How Protein Pathways Set Cell Clocks

Ben - Returning to our topic of circadian rhythms, the body clock and sleep, it seems that circadian rhythms are clearly important for staying fit, both in terms of good health and in terms of survival of the fittest. They fit chemical cycles to the day and night pattern, and this seems to have offered an evolutionary advantage.  But why would that be and what are these essential chemical pathways that encouraged body clocks to evolve?  

To find out more, we are joined by Cambridge University's Ak Reddy.  Ak, thank you ever so much for joining us.  First off, what do we think the evolutionary advantages are of having a body clock?

Ak -  Well, the ideas that have been bandied around in the past are to do with trying to separate out things that should happen in the day and night, and one of the great examples that was used in the past was about cell division cycles.  So, in the days when cells were first evolving, people thought that it might be advantageous to protect DNA replication which is very sensitive to UV radiation from the Sun and have that going on in one part of the day and then not have that protection at night time for example.  Then you separate out these two phases - hHow do you do that?  You have a timing mechanism that basically keeps track of when the day and night is going to come, and basically wire it into the way that the cell divides; the cell cycle.

Ben -  So, do we see it in a wide range of species?  We've already discussed the fact that plants seem to show a similar circadian rhythm as well..

Ak -  Absolutely.  In fact, animals and plants dominated how we thought about clocks, and it wasn't until about 20 years ago that people first started looking in bacteria.  People had mentioned bacteria or mentioned the fact that bacteria may have clocks many years ago, but it kind of got wiped out because people thought, well why does a bacterium, something that divides every half an hour, or even more rapidly in some cases, why does that need to have any knowledge of a 24-hour cycle?  But it turns out actually that bacteria did evolve to basically do what I said before and protect themselves from DNA damage in parts of the day versus the night time and so, they actually prefer dividing in the night time compared to the day time.

Ben -  So, even though you'll have multiple generations in the space of a 24-hour cycle, you will still see a circadian rhythm.

Ak -  Exactly.  So they divide.  They continue on dividing, but they prefer to divide in the night time and we know that that happens in ourselves as well, in something that divides regularly like the liver for example.

Ben -  So what's the chemical background?  Is it genetically controlled or is there essentially a simpler process?

Ak -  Well it's actually a combination of both things.  So in a complex cell like our cells, we think that there are two main ways in which the "clockwork" is made up.  This is what we currently know.  The one that we talked about before was genetics, which is switching things on and off, basically, over a 24-hour cycle.  What we've discovered recently is that you can also get cycles without any genes whatsoever.  So you make proteins, they need to be there, you need a blueprint if you like, which is the DNA genetic code.  But once you make your proteins, they can actually oscillate on their own without genes being switched on and off, and we actually showed that in red blood cells, which don't have any DNA, and they don't make any new protein, but they're still able to tick and tock over the 24-hour cycle without any influence from the outside world.

Ben -  Speaking of influence from the outside world, what happens if you take away all of the external stimulus?  What about the bacteria that are at the very deepest deep seas that never see any daylight at all and those sorts of species?  Do they keep going?

Ak -  They keep going, yes.  As far as we know, I mean, we haven't gone to the depths of the ocean and picked out those bacteria, but people have worked on cave fish for example, that have been kept isolated for many, many generations to the extent that they even lost their eyes, so they don't actually bother keeping track of light anymore, but they still seem to maintain pretty ropey but present circadian rhythms.

Ben -  I guess there are other things that fit the same pattern, so even if you're not seeing any light, there will be changes in temperature perhaps, changes in tides, the way the water moves, and so on.  Do we think that these other physical factors might help keep things in check?

Ak -  Absolutely.  Temperature is probably one of the most fundamental synchronisation cues.  So we tend to think that light is the dominant thing, but temperature is something that's also been present ever since day one in terms of an oscillation, and indeed, oxygen cycles as well which is, is again, another synchronisation stimulus, and feeding cycles as well.  So, food availability from up above, stuff at the top of the ocean may feed down to stuff more deep in the ocean.  So everything is cyclical in the ocean and there are even tidal rhythms as well that overlap onto this.

Ben -  So, now that we have a better idea of what this protein clockwork pathway really is, can that tell us why, or can that give us some good avenues to look out for why it is that disrupted circadian rhythms seem to have these deleterious health effects?

Ak -  With all kinds of science and medicine, we need to really kind of understand the basics before we can start applying it and I think we're at the stage now where we have enough information about all of the different components of the molecular clockwork and we can actually start to kind of unravel how they might go wrong in diseases.  There've been a few diseases associated with mutations in particular circadian rhythm genes, but not that many.  Maybe we've been looking in the wrong places or we're just not looking at the right genes.

Ben -  So there's lots of new avenues for research, just from our basic understanding.

Ak -  We hope so.

Ben - Well, thank you very much.  That's Ak Reddy.  He's from the Institute of Metabolic Science here at the University of Cambridge.