
balanced situation all the thousands of
important parameters in the body like
blood sugar calcium are kept there good
level so that our brains can work our
body can work and this is done by
circuits of communication between organs
and between the cells and the organs
right so we're talking this level and
I'd like to demonstrate how our way of
thinking applies to the physiological
level too but in the physiological level
this level of organs there are new
problems to overcome we don't need to
worry now about fluctuations of proteins
inside the cell we have more dangerous
problems to think about we should for
example and the organs in our body the
cells turn over all the time they divide
and die and the cells basically replace
themselves every let's say few weeks and
still the body organs keep their proper
size it's not the deliver expands or
shrinks right it stains basically the
same size throughout adulthood
how do organs keep their size even
though they're made of exponentially
dividing cells so we'll talk about this
problem of so organ size control
big big issue and this check how come
our bodies right when I say the word
body a million cells in my body divided
and another million died and if that's
just a little bit different I'll soon
explode if it's more diversion or
degenerate if it's more death right how
does that work it's critical question
right also when you have this
communication between organs the liver
doesn't know the parameters of the brain
and the muscle sitter those parameters
can change so how can you communicate
despite variation in the parameters you
can say in the listening ability of
distant tissues distant organs and
finally our our bodies that says cells
are constantly turning over it's
inevitable that you'll get a mutation a
dangerous mutation that can let's say
make the cell now sense to sensitive or
insensitive to a signal so how do you
deal with that problem now robustness to
see resistance to mutations that are
guaranteed to to arise because there's
so many divisions you know when you
reach old age and more and more
mutations so we're going to deal with
these three naturally occurring
variations and see how how it basically
a really elegant circuit in our body it
can it's once deal with all three so
they say three problems solved in one
any questions so far about the
motivation for this lecture
I'm positive there is a question who's
going to ask the question you okay so
that's the mystic a nice deep sigh of
relief
things are so crystal clear and so we
looked at the cell circuits organs and
I'm going to talk here just to
demonstrate this about the probably the
best characterized hormone circuits
communication between tissues and that
is the famous a hormone circuit for
glucose and insulin yeah
just wondering how many of you have
heard of insulin so majority so I want
to describe the circuit a and and see
how how it deals with these problems
we can have the privilege of dealing
with problems that can be solved in
principle and not think about the news
at least for the next hour and a half
you know okay let's take a nice deep
sigh of relief yeah and so when you look
at one of the important parameters
that's in the body is blood sugar
glucose glucose is the sugar not only
bacteria love it ourselves love it it's
the main fuel of the brain and it's it's
very important to have a good level of
glucose because if it drops you can
faint this beer doesn't enough energy
you can die because the brain makes
alternative energy sources which are
acidic and you can you can basically die
from too low glucose too high glucose
it's a big problem it causes the
symptoms of diabetes it starts getting
attached to different proteins in the
body and messing up our blood vessels
and you have these symptoms I think
you're all aware of so you need to keep
glucose in a good level and indeed if
you do a blood test you'll see that you
supposed to have five milli molar
glucose and plus minus 10% is the normal
range so different people here in the
room at different times have a set point
well five millimolar then when you're
fasting at night because deliver deliver
makes glucose for you when you're not
eating and then when you eat a meal the
sugars are absorbed and glucose Rises
right and causes the glucose called G of
T to rise but then it goes back to five
millimolar
so in the classic glucose tolerance test
for instance there's a lot of people in
pregnancy a good you get 75 milligrams
of glucose to drink that's disgusting
and then you measure glucose in the
blood this is the meal input okay and
goes up and then it goes down so it goes
back to five millimolar maybe goes up to
six seven something like that within
about an hour now different people not
only have the same five millimolar
different people have the same dynamics
in this glucose tolerance that's
different I mean people who are healthy
people so different people of the
ZeniMax if you get this that's if you
get eleven millimolar after two hours
that's that's that's a criterion for
diabetes so these dynamics are very well
controlled they explain myself so far so
we want to understand this this five
millimolar setpoint and in the entire G
of T dynamics after given very little
very controlled stimulus now when the
body really you eat you have all x
sugars fats amino acids they all play
into this I'm going to ignore everything
but glucose input and ignore a lot of
other details in order to just get to
the essence so we're so we said five
molar glucose the glucose tolerance test
you know what what makes this go back is
glucose is removed and so what makes us
go back is basically the body all those
organs I feel like must
in fact they take up glucose from the
blood removed and this removal by
muscles for example muscle fat liver and
removal is stimulated by a hormone
called insulin so different cells in our
body
send the muscles have receptors for
insulin and when they sense insulin they
make and put into the membrane pumps
that transport glucose from the blood
and therefore remove glucose from the
blood they explain myself then they make
pumps the take glucose from the blood
and glucose levels go down know what who
makes insulin so we have a little organ
in our body called the pancreas I love
love and on this Oregon it does a lot of
things are tiny little islands of South
of a thousand cells each a million
little islands like that made of special
cells called betta cells make insulin
produce insulin that's their main job
their insulin factories yeah and and
when glucose is in the insulin a in a
rate that depends and increases with
glucose in the blood so the more glucose
the more insulin the more insulin the
last glucose so here is the better cells
they have some function he sends how
much glucose new reason they produce
insulin and insulin increases the
removal rate of glucose
there's an important parameter here
called insulin sensitivity which is the
effect of one unit of insulin on glucose
removal so this has to do with what I
said how distant tissues can hear you so
different distant tissues a given unit
of insulin can be more or less powerful
in removing glucose and soon read write
the equations and yeah yeah typically
normally different tissues have
coordinated needed sensitivity yes and
if they don't that's a problem that
effect that's it that's a disease state
you can say and this instant sensitivity
is is used by the body it's not just
varying for no reason it's used by a
body because the body wants to allocate
glucose properly so if you're exercising
for example for a long time the body is
going to make the cells in your whole
body more sensitive to insulin so that
means that they're giving them out of
insulin the body takes more glucose your
muscles take more glucose because you're
exercising it so exercise make this
insulin sensitivity go up but things
like a infection now you have a pathogen
and basically your immune system which
is in the blood primarily needs a lot of
glucose so what it does is mix the
muscle and all the other tissues take up
less so you have more glucose in the
blood that the immune system can use it
I know also the bacteria can use it but
it's more important the immune system
can use this so s goes down so this is
called insulin resistance and maybe
you've heard of insulin resistance it's
a big problem in our society in Western
world because insulin resistance also
happens with obesity
it happens with lack of exercise
it happens with does anybody know
insulin resistance with age what else
insulin resistance how many of you heard
of insulin resistance this issue okay
and and so this parameter changes it's
changes that's a fact and it's different
physiological situations change it it
varies between people that say by a
factor of ten but but I still want to
say most people with obesity let's say
I'd say 80% of people with publicity
which I should say which all have all
people to visit of insulin resistance
but they still have normal glucose five
millimolar normal dynamics so despite
let's say a tenfold variation in how
much they're distant issues here insulin
so there's s is a tenth of that of a
lean person let's say detain the five
millimolar and the dynamics in the
glucose are on distance are fine yeah
what is the physiological mechanism for
instance sensitivity and so an infection
I think it's in kind of immune cytokines
that are sensed by the body which is a
sign of affection and they make the
signaling system that sends insulin less
active so there's like you can think of
the receptor in the cells and all the
signaling mechanism can be tuned by
other physiological systems also in
pregnancy agency where pregnancy the
fetus secretes hormones into mom that
makes the mother insulin resistance why
does that make sense it means that after
a meal mom takes less glucose into her
system and more goes to the fetus so
it's a and in pathological situations
you can get pregnancy induced diabetes
which is why a lot of people will
impress me take this glucose tolerance
test to make sure that things are fine
or not they explain myself what can I am
saying that a the a pregnancy induces
insulin resistance and now depends on
the person lifestyle resist a genetics
it said or whether we get diabetes and
we'll talk about how you get diabetes in
this lecture you'll end this lecture I
hope your understanding is there at
least one way of thinking about and a I
think that off
does anybody know here does it after
pregnancy does it can you still stay
yeah it can stay yeah it's also high
risk for type 2 diabetes later right
yeah your name is then in your where do
you work yeah
rotation thank you in your last name one
benefit okay so I just wanted to give
credit there's a lot of knowledge here
yeah yeah so can you reduce resistant so
the princess you know what in diabetes
prescription is changing diet and
exercising right so exercise definitely
improves it's a great great thing to do
yeah and fasting and I'm not
yeah fasting yeah the diet rates in
general diet dietary changes will affect
insulin resistance and it will affect
also in the circuit because of this
input yeah so the timescale of the
resistance I think that tensile
resistance resistance can change quite
dynamically so it's because the body
needs to it's basically the resource
allocation which part of the body now
needs more or less glucose and it's
fizzy but it's good resistance it's good
it has an involved purpose to allocate
resources so it's a dynamic thing shall
we continue
yeah why or how okay so let's talk about
this we have what how and why so thanks
for asking it's really important because
of course it's not obvious when I say
what I say
things like what are we working on
insulin resistance and then how what is
the mechanism of this resistance so I
can say let's say and in the case of
infection it's the site of certain
cytokine that binds receptors in the
cell the changes gene expression to
affect the insulin binding pathway to
make it let's say more have a higher
amplification that's a how then the Y is
usually an evolutionary question so
exercising means your muscle needs more
energy so if you make us bigger a given
unit of insulin will make put more more
glucose into your muscle into your liver
into your and all the our organs of
concern so that's the the why so there's
usually what how and why in this course
we talk about
all three hey hopefully right so this
why why a could be a robustness
principle how is it achieved so thanks
it's really I love this I love this
point about how what and how what and
why in biology and so we talked about
insulin muscle liver fat insulin
sensitivity obesity insulin resistance
and now we can ask how do we understand
how is it that people can have 10 fold
lower s but identical dynamics in
basically a differential equation in a
feedback circuit how can you change the
parameter by 10 an important parameter
and still have dynamics that are
identical there's hardly any equations
it to do that it's very unusual okay and
just to demonstrate that I'm gonna write
down the standard model for glucose
insulin which is used it's important
actually was developed in 1979 and and
it's used to interpret these glucose
tolerance tests the clinically relevant
model that's actually in the example of
mathematical model that had big impact
on medicine hey but I'll show you it
doesn't address this particular question
it doesn't explain sensitivity to what's
the point what's the point of changing
of the physiological changes in s what I
said that most obese people people with
obesity you should say and remember
they're people because there's a
question of time skills so when you
write after you change the parameter you
get an effect on resource allocation but
I'll show you the compensation if you if
the parameter change is different for a
long time weeks the system can
compensate for it
understand why that is so this this is
the situation so there's a fast time
skill where you change resources
exorcising infection days let's say and
then the slow time skill where you want
you don't want to be away from your set
point for for very long so that's that's
what happens yeah so thanks these
questions really help because you know
this is a new chapter in the book I'm
writing up these new chapters and
putting it you know for you on the
website and also the movies are there
and I hope you can how many people have
seen the movie movie of the course so
far ok so I want to know and also I'm
going to ask you guys to comment on the
PDFs of the book chapters because your
input could help me write this text of
second edition of the textbook and prove
it for other people to benefit so if you
get the PDF and you write comments on it
and you said to me I'll be very grateful
ok I'm going to stop with the question
now okay I'm gonna write the minimal
model I can't can't wait to write the
minimal model so I'm gonna just do it
and and how would I do it I'm gonna just
do it right so again what we're doing
this in our course is translating
biology into math so the point will be
the dis minimal model explains a lot of
things but not this ability to
compensate for the parameter so what I'm
going to write I'm gonna write how
glucose changes with time so glucose
changes with time is M this is the meal
input fine and now it's removed so
removable remember it's always glucose
times the removal rate like in so far we
talked about removal by cell growth and
dilution here it's removal by other
different tissues taking up glucose and
and and the removal rate is this s times
I because and the more insulin there is
the more removal and s is this parameter
insulin sensitivity how much a unit of
AI affects the removal so this is
insulin sensitivity and I of course is
insulin any questions about this
equation yeah
that's right thank you so this number s
depends on the number of receptors and
on many many molecular details
downstream of the receptors all the
phosphorylations everything that allows
you to tune the gain of this of this
amplifier a little bit like we talked
about these input-output relationships
now you amplify them or should I explain
myself yes that's all rolled up here so
we're talk about a level of organization
out of organs we have parameters that
including them let details on the lower
level of organization all the proteins
in the phosphorylation that's what
happens when you do multi each scale
like if I talked about glucose it's made
of carbon atoms that have electrons and
protons but I don't care about that they
can roll them up into chemical
properties of glucose they do care about
yeah yeah how you measure yes thank you
yes of course you can measure clinically
by the following you inject a unit of
insulin and you measure blood glucose
and you see how this unit insulin causes
a reduction in glucose you don't take a
meal you increase insulin yeah it's
increased insulin and see how glucose
goes down that's how you can give a
number a number for s for a given person
okay this is urgent
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