BIOLOGICAL PACEMAKER. Understanding sleep disorders

On a walk a few summers ago in New Mexico, Michael Warren Young of the US, the 2017 Nobel laureate for Physiology & Medicine, and his wife came across a plant called the Colorado Four O'Clock. At 2 O'Clock they noticed that all the blooms had a withered appearance and were tightly closed. Four hours later, on their return trip, they were startled to see the same little plant covered with fully opened blooms.

This rhythm of flower opening and closing is believed to be due to the behaviour of its pollinator, a hawk moth, which is active at night. In this desert environment water is precious, but is needed to open the blooms. So this appears to be a strategy that conserves water in an arid environment: flowers are available for pollination at times that match the behaviour of their pollinator.

Another example of these ubiquitous, daily rhythms can be seen in records of a laboratory rodent’s behaviour. An animal kept in constant darkness for almost a month will display precise, daily rhythms of locomotion. The regularity of this behaviour is so consistent that you can predict within a couple of minutes each day when the animal is going to become active and when it will begin to sleep. These rhythms are rarely, exactly 24 hours.

Instead, they have a species-specific period that is somewhat shorter or longer than 24 hours, for which reason they are called circadian (about a day). Because they require no ongoing environmental cycle for their production, scientists realised that these rhythms must rely on an internal, biological pacemaker.

Giving these interesting examples at the 38th Foundation Day lecture of GITAM University, Visakhapatnam, Andhra Pradesh recently, Young said the work of his laboratory was focused on understanding the molecular composition of such a circadian clock, which was first identified in a genetic screen performed by Ron Konopka and Seymour Benzer at Caltech in the early 1970s.

An important feature is the role of Cryptochrome (blue light receptor in plants), which in humans has become the partner for PER (a clock protein).

Tinkering with body rhythms

To understand the phenomenon better, “Let’s understand the consequences arising from a misalignment of cellular clocks all over the body, typically imposed by shift work and contemporary travel,” said Young.

Many years ago, Michael Menaker at the University of Virginia and Ueli Shibler in Geneva independently performed experiments in which they established a brain-body conflict by allowing the rodent to eat only in the middle of the day, when it should be sleeping.

They did this by providing access to food for an hour or so in the middle of each day. They found that after a few days, these animals would wake spontaneously before the food was delivered, eat and go back to sleep, and then use a running wheel in the cage to exercise all night.

A few days after this routine, clocks everywhere except the brain, had changed their phases. So they had in effect an animal with a collection of clocks that would not agree, the Nobel Laureate explained.

Jet lag & biological clock

The Nobel Laureate said this is remarkably similar to what happens when we undergo jet lag, because clocks in different organs proceed to the new time zone at different rates – the brain resetting first followed by clocks in peripheral tissues resetting variably over the next several days. During this time of re-adjustment, the jet-lagged traveller carries a biological representation of multiple time zones.

Now consider if your clock doesn't agree with the environmental cycle? What if you're genetically programmed to have a clock that runs fast or slow as we've heard in flies that carry a period-short or a period-long mutation?

“Our recent works has focussed on studying a syndrome called Delayed Sleep Phase Disorder (DSPD). We can think of DSPD individuals as night owls - late to bed, late to wake. They have a perennial delay in the phase of their sleep/ wake pattern in relation to the societal norm. We think DSPD affects about 5 per cent of the U.S. population from the problem”, he said.

With these findings along with the body of knowledge that is emerging, it is now possible to connect and intensify studies to understand sleep disorders with other medical conditions (metabolic & psychiatric), Young felt.

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