Tuesday, 3 October 2017

I got rhythm: and so have you?

The Nobel Committee in Stockholm, yesterday awarded the Prize in Physiology or Medicine to three Biologists who discovered the genetic basis of our own personal "cellular clocks". You may recall in 2014, the Prize was awarded for work on the brain's very own "satnav" system, which makes sure we know where we are going and where we have been. The work on "Circadian Rhythms" by Jeffrey Hall, Michael Rosbash (Brandeis University, Boston) and Michael Young (Rockefeller University, New York) provides an insight into our connection with night and day. Through their work, we can now appreciate how life on Earth is related to the movements of the sun, the moon and the Universe in general. 

Image result for night and dayThere are some words you will need to be familiar with in understanding this post. Diurnal is derived from the Latin meaning of the day or daily and comes from the word dyeu to shine (diamond?). Nocturnal, I think you will know refers to the night and finally, circadian (combined here with rhythm), comes from circa (about or around) and day and is an adjective that describes a process that occurs on a 24 hour cycle. Some species are awake in the day and sleep at night, like us (and I will come back to the problems that shift work and long plane journeys can cause) and others are nocturnal, like bats: sleeping all day and foraging at night. I hope you can see here how evolutionary adaptation is linked to the motion of the planets. Let's look at what they discovered, before I return to the planets!

In 1971, the great US geneticist Seymour Benzer and his colleague Robert Konopka, isolated a mutation in the fruit fly (drosophila), that had an altered pattern of behaviour. More specifically, the mutant flies seemed to have an elongated circadian rhythm of 29 hours instead of 24. They named this gene period, or per for short. This landmark discovery paved the way for the work honoured this week, by the three Nobel Laureates above. The per gene turns out to encode a protein that regulates its own production and destruction: levels of the messenger RNA (mRNA) that encode the PER protein peak during the night and drop down in the daytime (as you can see graphically, top left: the x-axis is in hours). However, the PER protein is produced in the cytoplam of the cell and of course the genes are in the nucleus. It was Young who, in the early 1990s identified the timeless gene, encoding the protein TIM. TIM binds specifically to PER and transports it to the nucleus, where it can now act accordingly. A further protein, identified by Young and this time called doubletime fine tunes the whole process, allowing for occasional adjustments to the 24 hour fixed period. In humans, the network of genes/proteins involved in regulation the body's circadian rhythms is a little more complex than I have described, with the usual collection of protein phosphorylating molecules (kinases and their counterparts phosphatases) ensuring the levels of PER proteins are exquisitely balanced. Finally, the "steady state" levels of the PER proteins are subject to controlled proteolysis in a manner reminiscent of the control of the cell cycle itself by cyclins, which Sir Tim Hunt told us all about when he visited the UTC.

I hope you can appreciate that the genes and proteins involved in maintaining the correct 24 hour clock in cells has now been firmly established by an elegant combination of genetics and biochemistry. Seymour Benzer, who was originally a physicist with interests similar to the young Einstein, set the Nobel Laureates on a journey that has linked Biological Evolution to our place in the Universe. The typical day on Earth is 24 hours, which is determined by the rotation of the Earth during its orbit around the sun, but night and day is opposite to us, if you live in Australia. Given that Mars has a solar cycle that is just over 39 minutes longer than our own: we might expect that life forms on other planets have evolved to match their own solar cycles.

Finally, beyond the fundamental importance of molecular basis of Circadian Rhythms, why may they be important in respect of our health and well-being? As I mentioned above, by flying in the face of our diurnal nature, the regulation of the PER system needs to adapt: this happened when you fly a long distance or you adopt the working habits of a badger and work shifts. Many people choose to work permanent nights, and must therefore re-configure their body clock. Try it once when you are not forced to! [I should mention that the PER network of regulation interacts with light sensors (cryptochromes) thereby providing the cell (and the body) with valuable cues which fine tune the body clock. It is also becoming clear that there is a correlation between the action of certain drugs and the body clock. If you are interested you can read these "rapid response" articles that appeared just after the announcement.

The Biochemical Society
The New York Times
The Nobel Foundation