March 8, 2010
Uncovering the molecular secrets of what makes us tick
From bacteria to humans, the biological clocks in living things help them determine when to eat, when to sleep, even how to avoid becoming some other creature's lunch.
Many humans are best acquainted with their clocks when they are out of whack: like after a long transcontinental flight that flip-flops day and night.
"It's a fundamental adaptation that helps organisms anticipate the daily light-dark cycle on the planet," explains University of Georgia geneticist Jonathan Arnold.
With the help of the National Science Foundation (NSF), Arnold is examining the molecular basis of the biological clock. "The clock is a fairly complicated timepiece inside each of us," notes Arnold. "In order to understand how it works, we started with an organism that is very simple, (one that) doesn't have as many gears to worry about."
The organism? It's a workhorse in the scientific community: The fungus Neurospora crassa, and better known as bread mold. Neurospora has about 11,000 genes, compared to more than 35,000 in humans. Early on, Arnold and his colleagues had no idea how many of those Neurospora genes were controlled by "clock" functions.
"The surprising answer is that a quarter of the genome, about 2,400 genes, actually have a circadian rhythm. And that came to us as quite a surprise. It's also an interesting surprise because it means there's a lot about the clock we don't know," he says.
The clock and its wide range of functions could be more important to living things than previously thought.
The biological clock in some plants--for example, plants that deploy their leaves during the day and fold them up at night--makes them more efficient in using sunlight for photosynthesis.
"There's a whole biochemical process that has to get set up in the cell to prime the pump and harness that energy from the sun. So, it's good if the organism could get all the machinery in place so that when the rays start creeping over the horizon, it can start collecting. That's what enables it to survive better than an organism without that capability," notes Arnold.
Small rodents, such as mice and voles, have a clock function that triggers them to eat while helping them avoid becoming a snack for predators flying above. It's called synchronous feeding.
"The synchronous feeding behavior confuses the predator," says Arnold. "So, when the hawk looks down and sees hundreds of mice or voles running around, it gets confused as to what to go after. That's another example of how the clock is working to enhance the survivorship of those voles and mice."
Studying 11,000 genes and all of their functions is a daunting job. "We have to isolate the product of all the genes in the genome. And then, what we have to do is measure what each of those genes is doing. So you are taking 11,000 different genes within a collection of cells and asking what are they producing over time, and whether or not it is rhythmic. And you need very special technology to do that," explains Arnold.
So the study has included the efforts and analysis of University of Georgia physicists Bernd Schüttler and Xiaojia Tang, using a new technology called "Computing Life." This technology integrates several cycles of modeling and experiments to determine information about a genetic network.
"Computing life means that at each step, each new experiment takes all of the previous information that you have accumulated and says, 'What is the next experiment that I should do to get the most information about the underlying clock that I am interested in,'" adds Arnold.
For Schüttler, it's been a new realm for him as a scientist.
"Making this biological clock work was sort of my transition from a more traditional field in physics, computational statistical mechanics, where we had developed many of these methodologies that we are now applying in biology," says Schüttler.
"What was really exciting and actually exhilarating about this project is you can take all of that stuff that's been sitting on our shelves for decades, and you can throw it at this and it's amazing what kinds of things you can pull out of the biological data using this sort of methodology," explains Schüttler.
"We are using this ensemble of models to then help design new experiments and to get the biggest bang for our buck, to design new experiments that give us the maximum amount of information beyond what we already know," he adds.
Understanding specific clock functions may have applications in medicine, from sleep disorders, to heart and lung disease, to aging and reproduction. Strokes and heart attacks, for example, have their own circadian rhythm. And, some drugs work better depending on when a patient takes them. So, learning the intricacies of the timepieces of cancer cells could help control them.
"Cell division has been shown to be under clock control and that is one of the features you have to worry about; when inappropriate cells decide they are going to kick in and start dividing. That's where one of the connections may be occurring with cancer," says Arnold.
Xiaojia Tang focuses on the property of temperature compensation in biological clock functions. A good property of a clock is to keep the same time in different temperatures.
"Temperature is very important for all living things. When the temperature changes, everything in the biological clock, the whole network works together to make it stable," says Tang. "Our work is trying to explain that in a computational way."
While Tang says many people don't understand the intricacies of this research, almost everyone is curious about one thing: When will that pill be available to get rid of jet lag?
Any opinions, findings, conclusions or recommendations presented in this material are only those of the presenter grantee/researcher, author, or agency employee; and do not necessarily reflect the views of the National Science Foundation.