- Hi, I'm Dr. Joshua Beckman, and I am the

chair of the PVD council of the AHA.

I'm speaking to you from the ATVB, PVD, FGTB,

annual scientific sessions.

Today it's my pleasure to talk to you

with Dr. Gary Fitzgerald.

He's our distinguished lecturer and has given

a wonderful lecture on molecular clocks

and cardio-metabolic disease.

Dr. Fitzgerald, can you tell us what

a molecular clock is and how it relates

to metabolic disease?

- Molecular clocks are present in almost all

of our tissues.

Not present in the testes, for some reason

that has yet to be discerned,

but there is a central clock

in the suprachiasmatic nucleus in the brain,

and peripheral clocks can be entrained by

the central clock to maintain a 24-hour rhythm.

It's an interesting connection,

it's a little like an orchestra.

The peripheral clocks have the capacity

to follow the instructions from the center,

but also have the potential for autonomy.

Furthermore, we find that peripheral clocks

can send signals back to the brain

to entrain central function.

So, it's very much like a concert master in an orchestra

where everyone has the capacity to play on their own.

Generally, they follow the concert master's orders,

but their way of playing can influence the way

the concert master performs his duty as well.

- And so what's the link to cardio-metabolic disease?

- Well, clockworks are a very interesting

biological network.

They play an important role in knitting together

biological networks across organisms.

Therefore, when they break down,

we get the display of metabolic dysfunction,

as in a metabolic syndrome.

We get disordered response in terms

of immunoregulation, so we get inflammation,

and disordered clockworks have been

implicated also in aging.

- Is it possible that there is a centrally

dysfunctioning clock that then drives others,

or is it usually a pattern of clock disturbance

that causes disease?

- So, we know from, In terms of that question,

most of what we know actually derives from work in mice.

We and other people have disabled the one

non-redundant core clock gene, Bmal1,

in multiple tissues by now.

We know that disabling it in the center disorders

alternating rhythms, but you can knock it out

selectively in vascular muscle cells and

endothelial cells, in adipocytes and in the liver,

and get an array of different expressions of elements

of the metabolic syndrome.

- Okay, and has this work moved into the

human investigational room yet?

- We're very excited particularly about that.

So, most of what we know in humans so far

derives from what are called forced desynchrony

protocols, where people are studied under

very controlled circumstances.

The amount of time they have available

to sleep is regulated and disordered.

These forced desynchrony protocols allow us

segregate endogenous rhythms of the molecular clock,

and rhythms driven by environmental cues,

most of which we don't understand.

We've been very informed by that type of work,

but we've also been interested to see if we can

discern circadian rhythms in humans in the wild.

In other words, is there a sufficient signal

for us to be able to detect circadian patterns

against the noise of the diversity of human behavior?

We've recently completed a pilot study in

a small number of individuals, where to our surprise,

we've been heartened by the fact that we can see

diurnal oscillation in the micro-biome, for example,

in elements of the metabolim and proteam

as well as the genome, and we've integrated that

with multiple approaches to remote sensing.

So, we're encouraged to project this study

onto scale, and to look with sufficient power

to characterize what we call the

physiological pronobiome, and it's important

to do that because we need that information

before we can start looking in an unbiased way

for mechanistic information that might explain

the time dependent expression of disease,

and we know that, for example, diseases like asthma,

myocardial infarction, stroke, depression,

they all osculate, even aches and pains

in your joint due to the cartilage clar,

they all osculate as a function of time of day

in terms of their expression, but we have very little

understanding of is the mechanistic explanation of that.

- That's a pretty incredible journey

from the bench to the bedside.

I think the lecture's absolutely spectacular,

and hopefully you'll get to look at it online

at another time.

Thank you very much for you time.

- Thanks very much, Josh.

(upbeat, bright music)