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Nobel in Medicine for Discovery of ‘clock genes’

Nobel Prize in Physiology or Medicine 2017 has been awarded by the Nobel Assembly at Karolinska Institutet, on Monday October 2, 2017 jointly to three Americans Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecular mechanisms controlling the circadian rhythm; the Scientists elucidated how a life-form’s “inner clock” can fluctuate to optimize human behaviour and physiology. “Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth’s revolutions.” Nobel Prize has been awarded since 1901 to scientists who have made the most important discoveries for the benefit of mankind.

Working with fruit flies, the scientists isolated a gene that is responsible for a protein that accumulates in the night but is degraded in the day. Misalignments in this clock may play a role in medical conditions and disorders, as well as the temporary disorientation of jet lag that travellers experience when crisscrossing time zones.

These scientists had been working on this since 1984 when Hall and Rosbash worked together at Brandeis and Young at Rockefeller University and the trio isolated the “period” gene, which controls the circadian rhythm of fruit flies. Hall and Rosbash then showed that the level of the protein encoded by this gene changes in a 24-hour cycle, going up during the day and down at night. They theorized that this protein blocked the activity of the period gene.

Young discovered in 1994, a second clock gene, “timeless” and figured out how, the protein would have to reach the genetic material in the cell nucleus, to have this effect. He showed that when the protein encoded by timeless bound to the protein made by the gene period, they were able to enter the cell nucleus. He further identified a third gene, “doubletime,” which appeared to control the frequency of the oscillations over a 24-hour period.

Rosbash, a Howard Hughes Medical Institute investigator, explained in the Institute’s Bulletin in 2014 that, “The circadian system has its tentacles around everything.” “It’s ticking away in almost every tissue in the human body.” It’s also in plants, including major food crops, the article noted, and appears to be tied to “disease susceptibility, growth rate, and fruit size.”

Young said that in the early days of their research many scientists thought of their work as a subset of neuroscience. They theorized that the brain may have a single, central clock controlling the cycles we’ve observed such as the rise and fall of our body temperature and blood pressure throughout the day. Now we know each living thing, including those without brains, may have many different clocks. Young stated that, “We learned we are truly rhythmic organisms.” Today, “it’s hard to find a cell that does not oscillate in response to these clocks.”

According to Erin O’Shea, president of the Howard Hughes Medical Institute, people have observed for centuries that plants and animals change their behaviour in sync with the light present in the natural environment. And Hall, Rosbash and Young figured out is how this happens, “Genes make up the mechanics by which organisms can keep track of time and this allows them, just like your wristwatch, to coordinate their behaviour their sleep-wake cycle with the changes in the light-dark cycle”.

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The Nobel Assembly at Karolinska Institutet cited that the circadian clock anticipates and adapts our physiology to the different phases of the day. Researchers in the field of circadian biology, nicknamed as “chronobiology,” opine that the scientists’ work has had a major influence on their work in human health and medicine. Alzheimer’s, depression, attention-deficit/hyperactivity disorder (ADHD), heart disease, obesity and diabetes and other metabolic issues are among the many conditions that appear to be linked to circadian rhythms being out of whack.

Erol Fikrig, a researcher at Yale University who is studying whether the timing of insect bites impacts our ability to fight off diseases like dengue fever or Lyme disease, explained that our immune system, too, “is influenced by circadian rhythm, which can alter our ability to fight infections.”

Amita Sehgal, a neuroscientist at the University of Pennsylvania, was a postdoctoral student in Young’s lab from 1988 to 1993 and worked on the clock genes. Her research these days involves looking at how sleep appears to be controlled by the circadian clock. Although we sleep at night, our need to sleep appears to be independent of the clock. “If you didn’t have a clock, you would still sleep, but it would be randomly distributed throughout the day,” she said.

Young said that one of the most important areas of study built on their work is what happens when the clock runs too fast or too slow. Most recently, scientists have discovered that one per cent of humans worldwide have a mutation in the clock genes that is associated with delayed sleep or being a night owl. He said many of these individuals show up at sleep clinics wondering what to do, and the work provides a target to work on. According to Young “That’s powerful information that can inform lots of future work in the development of therapies” and there’s also growing research, mostly in animals, that supports the idea that maintaining a more regular schedule, including eating and sleeping, may contribute to longevity.

Jeffrey C. Hall was born 1945 in New York, USA. He received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 to 1973. He joined the faculty at Brandeis University in Waltham in 1974. In 2002, he became associated with University of Maine.

 

Michael Rosbash was born in 1944 in Kansas City, USA. He received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following three years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, USA.

 

Michael W. Young was born in 1949 in Miami, USA. He received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York.

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