Nobel In Physiology, Medicine Awarded To Three Americans

By Ariana Eunjung Cha, Washington Post

Three Americans — Jeffrey C. Hall, Michael Rosbash and Michael W. Young — have won the 2017 Nobel Prize in physiology or medicine for their work on molecular mechanisms that control circadian systems.

Hall was born in New York, Rosbash in Kansas City, and they both worked at Brandeis University. Michael Young was born in Miami and worked at Rockefeller University.

In announcing the winner in Stockholm, the prize committee said the scientists elucidated how a life-form's “inner clock” can fluctuate to optimize our behavior and physiology. “Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth's revolutions.”

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 travelers experience when crisscrossing time zones.

“The circadian system has its tentacles around everything,” Rosbash explained in an interview with the Howard Hughes Medical Institute Bulletin in 2014. “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 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 percent of humans worldwide have a mutation in the clock genes that is associated with delayed sleep.

“Many of these individuals show up in sleep clinics wondering what to do. We now have a molecular and genetic basis… That gives us a target to work on,” he told reporters shortly after the announcement.

The scientists’ paradigm-shifting work revolves around three genes dubbed “period,” “timeless” and “doubletime.”

Their early work took place in 1984 when Hall and Rosbash worked together at Brandeis and Young at Rockefeller University to isolate 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.

But to have this effect, the protein would have to reach the genetic material in the cell nucleus, and no one was able to figure out how it got there until Young, in 1994, discovered a second clock gene, now known as “timeless.” 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.

Researchers in the field of circadian biology — or “chronobiology,” as it is nicknamed — said that the scientists’ work has far-reaching consequences for all life on Earth.

Among them, “major impacts to human health that have yet to be fully recognized,” Duke University’s Xinnian Dong said.

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, chief of the infectious diseases at the Yale University School of Medicine, 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. She said that it wasn’t clear at the time where the field was heading and that many felt “it was very esoteric, kind of tangential.” But thanks to the Nobel Laureates’ work, the field has exploded and we now know that there are circadian clocks in all our body organs — in the liver, in the gut, in the lung, for instance — and that much of our physiology is rhythmic. Our blood pressure and body temperatures rise and fall at different times of day.

Sehgal's own research these days involves looking at how sleep appears to be controlled by the circadian clock because 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.

This year's winners probably weren't in a lot of Nobel Prize betting pools, because the medicine Nobel is notoriously hard to predict. In fact, during a news conference at which the awards were announced, a member of the Nobel Assembly at Karolinska Institutet said that when he informed Rosbash that he had received the award, his response was, “You are kidding me.”

The highly secretive Nobel committee does not release a list those under consideration for its awards and never has in its 116-year history. The names being thrown around as deserving of the prize in the weeks before the announcement is always very long and highly speculative. David Pendlebury, formerly of Thomson Reuters and now with Clarivate Analytics, bases his picks on an extensive data analysis and has an impressive track record of correctly picking numerous Nobel Laureates over the past 15 years (although not always in the right year).

This year, he identified as possible winners Yuan Chang and Patrick Moore of the University of Pittsburgh for their work with human herpesvirus 8 (KSHV/HHV8) which is associated with cancer; Lewis Cantley of Weill Cornell of Medicine for the discovery of a cell signaling pathway and its role in tumor growth; and Karl J. Friston of the University College London for his work on algorithms and techniques for the analysis of brain imaging data. Perhaps one of those picks will win next year.

In recent years, the Nobel in medicine has been awarded for breakthroughs in a wide range of work in human biology: a Japanese scientist who discovered a key mechanism in our body’s defense system that involves recycling parts of cells and plays an important role in cancer; a trio who worked on treatments for river blindness and malaria; and researchers who deciphered the brain's “GPS” that allows us to orient ourselves in space.

The Nobel Prize in physics will be announced on Tuesday, October 3rd, the chemistry award on Wednesday, the 4th, and the peace prize on Friday, October 6th. An award in economics in memory of Alfred Nobel (which is not one of the original Nobel Prizes) is still to be announced, and the date of the literature Nobel will be announced soon.