The Rhythm of Life

Graduate Division

This year’s Nobel Prize winners in medicine were three unique scientists who deconstructed how cells keep time.

On Oct. 2, the Nobel Assembly awarded its 2017 Prize in Physiology or Medicine to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young “for their discoveries of molecular mechanisms controlling circadian rhythms.”

The foundations these men laid in the biology of timekeeping established greater understanding of the connection between our genetic material and the Earth’s daily rotation.

These pioneers were not the first to think about how organisms keep time throughout the day — or chronobiology. Jurgen Aschoff and Cole Pittendrigh are regarded as the field’s founders, developing the concept of innate circadian rhythms (meaning “around a day”) and their environmental influences.

However, much of this early work was based on behavioral and physiological observations; the recent laureates’ breakthroughs gave chronobiology a molecular foundation.

Dozens of proteins in every cell in our body — and in those of nearly all organisms — coordinate with each other similarly to a complex timepiece.

Each protein accumulates, is activated, and degrades on a specific 24 hour schedule, with their relative abundances dictating to the cell the approximate time and therefore which of its daily processes to undertake.

As with many successful scientists, Hall, Rosbash, and Young began their careers in wildly different subjects than those where they finally performed their most enduring work. Each became separately interested in circadian rhythms through their research on fruit fly neurobiology.

Hall and Rosbash initially worked together at Brandeis university in competition with Young’s lab at Rockefeller. Their groundbreaking work began with the unveiling of one cog in the molecular clock: the dynamics of the Period protein, whose numbers swell and ebb on a daily schedule.

Louis Ptacek, a neurologist at UCSF, began working on circadian biology a few years after the Nobel laureates’ prize-winning work was published.

“it was clear pretty early on that this was incredibly important area that would be recognized by prizes,” said Ptacek.

In 1984, the two groups simultaneously published a paper outlining their discovery of the Period (Per) gene. Over the next decade and a half, the field scrambled to uncover more components of the cellular clock in flies and other organisms.

“There was a graduate student in my lab who was going around with a fly swatter trying to catch house flies,” Ptacek said. “He wanted to clone the house fly period gene. That was the first I ever heard about Per and circadian rhythms.”

Eventually, as chronobiology’s significance as a field grew, Ptacek too found his studies in human genetics redirecting towards the subject.

Hall, Rosbash, and Young paved the way for Ptacek and other groups of scientists to translate their findings into important insights regarding human physiology.

Circadian genes were found to be important for sleep quality, metabolic efficiency, and immune function. Their disruption leads to greater rates cancer, obesity, neurodegeneration, depression, and overall mortality; indicating their essential role in all aspects of our lives.

Today, medical professionals are even using knowledge of Period and other timekeeping cogs to understand how to time treatments for the best response.

Vaccinations have been shown to be much more effective when given in the early morning instead of evening and patients allowed to maintain a consistent sleep-wake schedule tend to recover much faster from a variety of major afflictions, both of which are dependent on the workings of these “clock” proteins

As with all major awards in the sciences, the Nobel prize-winning work was only made possible through the previous efforts of preceding great researchers. No breakthroughs are made in a vacuum, and as a result some scientists are unfortunately overlooked.

“It was Seymour Benzer and Frank Konopka who first found the mutant Per alleles; they didn’t find the gene, but they discovered the phenotype,” explained Ptacek.

Benzer’s work provided the foundation for Per’s discovery. After observations of mutant flies whose internal clocks ticked slower or faster than the standard 24 hour rhythm, his group named the responsible gene Period.

“It’s a shame Benzer couldn’t share in the prize as well.”

Since their discovery, each lab has continued their groundbreaking research, adding more proteins to the increasingly complex picture we have of the cellular clock. Rosbach and Young still run their respective groups, further investigating circadian rhythms in flies, while Hall has retired a professor emeritus from Brandeis.