good afternoon everyone welcome I'm Clayton rose I'm the president of the
college I would like to welcome in particular our families who are back for
family weekend it is awesome to have you here
today's common hour is the 2017 Arnold D Cates lecture and it's sponsored by the
Arnold E Cates lecture fund the fund was established in 2000 by Mark Garnica
Bowden class of 1968 and his wife Bobby Kate's carnac and honor of Bobby's
father the original purpose was to celebrate creativity and innovation in
health-related fields and to share that information broadly and the garlic's
more recently have expanded the terms of the fund to include other areas of study
and going forward the Cates lecture will become a regular part annually of family
weekend the program that you've received provides information about mr. Cates and
the reasons that he inspired the fund as well as about mark and Bobby and I
encourage you to read about each of these accomplished members of the Bowden
family we are very fortunate to have Bobby and Mark with us here today and I
invite you to join me in recognizing them for their great generosity to the
College
I am delighted to be introducing our guest speaker this afternoon Erin O'Shea
Erin is president of the Howard Hughes Medical Institute as well as the Paul C
Mangelsdorf professor of molecular and cellular cellular biology and of
chemistry and chemical biology at Harvard University I can't do that all
in one breath erin is also a friend and a colleague I've been fortunate enough
to serve as a trustee of the Howard Hughes Medical Institute for a number of
years and have gotten to know Erin very well in addition to being one of the
nation's most accomplished scientist she is a visionary leader and is leading
HHMI into some exciting new areas and the Institute for those of you that
don't know it is the nation's largest private funder of biomedical research
and an organization that is at the center of setting the agenda for basic
scientific research in this country erin was named an HHMI investigator in 2000
she was elected to the National Academy of Sciences in 2004 and both of these
speak to her position as one of a handful of the leading scientists in our
country today she became HHM eyes chief scientific
officer in 2013 and in 2016 was elected president of the Institute she earned
her PhD in chemistry from MIT and a bachelor's degree in biochemistry from
Smith College another great liberal arts college it's too bad it wasn't in
Midcoast Maine on but we're not all perfect erin is regarded as a leader in
the field of gene regulation signal transduction and systems biology and her
research focuses in the way that cells sense change and adapt to that change
and it has deep implications for among other things cancer and other related
diseases in her talk today how cells keep time the cyanobacterial circadian
clock Erin will help us understand how it is that cells actually do keep time
and more generally how it is that scientists think about the process of
discovery and research it is my pleasure to welcome Erin O'Shea to Bowdoin
College
okay Thank You Clayton for that wonderful introduction and also really
for this opportunity to come here I've had a terrific day and a half so far and
I'm really delighted to have this opportunity to share with you some of
the work from my lab and although the topic may sound a little Baroque as
Clayton alluded to I've I've selected this topic in the spirit of this day and
the poster symposium that will follow in which students will present their
research I thought given that context it would be appropriate for me to talk
about some of the work from my lab how we select questions to address in
biology and then how we try to answer them and I'm going to tell you today
about what I think is really just a remarkable aspect of biology and that is
the fact that within almost all of the cells in our body and in the bodies of
many other organisms reside ways of keeping track of time and so those are
clocks if you will inside of cells they're called circadian as you'll see
because they keep track of time with 24-hour period isset e meaning they
repeat every 24 hours and so this really is a remarkable thing when you think
about it right that we have ways of keeping track of time inside of
individual cells and so I want to tell you a bit about what we've learned about
how cells keep track of time and why this might be generally and interesting
okay so so as I said circadian clocks our 24-hour biological oscillators so
all this means as I said is that they are clocks that keep track
time with 24-hour period isset e so this wristwatch here which has 12 numbers on
it keeps track of time with essentially 12 hour periodicity right so if i pick
any point on this wristwatch it takes 12 hours to get back to this same point and
that's what I mean by periodicity and we'll talk about this on the next slide
so these clocks keep track of time with 24-hour period isset e so if I start at
a given point it takes 24 hours to get back to that same point these clocks are
critical for controlling a number of aspects of physiology inside organisms
organisms like humans but also organisms like the fruit fly shown there which
we'll come back to in a minute plants mice and also some bacteria which
is what I will talk to you about today so with respect to humans the clock
controls a number of important physiological processes things like when
we sleep and when we're awake how alert we are and when we eat and you all know
this because you know that when you fly to a different time zone you feel jetlag
and as we'll talk about this jetlag is an issue with the way in which your
clock the lack of synchronization of your clock with the change in the
environment so a very special property of all real circadian clocks is that
they keep track of time even in the absence of any environmental cues so
this is opposed to a situation where you could imagine like an hour glow
glass that required the night to be reset each in order for the hour glass
to be turned over each day that is not what a true circadian clock is like a
true circadian clock is like this watch here the time is running independent of
what happens in independent of whether it's dark or
light out for example so organisms of all different types as I said have
evolved these clocks over a long period of time to allow the organism to take
advantage of the predictable changes that occur in the environment right the
Sun comes up every morning and sets every night and many organisms exploit
that predictability to schedule various physiological processes like sleep to
occur at the right time you want to sleep during the night time and be awake
during the day and so the clock has evolved to exploit the predictability in
the environment in order to be able to schedule various biological processes so
as I said the hallmark of circadian clocks is this periodic output and
that's what's depicted schematically here just output from the clock as a
function of time and as I told you the clock has 24-hour period issah T and
that means if we start at a given point it takes 24 hours to get back to this
same point and then the cycle repeats all over again indefinitely so that's
what we mean by the period the period of the clock is 24 hours it's the time it
takes to repeat the other term I need to introduce is phase and so the phase is
the relative relationship between two of these oscillators between two of these
clocks and you should all care about this because this is what happens in jet
lag right your clock is oscillating with a phase that is not synchronized with
the environment it's not synchronized with the day/night cycle when you go to
a different time zone and your clock must adjust it must become synchronized
with the new environment you know for you to get over jetlag and so this
lack of sacristy synchronicity is a difference in face left of synchrony all
right so you've probably heard that the Nobel Prize this year in medicine was
given for the discovery of genes involved in circadian clocks and for an
understanding of how these genes work together to help keep track of time
and that prize was given to Jeffrey hall and Michael Ross patch as well as
Michael Young and I'll just summarize on the next slide sort of what their real
discovery was their conceptual discovery about how the clock worked so they
studied the fruit fly Drosophila melanogaster and they identified genes
right that produce proteins those are the workhorses inside the cell and those
proteins were parts of the clock and the way in which they and and we currently
think that the clock in flies and also perhaps in humans works is diagrammed on
this slide so here this blue bar here represents a gene it's a piece of DNA
and this piece of DNA of course eventually will go on to produce through
a number of biological processes that we need not concern ourselves with the gene
will go on to encode a protein so a protein will be produced from this gene
through an intermediate that we call messenger RNA and via processes that we
refer to it's transcription and translation and I mentioned these only
because the model uses these terms in the name but you need not worry just the
information Imogene will produce this protein and it
is a protein involved in the clock and what they postulated Ross Bosch Hall and
Young is that this protein would be produced and it would take time to
accumulate inside the cell right and to be modified to be changed to make it
active so this takes time and so if we just plot the amount of this protein as
a function of time this schematic here shows that it just accumulates over time
all right and when it reaches a sufficient level what Ross Bosch Hall
and Young showed and proposed in this model is that this protein then goes on
to turn off its own production right and if it turns off its own production then
the levels of this protein drop because the protein X is no longer being
produced and now the so now you have part of the cycle right one full cycle
but it has to repeat again and the way it repeats again is that this protein X
which is turning off its own production he's then degraded it's removed okay and
that allows this cycle to start again and so the clock in humans and in fruit
flies and in many other organisms is thought to rely on this structure that's
called transcription translation oscillator right and it's called that as
I said because transcription and translation of the gene are required to
produce a protein that then goes on to regulate its own production okay so
transcription translation oscillators and for this as I said they were awarded
the Nobel Prize all right so what I want to talk to you about is how we
unraveled the way in which the clock inside a different organism works and
how it's similar and different from this picture that I just showed you on the
previous slide so the big questions I want to talk about are what are the
parts of the clock and I want to talk about how we figure that out how do we
know what are the parts of the clock and by parts of the clock I mean like if you
open up a wristwatch you see a complicated set of pieces how do we know
which of these pieces are critical for keeping track of time we also want to
know how is information about time read out by the cell right how does the cell
know what time it is from this clock that's operating inside it right with a
traditional clock or my wristwatch I know time is right out by the position
of the hands on this clock but there are no hands inside the cell that are
representing time and so we want to know what the sort of molecular analog is of
the hands on the watch how is time readout and as you'll see this is a very
elegant solution that the cell has to read out information about time from
this clock that is contained within the cell and finally and perhaps the most
are oscillations generated right how do you generate these oscillations inside
the cell then enable the cell to keep track of time and I've shown you one way
that was proposed by Paul Roth's fashion yawn and you'll see that the organism we
work on has found a very different and also very elegant way to to generate
oscillations and I'll talk about how it's similar yet different from the
solution the fruit fly has found so the organism that we work on is a crazy
they're called cyanobacteria this is a picture microscopic picture of the
cyanobacteria there's single cells they look green when you grow them in a flask
they live in water some live in fresh fresh water some live in in the ocean
these organisms are interesting and have attracted a lot of attention because
they rely on photosynthesis they rely exclusively on photosynthesis to get
energy so photosynthesis right is what all kind of plants - they use the energy
derived from light from the capture of photons light to produce a chemical that
is the currency energy currency inside cells and that chemical is of course ATP
or adenosine triphosphate so photosynthesis is this process it's very
complicated process by which many different organisms including this
bacteria but plants can convert the energy inherent in light into a chemical
that they can use for energy this ATP cyanobacteria are the ancestors of
chloroplasts this is where all the photosynthesis takes place inside of
plants so chloroplasts are came from cyanobacteria they're responsible for
the majority of photosynthesis in the open ocean and in fact a significant
fraction of photosynthesis on this planet many sign a bacteria in fact
almost all of them have a circadian clock and now based on what I told you
you can imagine why this might be so the cyanobacteria they rely on
photosynthesis so this means they rely on sunlight to make energy and so it's
at you can imagine why it might be advantageous for them to schedule the
process of photosynthesis to take place only when light is available you don't
want to try to do photosynthesis at night because they're no photons no
lights available so many of the cyano saina bacteria as a result have evolved
this 18 o'clock and we study them because we
can do a lot of experiments in this organism that you can't do even in the
fruit fly they have they're extremely easy to work with and we can do a lot of
genetics as you'll see so one of the sort of coolest things about the
cyanobacteria is that we can see and I'm going to show you we can really see
circadian rhythms we can see the functioning clock inside of single cells
and we can watch how what happens to the clock how it changes over time and the
way in which we do this is using this thing we call we call a transcriptional
reporter okay did the term here doesn't really matter but I might say it so I'm
pointing it out and all this is is a gene so a piece of DNA that will produce
a protein right the workhorse inside the cell that can produce light when you
shine light of a given wavelength on this protein it will produce it will
emit light of a different wavelength okay that's fluorescence absorb light of
one wavelength emit light of a different way one okay so we can measure the
emitted light that's fluorescence so you can just think of this it's like a light
bulb inside the cell and it turns out its reporting on the clock and the
reason it's reporting on the clock is that there is a piece of DNA that
controls the transcription or expression or production of this fluorescent
protein and that control element which is a piece of DNA is responsive to the
clock so this is an indirect way of looking at the output from the clock
right so this black thing controls the expression of the
bringing protein that's the light bulb and it's responsive to the clock and so
if we measure fluorescence as a function of time you see this is a schematic but
what we see is that the fluorescence oscillates with 24-hour period ISTE
right and repeats every 24 hours and this reflects the activity of the clock
okay so um as I said you can really see this and so this is a movie and on the
top you see these dark little rods those are the cells and on the bottom here is
the fluorescence image this is now you're looking at the light bulb
essentially inside these cells and I'm going to start the video and you'll see
the cells grow and divide they get longer and then they divide in half
etc etc but pay attention to what happens to the light coming from the
light bulb the fluorescence here and what yeah
what you can see see it gets bright and then dim and then bright and then dim
and then bright again okay so really it's amazing I mean we are looking
indirectly at the clock and you see a few things I mean one is that you can't
tell that it oscillates with 24-hour period Issy but you have to take my word
for it it does and the second thing is and we can come back to this and the
questions you see all those cells are basically marching in lockstep they're
all getting dimmer and brighter and dimmer and brighter more or less at the
same time okay so that's another interesting aspect but so we can use
this tool to study the clock and one thing we can do with the tool is to ask
what are the parts of the clock and we know what the wristwatch looks like if
we open it up there are a whole bunch of springs and wheels and each of them has
a specific function and now this is okay so know which parts of the clock
are important I'm sure your intuition would tell you the experiment that you
would do is to take pieces out of this wristwatch and ask what happens to its
ability to keep track of time right and some of them would have more of an
effect than others and that would allow you to conclude
that those pieces that you pull out when the clock is broken that tells you those
pieces play an important role and that's exactly what we do and this was work
done before I got involved in this project Kondo Japanese lab about the
same time as the work was done in Drosophila for which the Nobel Prize was
awarded Khan don't look for sign of bacterial cells that no longer show
oscillations right so the normal cells show this oscillation that I showed you
that we can measure with this reporter and he looked for mutants that just
means like defective cells anymore and then he identified the genes the pieces
of DNA they contained the mutations that contain the changes right and then he
studied the proteins encoded by those genes and this is also where my lab came
in and it turns out there are three clock proteins they're called Chi HIV in
Chi C and I've just drawn them schematically here and it turns out they
comprise the clock only these three in the cyanobacteria and so now I have to
tell you just a little bit about these proteins and the most important of them
is this protein called Chi si
meaning it can really make a chemical modification and and what it does is to
add this group here this is a phosphate it has phosphorous poppy and oxygen
bonded to each other and then these two minuses represent negative charges okay
and this phosphate comes from ATP this energy currency inside the cell that I
was talking about and what happens is PI C can put phosphates attached them like
attach them to itself and so that's what these little black balls represent the
attachment of this phosphate group on to the Chi C protein
all right this process is called phosphorylation but that doesn't really
matter I'll talk about the black balls being put on Chi C and we we can measure
the amount of Chi C that has the black balls on us okay and it oscillates with
P R its 24-hour of periodicity okay so so now now we're measuring the clock
directly and we see this 24-hour curiosity so Chi C is phosphorylated in
vivo with this rhythmic periodicity and it turns out that Chi C has two
activities it can both put the black balls on and it can take them off and
for those of you in the know putting them on is kinase activity and
the taking them off is phosphatase but I'll just refer to them as putting the
black balls on and removing the black balls and the black balls are important
they change the activity of this protein okay that then affects output from the
clock affects the ability of the clock to control Physiology to control
photosynthesis okay so the black balls are important and the other thing I
should say and now here was huge surprise and they're going to be
two big surprises here in the first part of this talk and that is that the
oscillation doesn't require transcription or translation so remember
I told you Paul Ross Bosch and Jung won the Nobel Prize this year for the
discovery of this transcription translation oscillator in drosophila
that means oscillations and the clock function rely on these processes what
this clock doesn't we'll get back to this yet similar towards the end if I
have time so the most remarkable thing about this cyanobacterial clock is the
following and that is that you can take these three parts of the IC their
proteins and mix them together in a test tube
with ATP this energy currency called magnesium and you can reproduce
oscillations in the amount of Chi see that has black balls on it okay so this
is really amazing right taken out of the cell the proteins alone make
oscillations and keep track of time this keeps track of time indefinitely as
long as you supply ATP okay so that's a huge mystery right and and we're going
to talk about how this happens right so only three purified proteins are needed
to keep track of time in this organism and it turns out the other thing I need
to tell you is about this inter conversion of the Chi see there's no
black balls it has the black balls is that that's the role of these other two
proteins so when this protein Chi present kasi puts black balls on itself
okay so in the presence of Calle we get this Chi see with black balls and in the
presence of Chi be what Kaiba does is to inactivate Chi
so if Calle is inactive the black balls get removed by Chi see
alright so wit Chi and get black balls with Chi B we get no black balls
alright so now you see a lot of the you see how oscillations might come about
and I'll tell you how this works in a minute and you see the role for these
two proteins Chi and Chi B they control the activity of Chi Street
meaning they control the ability to press e to put these black balls on
itself and take them off alright so now you know about the parts of the clock
and this remarkable ability of the clock to keep track of time in a test tube
with just three pieces now we want to understand we want to use that system to
understand how is time readout right so in the wristwatch of this clock here
it's readout with these hands and I told you about some ways to readout time in
this system right and I specifically have said I told you about the reporter
but closer to the clock I told you about reading out the amount of Chi C with
black balls right did that oscillates with 24-hour period isset E and then
it's an important part of the clock but this can't be how time is right up and
the reason is just like this wristwatch here that has 12 hours on it when I look
at three o'clock I don't know whether it's AM or PM and there's the same
problem here right if I read out time by reading out the fraction of Chi see that
has black balls on it whether I'm in this rising phase of the
oscillation or in the declining phase so the oscillation passes through this same
point the same amount of blackball Chi C in both phases okay so that can't be how
time is right out and it turns out the answer about how time is read out is
really I think very elegant and simple to understand and it lies in the details
of those black balls that I told you about so it turns out that there aren't
just black balls there are two kinds of black balls red ones no seriously this
is easy to understand now now you can put red balls on pi C or green balls or
both and now you can imagine what the answer is here so there are four
possible kinds of pi C only or both red and green balls okay and it turns out
when you what we did is to measure the amounts of these forms of Chi C as a
function of time and what we found is something very cool so here in black is
just black ball Chi C not looking at the individual green and red balls and now
here on the bottom our green ball only red ball only and
blue represents molecules that have green and red balls and you see that all
of these different forms of Chi C they oscillate with 24-hour period isset E
but the phase is different now remember the face they're offset and now here's
the secret to how time is readout so what happens I've already said that each
form oscillates with a different phase and time is stored in the relevant
relative amounts of the green ball Chi C double-reed green
red ball Cassie and red ball Cassie and you can see this so if we just compare
these two points that have the same appeared to have the same level of black
ball KY see when we look in depth and break down the modification into green
red and blue you see at this point there's a predominance of the green one
and then equal amounts of blue which is has both green and red balls and over
here the red one predominates so the cell can tell what time it is by
monitoring the different amounts of Chi see that's modified with these green
balls red balls or both balls that's how time is read out and now we
want to know how our oscillations generated and in the wristwatch a
mechanical wristwatch it's actually complicated there are all kinds of
pieces of mainstream mainspring that stores mechanical energy and a balance
wheel that's a weighted wheel rotating back and forth it's controlled by that
spring and that sets the period I mean this is also a fascinating issue right
what sets the period and I think we understand this with the wristwatch and
you can ask me in the questions how the period is set in the circadian clock
that's a whole other fascinating topic but we want to know how do you get
oscillations right I've told you about the three proteins and how the x readout
and the different balls on chi see but there's a huge issue about how you get
stable oscillations I told you about these two proteins they control whether
Chi C puts black balls on itself or removes them and if you think about this
there's a big question about why the reaction doesn't just go to what we call
a steady state and that's just some fancy word that
means not changing over time and and I think I can make a good analogy here if
one has a bathtub where you're putting water in and draining water out the
level of water that you have if you're both putting it in and draining it out
is determined by how fast you put it in and how fast you drain it out and
eventually if you turn on the faucet and you open the drain a little the water
will reach some stable level that's determined by the relative rates of
water in and water out and you know this from your own experience and that is
this steady state so this is the same kind of setup here two opposing
reactions water in and water out and the relative amount of blackball Chi C
should just be determined by how fast the balls are put on and how fast
they're taken off just like the water in the bathtub and so what we see instead
of this studies there are these oscillations and this would be as if you
put water in the bathtub you turn it on and you open the drain a little and the
water oscillates up and down okay and that is not what happens but it is what
happens here so this is really I mean it turns out it's a remarkable thing and
there very few systems in biology that exhibit this property and I'm just going
to tell you that what we need is some time delay between putting the black
balls on and taking them off if they're put on and taking off with the same time
same time scale you can't get oscillations and I think this will
become clear why in a minute and the other bigger problem is that there are
billions and billions of molecules of this Chi C protein and the other Chi and
Chi B proteins in a test tube and just like the cells I showed you this is an
even harder problem to get oscillations these molecules need to be marching in
lockstep they have to be putting the black balls on
and taking them off all almost all the molecules at the same time they can't be
a synchronized right they can't be out of sync if you will and that is a hard
test how you keep the billions of molecules in sync with one another and
that's this synchronization and you'll see the answer lies in those two
proteins ka and kunti and so we figured this out by studying in a test tube
these subsets of clock proteins so I see no black balls all by itself what does
it do I see with this tight eight proteins that tells it to put black
walls on and then I see with type II and I'm not going to show you any
experiments I'm just going to tell you what we learned yeah exactly so so
putting the black balls on and taking the black balls off of coxy or really
slow and this is like crazy in biology normally in chemistry reactions normally
take place on a time scale that's seconds or less very fast but here these
reactions are really slow and this is just a property of this protein Chi C
and we can talk about why at the end but this is what gives rise to the period
being so long okay and it's a peculiarity of this
protein so that's one thing we learned from these reactions and the other thing
we learned is that if we measure Chi C with the green balls the red balls and
both balls what we see is they're the balls are put on and taken off in a very
stereotyped order so what happens is the molecules essentially always put the
green ball on first then they put the red ball on to make this
blue thing and now both balls are on right that's what this don't worry about
the SMI team but both balls are on and now the protein always removes the green
ball first to leave the red ball right there and then the red ball is removed
to make on modified Chi C okay so there's some order here and it's the
same order we see when all the proteins are present and now we can see we get
oscillations we need to get oscillations we need this delay between putting the
balls on and taking them off and the delay comes from this order it is just a
property of the enzyme in its obligate it has to happen this way
you start with no balls on put the green ball on put the red ball on to make this
both balls there and now there's a delay I mean there's a delay in removing the
balls there's no where to go here except to remove balls and it always removes
the green ball first to leave the red ball and then the red balls removed to
produce the unmodified form so the delay comes from this order here in the cycle
of addition and removal of the balls okay and now I told you that we need
some way to keep all the molecules marching in lockstep right and this is
really a serious problem and the answer turns out to be a very elegant solution
so here you're adding green balls then you add the red ball to make both balls
on there and the Chi a protein I told you is telling Chi C to put the balls on
and now what happens and the way the cycle is reversed and the way the
molecules are kept in sync is as follows I told you next after both balls are put
on the green one is it's always put on first and removed first and it's removed
then you just have the red ball in this form of Chi C with the red ball plays a
very important role what it does is to bind
it forms a complex with this protein Kaiba and I told you Kai B then
inactivates Kai a if you inactivate Kai a now no more balls are put on and
instead the balls all get removed so if you add two balls on you go to this if
you have the one ball you go to the unfolded or unmodified and eventually
down to here and you start the cycle anew so the way the molecules are kept
in synchrony is this special form of Chi C with the red balls triggers this
regulation that inactivates the protein that puts the balls on Chi C so it's
really a crazy situation where all the molecules are bathed in a sea of these
regulatory proteins all the Chi C molecules and if you control the
activity of the regulatory proteins then you control the activity the
modification of Chi C so I told you the parts of the clock are these three
proteins and ATP is critical in this system this energy that's where the
balls come from they come from ATP I told you about how time is read out it's
read out by these different forms of Chi C forms meaning Chi C that has these
different balls they're phosphorylation modification by phosphorylation but you
can think of them as different balls and that's how time is read out and how the
clock knows whether it's in the rising phase or in the falling phase of the
cycle I told you about how oscillations are generated by this form of feedback
effectively that controls the phosphorylation of Chi C and now in the
last less than 5 minutes I want to turn back to this issue of I set the whole
thing up with the Nobel Prize and the transcription translation oscillator and
I told you that transcription translation awesome
it's how the clock and humans is thought to work and how the clock and the fly is
thought to work and now I told you something totally different about these
bacteria right like told it like nothing related but it turns out that that
aspect of transcription translation feedback that I showed you the details
of which don't matter also occurs in the cyanobacterial clock ok so there's
something very interesting going on here and and what by what I mean by this is
so the clock is composed I told you of these three proteins that generate
oscillations to control output and it turns out they control expression of
genes including these genes the clock genes themselves all right so the clock
controls the expression of clock genes and that's what this arrow means so the
clock is controlling its own expression just like I showed you for the Flies and
what is thought to happen for the humans and so the issue is why do these
bacteria have this other layer of regulation regulation that looks just
like the mechanism underlying that creates oscillations in the fly system
why would the bacteria have that when I just got done telling you that the
oscillations come from this crazy mechanism with the balls on high C right
why do the cells have this and and I'm just going to tell you that it's the
answer is very cool answer so we broke this we can break this expand experiment
that I won't talk to you about and what happens is very revealing
so this clock essentially has two gears so here's the gear with the balls being
put on crises that's what I told you about and the the
cyanobacterial clock also has this transcription translation feedback thing
that I told you about it's operating in the flies and human so this is indeed
the balls they are required and sufficient for the oscillations but then
why do we bother with this and now I'm going to show you the only like real
piece of data besides this video but it's easy to understand so here in the
top the light bulb in the individual cells of the bacteria and I traced you
can barely see but see these thin lines representing individual cells and you
see that more or less they're marching in lockstep they have different levels
of brightness to it and that's why some are way up here and some are down here
but they're marching in lockstep with the same things that's the normal
situation we call wild-type it's just normal steps and now when we break this
feedback that I told you about the transcription translations feedback so
now the clock doesn't control its own expression and this is what happens now
you see the cells are all be synchronized they're asynchronous they
can't keep track of time and synchrony and so it turns out that this feedback
is required for the clock to stay stable in sync the cells to say in sync with
one another and that turns out to be the function of the clock and so I'll end by
just commenting that I think it's not clear evolutionarily this is likely a
very ancient clock this circadian clock and it may be that this is the ancestor
of all circadian clocks and that the regulation I told you about for which
Paul Ross fashioned young were awarded the Nobel Prize
he's then taken over as mechanism underlying oscillations in
more complex systems and this has been lost but retained for whatever reason in
cyanobacteria we don't really know but there's something peculiar going on here
and I'll just end by thanking the people in my lab who did the work I'm really at
all of the work on clock mechanism was done by one postdoc my crust who's now a
faculty member at University of Chicago actually and Joe Marksaeng who was a
graduate student with me and I'll stop there and I'd be happy to take any
questions
hi so I'm really interested in the way that you talked about these oscillators
and my question is you talked about how different cells synchronized with each
other but you also talked to the beginning about the environment so if
there are nice 24-hour cycles how if you get jet-lagged you get read synchronized
to the environment if that changes no I really sort of over this I didn't I
didn't tell you the answer that and you're very perceptive to pick up on it
so the reason the cells are out of sync with one another really has to do is
tied to this getting over of jet lag so we synchronize the cells with one
another by we can do this with special signals special meaning it's true of
humans - they're only special cues that can adjust the face of the clock those
cues are things like light that's why they tell you when you go to a different
time zone to be out in light food and not in this bacteria but in humans food
is also a dominant cue for the clock and that's why you should eat on the
schedule of the new time zone so those things are special cues that help adjust
the phase of the clock and in the laboratory we can use light or dark
darkness a pulse to adjust the phase of the clock and so we apply a pulse to a
population of cells that are not synchronized and we synchronize them
with that pulse of darkness and then they are all they start all marching in
lockstep and then in experiment that it was at the end that I
didn't describe well what happens if you don't have that feedback where the clock
is controlling its own production they quickly lose synchrony whereas the
wild-type the normal cells do not and we can talk offline about why that is we
understand a great deal about why they lose synchrony under those situations
but the answer to your question is yeah there are these cues that can adjust the
face of the clock special cues that's right and that's a process called
entrainment yeah hi um follow up on that one I know in another type of microalgae
dinoflagellates there's been work showing it's a blue light receptor that
can synchronize cell cycle and heard of point of blue light behind your leg for
jet lag have you looked at all that blue light receptors in saying about tears
yeah no I don't know that this is an interesting issue in science it it is an
interesting issue and in humans - - which wavelength is the clock sensitive
for this process of entrainment or getting over jetlag that's that's I'm
sure people have done such experiments in humans we've not done them in to the
best of my knowledge they've not been done in cyanobacteria I'm not sure Donna
flatulence I don't know so yeah this five minute so the she
tested blue versus red versus green and it was for a cell cycle yes right yeah
which is that circadian
I'm not sure that they actually have a clock yeah but it's still your question
is an interesting one yeah thank you sir the clocks operate independent of
environmental cues okay so I misled that's a great question and I misled you
little they're really not exactly 24 hours that's right it's absolutely true
it's not exactly 24 hours and that differs depending on the organism it's
right around 24 hours long but I mean like it's 23 or it's 24.7 or 25 but so
that's why we say circadian it's approximately 24 and and I think the
truth is you can this the the system can never have a period that's exactly
perfect because in the environment the fraction of the day that is light
changes with seasons with latitude with right so you always need entrainment to
mark to register the clock to a point in the day yeah so you see what I'm saying
so I I don't think these small differences in period I don't think we
understand well enough where we don't understand where those come from what I
can tell you is that there are mutants in the clock in the bacteria this is any
you want to study and if you create the situation you need means if you create a
situation where the environmental variation the periodicity of
environmental fluctuation like light-dark doesn't match the
oscillations in the clock the cells have a fitness defect they don't grow as well
as cells whose oscillations match those of the environment yeah so the clock and
this makes sense for the cyanobacteria because the they're growing only when
light is available and they and they have to use a huge amount of energy to
produce all these proteins that are involved in photosynthesis and so they
schedule it to produce those proteins right before they're needed if they
produce them all the time they would waste a lot of energy
Aeryn that was fabulous thank you
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