Drosophila melanogaster, the fruit fly that has served as the test bed of genetics for over a century, has again yielded fruit. The Nobel Prize in Physiology or Medicine has gone to three American molecular biologists who have used Drosophila since the 1970s in their work on the circadian rhythm, the internal clock that keeps us in sync with the world. It tracks the rotation of the Earth, tells us when to go to sleep and when it’s time to get up, and prepares us for the routine bodily tasks that we perform through the day and night — and for the challenges that we may face.
The rhythm ensures that we are at maximum alert in the mid-morning, which is rather useful whether you are a hunter-gatherer out foraging or a captain of industry at a meeting. It exerts its influence in unseen ways, too, regulating the cycle of blood pressure and body temperature. It suppresses bowel movements just before midnight and relinquishes its control early in the morning, ensuring that we don’t wake ourselves during the period of deepest sleep and lowest metabolic rate. Humans share the circadian rhythm with animals, plants, fungi and even archaic life forms like cyanobacteria — single-cell organisms which are so far back on the evolutionary chain that they do not even have clearly defined cell nuclei.
The circadian rhythm has been observed from antiquity — a trireme captain who sailed the Arabian Sea under Alexander the Great described the nutation of tamarind leaves. The first scientific experiment concerning the phenomenon dates to 1729, when the French chronobiologist Jean-Jacques d’Ortous de Mairan observed that the diurnal opening and closing of the touch-me-not (Mimosa pudica) stays in time even when the plant is kept in complete darkness. That was the first step towards understanding the science of the circadian rhythm — the insight that it is endogenous, and not triggered by external stimuli like sunlight.
While the circadian rhythm has been understood and described in detail, the 2017 Nobel Prize in Physiology or Medicine has been awarded to Jeffrey C Hall and Michael Rosbash, lifelong colleagues at Brandeis University, and Michael W Young of Rockefeller University, for getting under the hood of its mechanism — the mainspring of the biological clock that makes us tick. Like so many of life’s processes, it turns out to be an autonomous negative feedback loop. And it wasn’t identified yesterday, either.
The story began in 1984, when Hall and Rosbash isolated a ‘period gene’, a difficult enterprise at the time. When they won the Canada Gairdner International Prize for their work in 2012, Hall revealed that a colleague had remarked that it was the first time that a gene associated with a single function had been isolated. In 1990, it was found that the mRNA written off the gene moved out of the cell nucleus and synthesised a ‘period protein’, which drifted back into the nucleus and blocked the ‘period gene’, preventing further production. The cycle restarted when the incidence of the period protein fell off. The on-off sequence produced a 24-hour sinus-like wave in the levels of the protein, corresponding with day and night. This is the tick-tock of the clock that powers the circadian rhythm.
However, while the rhythm is endogenic, it is open to correction. Most cells in the body seem to have it, and they connect with a biological clock in the central nervous system when they drift out of phase, in the way that Internet-connected computers synchronise their clocks with universal time servers. In addition, sensory stimuli like daylight synchronise the whole system with the world. A completely blind person has a working circadian rhythm, but in the absence of external correction or ‘entrainment’, he or she could be out of phase with the world.
People with sleep disorders may have similar problems — a circadian rhythm which is slightly out of phase with the external world. Jet lag is a catastrophic phase problem, with the sufferer hours out of sync with the world, and likely to be in a confusional state until external cues reset the body’s clock. That is why one is advised to follow the sleep cycle of the destination as soon as possible.
In recent years, medicine has engaged with the periphery of the circadian regulatory system. The use of melatonin, a sleep-management hormone secreted by the pineal gland, has become quite a fad, and it is prescribed to manage jet lag and insomnia. The importance of chronobiology, pioneered by researchers like Mairan, is appreciated and correlations may be discovered between the timing of the administration of medicines and their effectiveness. Lifestyle disorders like diabetes and cardiovascular disease have been connected with disordered circadian rhythms. And there is concern about the metabolic effects of professions which forcefully depart from the normal circadian rhythm — airline crews are at risk, and the call centre business can permanently reverse the worker’s day and night.
These are peripheral engagements, but an understanding of the mainspring of the body’s clock could permit deeper interventions. And, while the work of Hall, Rosbash and Young is at the intracellular level, it should lead to a better understanding of how the millions of clocks in the body work together. Eventually, it could help to completely unravel the secrets of the ascending reticular activating system, the structure in the brain stem which regulates the transition between sleep and wakefulness, is believed to be the seat of consciousness and answers the most fundamental human question with the calm assurance: “I exist.”
Jeffrey C Hall, 72
Received doctoral degree in 1971 at the University of Washington in Seattle, was postdoctoral fellow at Caltech, 1971-73, joined Brandeis University in Waltham in 1974, became associated with University of Maine in 2002
Michael Rosbash, 73
Received doctoral degree in 1970 at MIT, and was postdoctoral fellow at the University of Edinburgh in Scotland for the next three years. Since 1974, he has been on faculty at Brandeis University in Waltham, USA
Michael W Young, 68
Received doctoral degree at the University of Texas in Austin in 1975. From 1975-77, he was postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York
ALFRED NOBEL: The Man Behind the Prize
Alfred Nobel, Swedish chemist, engineer, inventor, businessman and philanthropist, was born in Stockholm on October 21, 1833. In 1867, at the end of several years of experimentation with the chemical nitroglycerine, Nobel patented dynamite, which revolutionised mining and civil engineering in the 19th century. He continued to work on explosives technology and other chemical inventions and, by the time of his death in 1896, had 355 patents. Nobel founded and owned a galaxy of companies, including, from 1894 until his death, Bofors.
On November 27, 1895, Nobel signed his third and last will, in which he left much of his wealth for the establishment of a fund, “the interest on which shall be annually distributed in the form of Prizes to those who, during the preceding year, shall have conferred the greatest benefit to mankind”.