QueeLim Ch'ng, Kings College London
Weíve known for a long time now that diet influences longevity and that the nervous system is involved in some way. What QueeLim Chíng wants to find out was how? Working on worms, heís tracked down how the availability of food affects gene expression in certain subsets of neurons which in turn alter the physiology of the entire animal.
QueeLim - The point of the study was to look at this long standing problem which that people have known that diet influences longevity and lifespan. And there were hints that the nervous system was involved. What we wanted to do was to pinpoint what the nervous system was exactly doing. So, we did this by studying two genes, both of which are important in hormonal signalling in the nervous system. One of them is called tph-1, the gene thatís important for making serotonin. The other gene is called daf-7. Daf-7 makes a hormone called, TGFŖ, which is important in many different processes throughout the body.
Chris - So, why did you leap on those two genes initially?
QueeLim - There were some hints from work from many labs that suggested that these genes were important in food related processes. But the precise effects were not very clear.
Chris - So, how did you study them?
QueeLim - So, we want to look at these genes in greater detail than was ever done before. This required a very close collaboration with an engineer, Hang Lu, that designed the system that allowed us to look at lots of animals at once to determine how these genes come on and off. And by looking at very large populations of animals, we could actually measure how accurately these genes came on and off as the environment, such as food, was changed.
Chris - Which animals were you studying?
QueeLim - Obviously, we canít study people. So, we studied tiny little worms called C. Elegans. And C. Elegans is really cool, itís a very famous organism because itís already gotten three Nobel prizes and it was the first organism to have the whole genome sequenced. From their result, we actually know that C. Elegans shares a lot of genes with humans. And in fact, these two genes I talked about tph-1 and daf-7, their counterparts in humans are actually very important for metabolism and they also act in the brain.
Chris - So, the fact that youíve got, albeit, a worm, what youíre going to find from this worm is likely to be relevant to people anyway, isnít it? And what is the process that youíve now identified? So, what is the relationship, I suppose, Iím asking between the provision of food and food of different types, and the activity in these genes?
QueeLim - One major advantage of studying this little worm, C. Elegans, is that the entire nervous system has been figured out. We know the identity of every single nerve cell. And so, that allows us to focus on specific known nerve cells with known connections and known functions. And so, what we did was we looked at the expression of these two genes in three specific pairs of nerve cells. By looking at lots of animals, we could figure out how accurately the genes would come on or off as we manipulated the food level in the environment. And so from there, we found that different nerve cells have different responses to food. Some of them increased gene activity when you got more food. Others increased and then decreased as food goes up. While others have a more complex relationship where it increases and decreases, and then increases again.
Chris - Now is this a change which is a direct response to the provision of the food, or is this a response thatís downstream of some other sensor of the food thatís then informing these nerve cells about the provision of the food and that in turn alters the activity of the genes?
QueeLim - You know, that is a really cool question. We donít have an answer to that but we can make some guesses that we hopefully will be able to test. Because these genes are coming on and off in neurons that actually have little endings that are exposed to the outside world, these could be a fairly direct response to how much food there is in the environment because these are neurons that act like the nose of the worm, if you like.
Chris - So, do these cells effectively form a neural network that is capable of integrating information and working up how much food is there, and then they inform the rest of the wormís physiology in terms of what it should do?
QueeLim - Absolutely. So, the cool part about this is that you know that these neurons can tell you how much food there is with a certain level of accuracy. Itís not just a straight line from food to neuron, to the lifespan. What happens is that these neurons actually talk to one another using these genes to actually fine tune the accuracy of the overall system. Once itís settled on the relevant level of accuracy, it passes that information on to the rest of the animal. Itís kind of as though you know you and your friend heard something and then you check with each other to make sure that you heard the correct thing.
Chris - Does this, do you think, have implication for what we see in humans?
QueeLim - Oh, absolutely. So, these genes are actually important in human metabolism. And they act in the human brain to influence many different aspects of human metabolism and human physiology. So, we believe that they are likely to play similar roles in humans as well.