Gservo
20th January 2003, 03:00 AM
The biological clock acts as the timekeeper for virtually every activity within living things, from sleep patterns to respiration, but its exact basis has been a bit of a mystery up until now. Researchers at Purdue University have discovered that basis of the 'clock' is in fact a single protein.
The researchers behind the discovery are husband and wife team D. James and Dorothy Morré, and they believe that their findings could have wide-reaching implications for the medical community. Following four decades of research they have discovered a protein that is responsible for setting the length of periods of activity and inactivity within cells. If the protein is altered, an organism's body will experience "days" of different length (ranging from 22 to 42 hours in length in some cases).
"We can now begin to understand the complex chain of events that connect the clock to events in the body," said James Morré, a professor of medicinal chemistry in Purdue's School of Pharmacy and Pharmacal Sciences. "Since the clock affects nearly every bodily activity, this discovery holds myriad potential applications, from minimizing jet lag to determining when best to administer cancer drugs."
The basis of the biological clock has been a lifelong fascination for James Morré. "I first set out to find the source of the biological clock in 1962, when I was still a student," he said. "Back then the question was the subject of perennial and lively scientific debate. Theories abounded as to why the body was able to keep its own rhythm—some thought it was bound up in cellular chemistry, but others thought it could be influenced by anything from the lunar cycle to sunspots. No one could prove anything conclusively, though, so the physicists had a field day arguing about it."
A Timely Cause
But the argument was far more than simply a matter of intellectual interest. As far back as the early 1960s, scientists knew that cancer patients and the elderly often experienced disorders that they believed were related to the biological clock. As time passed, it also became clear that astronauts suffered bone loss and muscle wastage due, in part, to space travel's effects on their internal clocks. Not to mention, the common clock-related ailment of jet lag.
"We knew little for certain," says Morré. "But I always thought a better understanding of life's processes would result if we knew what made them tick."
One clue to the puzzle came in the 1960s. Heavy water—water made of two atoms of deuterium, the isotope of hydrogen with an extra neutron in its nucleus—could alter the clock to run on a 27-hour day.
"Investigators discovered that if you fed cells heavy water, they would operate on a 27-hour day. It was a clue that the clock had a biochemical basis, but heavy water's effect was almost forgotten as other explanations for the clock gained favour," said Morré.
Over the next forty years the scientist spent time on many other projects, but the question of the biological clock remained at the back of his mind until an examination of how cells grow led him to the discovery.
The Morrés discovered that cells increase in size at a periodic rate—enlarging themselves for 12 minutes, and then resting for another 12 before growing again. The complex interaction of proteins is the basis for many activities within cells, and James Morré theorized that some undiscovered proteins were responsible for the 24-minute growth cycle.
The breakthrough came when the team found that a single cylinder-shaped protein molecule with a unique characteristic regulated the cell enlargement cycle. This particular protein had two activities: one served as a catalyst for growth activities for 12 minutes and then rested while its other activity took over for the next 12 minutes.
"Our model is that of a Janus-head protein with two opposing faces," he said. "One 'face' handles cell enlargement. Then the protein 'flips over,' allowing the second face to carry out other activities while cell enlargement rests. While two functions from a single protein had been seen before, what is totally unique here is that these activities alternate, and with very precise timing. The activities don't both run all the time, but instead alternate to generate the 24-minute period length," explains Morré.
To confirm that the protein was responsible not just for regulating growth but for all activities set by the biological clock, Pin-Ju Chueh, then a microbiology graduate student in Dorothy Morré's lab, isolated the gene which produced the protein within cells. The team then cloned the protein and altered it in ways that produced different period lengths.
"We found that we could produce clocks with cycles of between 22 and 42 minutes," James Morré said. "The 'day' that the cell experienced was precisely 60 times the period length of the protein's cycle. We even found that feeding cells heavy water gave them a 27-minute cycle of growth and rest, so that old piece of information served to confirm our theory."
"Now we have an opportunity to tell how organisms tell time," said Dorothy Morré, a professor of foods and nutrition in Purdue's School of Consumer and Family Sciences. "This could give us new insights into cellular activity, such as cholesterol synthesis, respiration, heart rhythms, response to drugs, sleep, alertness—there's so much."
Sleep Easy
While it is presently difficult to make the biological clock speed up or slow down, it can be reset, a fact that could prove enormously beneficial to those with sleeping disorders.
"This discovery also affords an opportunity to improve our methods of clock setting, from minimizing jet lag to correcting sleep disorders," said James Morré. "We might even be able to develop simple artificial clock-setting environments to aid astronauts and those living near the Arctic Circle, where day-night cycles are absent for long periods."
But while the research could be applied to many disorders, the newly discovered protein first needs further attention.
"It is very difficult to look at the protein," James Morré said. "Usually with unknown proteins you can crystallize them and then examine them with a high-energy X-ray beam, but this one can't be crystallized because it's constantly moving. A better picture of the protein switching back and forth would greatly assist future practical applications of the discovery."
The researchers behind the discovery are husband and wife team D. James and Dorothy Morré, and they believe that their findings could have wide-reaching implications for the medical community. Following four decades of research they have discovered a protein that is responsible for setting the length of periods of activity and inactivity within cells. If the protein is altered, an organism's body will experience "days" of different length (ranging from 22 to 42 hours in length in some cases).
"We can now begin to understand the complex chain of events that connect the clock to events in the body," said James Morré, a professor of medicinal chemistry in Purdue's School of Pharmacy and Pharmacal Sciences. "Since the clock affects nearly every bodily activity, this discovery holds myriad potential applications, from minimizing jet lag to determining when best to administer cancer drugs."
The basis of the biological clock has been a lifelong fascination for James Morré. "I first set out to find the source of the biological clock in 1962, when I was still a student," he said. "Back then the question was the subject of perennial and lively scientific debate. Theories abounded as to why the body was able to keep its own rhythm—some thought it was bound up in cellular chemistry, but others thought it could be influenced by anything from the lunar cycle to sunspots. No one could prove anything conclusively, though, so the physicists had a field day arguing about it."
A Timely Cause
But the argument was far more than simply a matter of intellectual interest. As far back as the early 1960s, scientists knew that cancer patients and the elderly often experienced disorders that they believed were related to the biological clock. As time passed, it also became clear that astronauts suffered bone loss and muscle wastage due, in part, to space travel's effects on their internal clocks. Not to mention, the common clock-related ailment of jet lag.
"We knew little for certain," says Morré. "But I always thought a better understanding of life's processes would result if we knew what made them tick."
One clue to the puzzle came in the 1960s. Heavy water—water made of two atoms of deuterium, the isotope of hydrogen with an extra neutron in its nucleus—could alter the clock to run on a 27-hour day.
"Investigators discovered that if you fed cells heavy water, they would operate on a 27-hour day. It was a clue that the clock had a biochemical basis, but heavy water's effect was almost forgotten as other explanations for the clock gained favour," said Morré.
Over the next forty years the scientist spent time on many other projects, but the question of the biological clock remained at the back of his mind until an examination of how cells grow led him to the discovery.
The Morrés discovered that cells increase in size at a periodic rate—enlarging themselves for 12 minutes, and then resting for another 12 before growing again. The complex interaction of proteins is the basis for many activities within cells, and James Morré theorized that some undiscovered proteins were responsible for the 24-minute growth cycle.
The breakthrough came when the team found that a single cylinder-shaped protein molecule with a unique characteristic regulated the cell enlargement cycle. This particular protein had two activities: one served as a catalyst for growth activities for 12 minutes and then rested while its other activity took over for the next 12 minutes.
"Our model is that of a Janus-head protein with two opposing faces," he said. "One 'face' handles cell enlargement. Then the protein 'flips over,' allowing the second face to carry out other activities while cell enlargement rests. While two functions from a single protein had been seen before, what is totally unique here is that these activities alternate, and with very precise timing. The activities don't both run all the time, but instead alternate to generate the 24-minute period length," explains Morré.
To confirm that the protein was responsible not just for regulating growth but for all activities set by the biological clock, Pin-Ju Chueh, then a microbiology graduate student in Dorothy Morré's lab, isolated the gene which produced the protein within cells. The team then cloned the protein and altered it in ways that produced different period lengths.
"We found that we could produce clocks with cycles of between 22 and 42 minutes," James Morré said. "The 'day' that the cell experienced was precisely 60 times the period length of the protein's cycle. We even found that feeding cells heavy water gave them a 27-minute cycle of growth and rest, so that old piece of information served to confirm our theory."
"Now we have an opportunity to tell how organisms tell time," said Dorothy Morré, a professor of foods and nutrition in Purdue's School of Consumer and Family Sciences. "This could give us new insights into cellular activity, such as cholesterol synthesis, respiration, heart rhythms, response to drugs, sleep, alertness—there's so much."
Sleep Easy
While it is presently difficult to make the biological clock speed up or slow down, it can be reset, a fact that could prove enormously beneficial to those with sleeping disorders.
"This discovery also affords an opportunity to improve our methods of clock setting, from minimizing jet lag to correcting sleep disorders," said James Morré. "We might even be able to develop simple artificial clock-setting environments to aid astronauts and those living near the Arctic Circle, where day-night cycles are absent for long periods."
But while the research could be applied to many disorders, the newly discovered protein first needs further attention.
"It is very difficult to look at the protein," James Morré said. "Usually with unknown proteins you can crystallize them and then examine them with a high-energy X-ray beam, but this one can't be crystallized because it's constantly moving. A better picture of the protein switching back and forth would greatly assist future practical applications of the discovery."