Why circadian clocks? | Martha Merrow | TEDxVienna

Martha Merrow studied biology at Middlebury College in Vermont before working on her Ph.D. in immunogenetics at the Tufts University Medical School in Boston. She started working on her current research interest, the biological clock, as a Post Doctoral Fellow at the Dartmouth Medical School. Prof. Merrow then habilitated (a teaching degree) at the Ludwig-Maximilians-Universität in Munich before taking a tenure track position at the University of Groningen in the Netherlands. She left Groningen seven years later as a full professor to assume a Teaching Chair in her former department in Munich, where she is currently engaged. Her research is focused on understanding molecular aspects of how the biological clock synchronises with environmental cues. Beyond her teaching and research, Prof. Merrow works on developing scientific networks for chronobiologists and for women in science (e.g., OnTime, Frauentisch). She enjoys spending time with two wonderful daughters, going to the opera, cooking and eating, and studying the German language.

This talk was given at a TEDx event using the TED conference format but independently organized by a local community. Learn more at http://ted.com/tedx

Good morning, Vienna.

Okay, many cultures use
the expression 'night and day'

to describe opposites
that are somehow surprising:

Twins that behave completely differently
despite that they look the same;

someone who's drastically
changed their behaviour,

perhaps going from drinking
way too much to nothing at all.

'It's like night and day'.

Of course when we say this,
it's actually a metaphor

that refers to the stunning transformation

that the Earth goes through
every day as it rotates on its axis,

alternately sampling
warmer light environments

and darker cold ones.

It's like night and day, there's nothing
as different from night than day.

And we pass between these two states
every single day without exception.

Evolution is all about developing
adaptations to special environments

through genetic change.

And so it stands to reason evolution
has given us a mechanism

to deal with this special environment,
a mechanism embedded in our genes,

and a mechanism that actually samples
and tastes the environment

that's alternating
with high predictability.

And that mechanism
is the biological clock,

or the circadian clock.

So what is the circadian clock
and what does it do for us?

One of the most impressive
examples that I know about

are experiments
that take people like you or me

and put them into a time-free environment.

A subject goes into
a specially designed apartment,

usually just a single room,

that has no access to information
from the outside world.

So there's no clock on the wall,
there's no window

and there's no noise
from outside activities.

In this situation, a subject lives
not with a precise 24-hour rhythm,

they don't maintain that,

but they go to a circa-24-hour rhythm
in sleep-wake behaviour, for instance.

They basically sleep and wake
with the same interval every day,

but it's a little bit less than 24 hours
or a little bit more than 24 hours,

so it's a persistent oscillation
in our behaviour

in the absense of daily time cues.

And this is called the circadian rhythm.

With the word 'circadian'
coming from the Latin

for 'about a day'.

So -

so I think about how this works,

that you have no information from outside
and you still can do this quite reliably

in constant conditions.

This is what we mean by an internal clock,
a biological clock or a circadian clock.

So it's an alarm clock
that's built into our heads

that's telling us when to wake up.

And then I have to say that
I've been studying the circadian clock

for over 20 years now,

and I still am incredibly
impressed and amazed,

and it's still almost unbelievable to me

that we, who are so complex
and strong-willed in our behaviours,

show this persistent,
self-sustained circadian rhythm

in sleeping and waking, for instance,
and in many other things also.

But I've seen so many examples
of this 24-hour timing mechanism

in bacteria and fungi and plants
and humans and other animals

that there's no question in my mind
that it's a fundamental part of biology.

So as you probably know,

experiments that put humans
or any other living organism

into a time-free environment
like I just described

are actually highly artificial,

and they actually never
really happen in real life.

And you also probably know
that your sleep-wake cycle

is actually, on average, exactly 24 hours.

This process of adjustment
of this circa-24-hour rhythm

to exactly 24 hours is called
circadian entrainment,

and for our sleep-wake behaviour

it's mediated by specialised cells
in our retina that sense light.

The biological clock, however,

is built of many more cells than just
a few cells in the eye or the brain.

Basically, all of our cells
are oscillating.

What do these cellular
oscillations look like?

Well, we can measure oscillations
in RNA levels, for instance.

The genes express your RNA levels
in individual cells,

and you see here a tracing of cells

that are carrying on
for five or six or seven days

in constant conditions.

So about ten percent
of the genes in any given cell

are expressed with a circadian rhythm.

Of these, some of the proteins
will also be rhythmic,

and metabolism will become rhythmic also.

And so you get a network
of oscillations in each cell

that eventually come together

so that you get higher functions
that are also rhythmic.

Now, these cellular oscillations
are generally not entrained by light;

light entrainness is unique to cells
emanating from the eye, in the eye,

or connected to the eye, those cells.

These peripheral cells, in general,

will entrain to cycles
in our body temperature,

so our temperature is one to two degrees
higher at the end of the afternoon

than it is at the end of the night.

So now you should start
to get a picture of the circadian clock

in a human, for instance.

It's all kinds of oscillating cells -

really, literally, all kinds
of cells that are oscillating.

They're responding to various time cues:

light, temperature,

also nutritional status
and hormone levels, for instance,

and then they come together
to regulate many, many processes.

So cognitive performance changes
over the course of the day.

The perception of pain
peaks in the evening.

Physical performance like grip strength
peaks mid-afternoon,

and components of our blood

like the metabolic state of cells
or hormone levels

is also circulating with predictable
rhythms over the course of the day.

Andre Gide wrote
a wonderfully perceptive sentence:

'... if I were not there
to make them acquainted,

my morning's self
would not know my evening's.'

This is really perfect -
we are different people, night and day.

So, what does this mean
for us in everyday life?

The circadian clock regulates
the timing of our behaviour.

It determines our chronotype.

Chronotype is measured
by asking people when they sleep

on a free day with no obligations.

And like many behaviours,
it shows a distribution.

You get a few people who are sleeping
very early in the day;

you get most people who are sleeping
at similar times to each other;

and then you get some people
who are sleeping quite late.

(Laughter)

And yes, you can see
that teenagers and young adults

are disproportionately represented
in this late population.

They sleep much later
than young children and older adults.

That makes me think back
to actually what Gide wrote

about being different people
morning and evening

and I think that this explains
a lot of the conflict

between parents and teenagers -

that basically, the timing
of their behaviours is totally misaligned,

that's all it is.

(Laughter)

Okay, so ...

So I told you about age
and how that regulates chronotype,

and so think about this also,
that as you go through life, then,

you naturally pass through
a series of chronotypes

going from early to late
and then early again, okay?

So what else regulates chronotype,
or the timing of our behaviour?

One of the answers is genes.

And the most compelling -
not the most compelling, excuse me -

the first data that informed us
about the genes

that are involved
in regulating the circadian clock

came from fruit flies,

and we now have a lot of genes
that regulate the circadian clock

in isolated human cells.

Interestingly, when we look
at humans themselves,

it's much more difficult to figure out

which genes are involved
in regulating chronotype.

The most compelling examples
come from large family pedigrees

where an extreme chronotype
is inherited as a dominant trait.

However, the DNA sequences
responsible for those traits

are actually not found
in the general population,

so my conclusion from these observations

is that the genes that are involved
in regulating chronotype

are actually many,

with each having individual small effects
in the general population at least,

and therefore very hard to track
by standard genetics methods.

Another way that the chronotype
is regulated is with light.

So I mentioned that the clock is designed
to actually sample the environment,

so perhaps it's not surprising
that it actually checks in

and uses some of the information
from the environment.

So, how do we know that this is so?

If you live in a higher light environment
compared to a lower light environment -

so someone who gets outside compared
to someone who's inside all the time -

you'll generally have an earlier
chronotype vs. a later one, respectively.

If you live in the eastern part
of a time zone like in Vienna

compared to the western part
of the time zone,

you'll have an earlier
vs. a later chronotype,

and of course this is because
we express chronotype as local time,

whereas your clock is reading sun time.

There's some evidence
that we entrain differently

in the summer -
that's earlier in the summer -

than in the winter,
where we entrain later.

It might also help you
to think about jet lag

to understand intuitively
how light feeds into the clock.

So with jet lag
you've flown across time zones,

and it takes a really
surprisingly long time

to readjust to the new time,
and you feel really bad in the process

as your clock is running ahead
or lagging behind

of the new sun time.

Eventually you find a relatively stable
phase of circadian entrainment

that's consistent for your chronotype
in your new environment.

You feel better; you can sleep again;
and you get your energy back.

So, what are the implications
about all of this for you

in your everyday life?

First of all, I think it's pretty clear

that you will have a fundamentally
different circadian clock,

and therefore chronotype,
from your neighbours.

So you have different genes,
you have a different age,

and you have a different life history.

I want to do a little experiment here.

I want to let you understand that

by actually comparing yourself to others,

which is actually a really good way
to make people understand this quickly,

so I'm going to ask you to raise your hand
and tell us, and report to us,

when you prefer to go to sleep
on a free day with no social obligations.

Okay?

So who goes to bed before midnight?

Okay, look around and see
how many hands are up.

How about midnight to 1:00?

1:00 to 2:00?

2:00 to 3:00?

(Laughter)

And after 3:00?

There should be
some people here after 3:00.

So you've just reconstructed
the chronotype distribution

right here in this room.

So now you see how it works.

I recently came across a dramatic story
concerning chronotype.

This is a picture of the famous
castle Neuschwanstein.

It was built by Ludwig II,

who became the king of Bavaria
in 1864 at the age of 18.

Twenty-two years later
he was forcibly removed from the throne

when he was pronounced insane

by a board of psychiatrists
who had never examined him.

Ludwig may have had some troubles
in the mental health department -

I think no one can know
for sure; it's history.

What we do know

is that despite some considerable
popularity with his subjects,

the government was deeply disturbed

that through his palaces
and castles that he was building,

he was pushing the state
to the brink of bankruptcy.

They wanted him out.

When I read a bit more
about the daily life of Ludwig,

I became suspicious
of the diagnosis of mental illness.

Certainly, he wasn't coping
very well in general,

and he practised
some eccentric behaviours,

but the most specific description
concerned the timing of his behaviour.

He ordered breakfast
at 6:00 in the evening,

lunch at midnight,

and dinner in the early morning

before retiring to bed
to sleep through the day.

Very rarely one finds
a reversed chronotype like Ludwig had.

He seems indeed to have been
most relaxed at Schloss Linderhof here,

where he famously was riding around

in his sleigh through the night
around the grounds.

In contrast,

his official duties would have taken place
during the daylight hours,

which was unfortunately
during his night time.

Think about how you would feel
if you had to negotiate anything

in the middle of your night.

Ludwig found himself negotiating
the independence of Bavaria

in the middle of his night,
and he lost it.

This misstep essentially
created the German Empire.

(Laughter)

I find myself wondering
if the chronotype of Ludwig II

changed the history of the world.

(Laughter)

That's of course impossible to say,

but extreme examples like this
are very useful for making a point,

and the point here
is that like other living creatures,

we have our own
individual circadian clock

that in combination with our age
and our light exposure

will make us a certain chronotype.

Our clock directs
the timing of our behaviour.

Our chronotype is so strong

that it sometimes isolates us
like it did Ludwig II.

It does this in small ways.

When we want to be with someone
who has a different chronotype,

maybe we feel like doing something
that they don't feel like doing.

Our chronotype is so strong

that sometimes we have to modify it
with an alarm clock,

otherwise we might get in trouble
with work or school.

Both of these scenarios are suboptimal.

One of them results
in social relationships that suffer,

and the other results in sleep deprivation

as a result of the clash
of the biological and the social clock;

this is a condition
we call social jet lag.

And sleep deprivation is known
to lead to a variety of problems

ranging from poor performance to illness.

Is there anything, then, that you can do
to fine-tune your chronotype

so that you can have more harmonious time
with family and friends,

and you can lose less sleep to your work?

Can you unshackle yourself
from your clock?

The answer is: almost certainly.

If you think back to what I said
regulates chronotype -

that would be genes, light and age -

two of those things
you can't change overnight.

But light is something
that we can work with.

It's easy to find, it's cheap
and it's not unpleasant.

So the only problem is
that we don't have very good prescriptions

for how light will interact
with your specific chronotype,

because remember, you have
a unique collection of clock genes

that we don't really understand yet,

so we don't know
how they would react to light.

There is a general rule
that most people, however,

if they increase the light
they get in the morning

and decrease the light
they get in the evening,

for instance, from computers
and televisions,

that they will tend to move earlier
in their chronotype

and therefore have to use
their alarm clock less.

Okay?

Okay, 80 percent of you out there
are alarm clock users.

This should remind you every single day
that you have a circadian clock.

Your clock is showing itself
in your individual cells;

it's showing itself in your family
and in your community.

Despite the alarm clock,
which I hope you'll use now much less,

the circadian clock is a wonderful
addition to our poor existence.

It gives us more versions of ourselves.

We are, after all, different people
morning and evening.

Get to know you.

And since I'm a scientist,
I have to acknowledge my dear colleagues,

because no scientist stands up here alone
without a huge team behind them.

Maria and David who are here today,

Till Roenneberg who's rewritten the book
on human behaviour,

and many chronobiologists,

and please do discover your chronotype
at this web address: [www.euclock.org]

Thank you very much.

(Applause)