Nobel Prize in Physiology or Medicine 2017: Molecular Clock Genes and the Circadian Rhythm

This note covers the Nobel Prize in Physiology or Medicine 2017: who won it, how fruit flies helped scientists find the genes that run a living cell's internal clock, how the discovery unfolded over several decades, why a 24-hour molecular clock matters for health, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2017 awarded for?

The 2017 prize went jointly to three scientists "for their discoveries of molecular mechanisms controlling the circadian rhythm". In plain words, they worked out how a single cell can count roughly 24 hours on its own, without looking at a clock or even seeing daylight.

Almost every living thing, from plants to humans, keeps a daily rhythm called a circadian rhythm (from the Latin for "around" and "a day"). Sleep, body temperature, hormone release and alertness all rise and fall on this cycle.

For decades biologists knew the rhythm existed but could not say what inside a cell actually produced it.

The laureates found the answer by studying a gene and a protein that switch each other on and off in a loop lasting about a day.

The award is formally called the Nobel Prize in Physiology or Medicine, and this is how its full official name should be written.

Who are the laureates?

All three laureates shared the prize equally, and all three built their careers largely around studying this same tiny insect.

Jeffrey C. Hall

Jeffrey C. Hall was born on 3 May 1945 in New York, NY, USA. At the time of the award he was affiliated with the University of Maine, Maine, ME, USA, and held one third of the prize.

Hall earned his doctorate at the University of Washington in Seattle in 1971 and worked for many years at Brandeis University before his later association with the University of Maine.

Working closely with Michael Rosbash, he helped isolate the period gene in 1984 and showed that the protein it makes rises at night and falls during the day.

Michael Rosbash

Michael Rosbash was born on 7 March 1944 in Kansas City, MO, USA. At the time of the award he was affiliated with Brandeis University, Waltham, MA, USA, and the Howard Hughes Medical Institute, USA, and held one third of the prize.

He received his doctorate from the Massachusetts Institute of Technology in 1970. Collaborating with Hall at Brandeis, he co-isolated the period gene and proposed that its protein, PER, blocks its own gene in a feedback loop.

Michael W. Young

Michael W. Young was born on 28 March 1949 in Miami, FL, USA. At the time of the award he was affiliated with Rockefeller University, New York, NY, USA, and held one third of the prize.

He earned his doctorate at the University of Texas in Austin in 1975. Working independently at Rockefeller, Young discovered the timeless gene in 1994 and the doubletime gene in 1998, filling in missing pieces of the clock mechanism.

What problem were scientists trying to solve?

Living organisms are adapted to the spinning of the Earth, which creates regular cycles of light and dark every 24 hours. Long before anyone understood genes, naturalists noticed that plants and animals seemed to anticipate these cycles rather than merely react to them.

In 1729 the French astronomer Jean Jacques d'Ortous de Mairan placed a mimosa plant, whose leaves normally open towards the sun by day and close at dusk, into constant darkness.

The leaves kept opening and closing on their usual daily timing even without any change in light. This suggested the plant carried its own internal timer rather than simply responding to sunlight.

Draw two mimosa plants side by side. The left plant sits in normal day and night, leaves open by day and closed at night.

The right plant sits inside a dark box with no light at all, yet its leaves still open and close on roughly the same daily timing, showing the rhythm comes from inside the plant.

For much of the twentieth century it stayed unclear whether such rhythms came from an internal clock or from some outside signal scientists had not yet detected.

In 1971 Seymour Benzer and his student Ronald Konopka, working with fruit flies, found mutant flies whose daily activity cycle was broken, shortened or lengthened.

Genetic mapping suggested all three mutations sat in the same stretch of the fly's X chromosome, in a gene later named period.

This was the first clue that a single gene could control a whole organism's daily rhythm, but nobody yet knew how.

How was the first clock gene found?

The next step needed the actual DNA sequence of the period gene, not just its rough location. In 1984, working independently but on the same problem, Hall and Rosbash at Brandeis University and Young at Rockefeller University succeeded in isolating the period gene.

Having the gene's sequence, however, did not by itself explain the clock. Hall and Rosbash then measured the amount of the protein the gene makes, called PER, inside fly neurons over the course of a day.

They found that PER protein builds up steadily through the night and is broken down during the day, so its level rises and falls on roughly the same 24-hour cycle as the fly's behaviour.

The amount of period messenger RNA, the molecule copied from the gene before a protein is built, also rose and fell on a daily cycle, and its peak came several hours before the peak of PER protein itself.

This gap between the two peaks turned out to be an important clue to how the clock kept itself ticking steadily rather than running too fast or too slow.

How does the feedback loop keep the clock ticking?

Hall and Rosbash proposed a simple but powerful idea: the PER protein itself blocks the activity of the period gene that makes it.

This kind of arrangement, where a protein switches off its own gene, is called a negative feedback loop, and it can make levels rise and fall in a repeating cycle instead of settling at a constant amount.

1. During the night, the period gene is active and is copied into period messenger RNA.
2. The messenger RNA moves out of the nucleus and is used as a template to build PER protein in the cytoplasm.
3. PER protein slowly accumulates in the cell and eventually moves into the nucleus.
4. Inside the nucleus, PER protein blocks the period gene, so less new messenger RNA and protein are made.
5. As existing PER protein is gradually broken down, the block is lifted and the period gene switches back on, starting the cycle again roughly 24 hours later.

One puzzle remained: PER protein is built in the cytoplasm, outside the nucleus, so something had to help it enter the nucleus at the right time.

Michael Young solved this in 1994 by discovering a second clock gene, timeless, which makes a protein called TIM.

Young showed that PER and TIM bind to each other, and only this paired PER-TIM combination can enter the nucleus and switch off the period gene, closing the feedback loop.

What other genes complete the clockwork?

A pure PER-TIM feedback loop still left a question open: what sets the exact speed of the cycle so that it matches a 24-hour day rather than running faster or slower? In 1998 Michael Young identified a third clock gene, doubletime, which makes the protein DBT.

DBT is an enzyme that attaches a phosphate group to PER, a chemical tag that marks PER for breakdown by the cell.

By controlling how quickly PER is destroyed, DBT delays the build-up of PER protein and helps stretch the whole cycle to close to 24 hours.

Later work by the same laureates and other researchers identified further proteins needed to switch the period gene back on after it is blocked, and proteins that let light reset the clock each day.

Two of these, named CLOCK and CYCLE, act as the "on switches" that drive the next round of period and timeless activity, completing a stable loop of interacting genes and proteins.

Once this fruit fly mechanism became clear, researchers found that cells in mice, other animals and humans use very similar genes and the same basic feedback loop to keep their own 24-hour clocks running, including a master clock in the suprachiasmatic nucleus, a part of the human brain within the hypothalamus.

How did the discovery unfold?

Why does it matter?

The laureates' work showed that the daily clock inside our cells runs on the same basic feedback-loop principle in flies, plants and humans.

A large share of our genes switch on and off following this clock, so it affects far more than sleep: the press release named behaviour, hormone levels, sleep, body temperature and metabolism among the functions it regulates.

When the body's internal clock falls out of step with the outside world, such as after flying across several time zones, the familiar discomfort of jet lag follows because different organs and systems take time to resynchronise.

More seriously, there are indications that a chronic mismatch between a person's lifestyle and their inner clock is linked to a raised risk of various diseases.

The Nobel Committee's materials describe the laureates as having been able, in the Committee's words, to "peek inside our biological clock and elucidate its inner workings", turning a long-standing mystery about daily rhythms into a well-defined molecular mechanism.

Because almost every multicellular organism studied so far uses a related transcription-translation feedback loop, the discovery opened an entire research field, circadian biology, connecting basic gene regulation to practical questions about shift work, jet lag and the timing of disease risk.

How does this connect to what you study?

This discovery sits squarely inside topics most school biology courses cover under genetics and cell biology: how a gene is copied into messenger RNA, how that RNA is used to build a protein, and how a protein can feed back to switch its own gene off.

The fruit fly clock is simply a vivid, real example of this gene-to-protein-to-feedback pathway running on a 24-hour timer.

It also connects to human physiology topics such as the nervous and endocrine systems, since the same kind of molecular clock in human cells helps set sleep patterns, hormone release, body temperature and blood pressure.

Studying this prize is a useful way to see classroom ideas about genes and proteins applied to a concrete, everyday phenomenon that every student has experienced in the form of feeling sleepy at a particular time of day or struggling to adjust after a long flight.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2017 was awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young, each receiving one third of the prize, "for their discoveries of molecular mechanisms controlling the circadian rhythm".

The announcement was made on 2 October 2017 by the Nobel Assembly at Karolinska Institutet.

Using fruit flies, the laureates isolated the period gene in 1984 and later found the timeless (1994) and doubletime (1998) genes, showing how a protein feedback loop keeps a roughly 24-hour clock running inside cells.

All three laureates were born and worked in the United States, at the University of Maine, Brandeis University and Rockefeller University respectively, and the discovery underlies understanding of sleep, jet lag and related health effects.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Circadian rhythm — a biological cycle lasting roughly 24 hours, found in plants, animals and humans.
• Gene — a stretch of DNA that carries instructions for making a particular protein.
• period gene — the first circadian clock gene isolated, found in fruit flies in 1984.
• PER protein — the protein made from the period gene, which builds up at night and is broken down by day.
• timeless gene — a clock gene discovered in 1994 whose protein TIM pairs with PER to enter the nucleus.
• doubletime gene — a clock gene discovered in 1998 whose protein DBT marks PER for breakdown, helping set the clock's pace.
• Negative feedback loop — a system in which the product of a process reduces or blocks that same process.
• Messenger RNA (mRNA) — the molecule copied from a gene's DNA and used as a template to build a protein.
• Nucleus — the part of a cell containing its DNA, where PER-TIM must enter to block the period gene.
• Phosphorylation — the chemical addition of a phosphate group to a protein, here used by DBT to mark PER for breakdown.
• CLOCK and CYCLE proteins — proteins that switch on the period and timeless genes, driving the next cycle of the loop.
• Jet lag — tiredness and discomfort caused when the body's internal clock is out of step with a new time zone after travel.
• Zeitgeber — an external cue, such as light, that resets or synchronises an internal biological clock.

Common errors and misconceptions

• Misconception: The three laureates discovered that a biological clock exists. Correct: Earlier scientists, such as de Mairan and later Benzer and Konopka, already showed such a clock existed; Hall, Rosbash and Young explained its molecular mechanism.
• Misconception: The period gene alone fully explains the clock. Correct: The period gene works together with timeless, doubletime, clock and cycle in an interlocking feedback loop.
• Misconception: PER protein level stays constant through the day. Correct: PER protein rises through the night and is degraded during the day, oscillating on a roughly 24-hour cycle.
• Misconception: All three laureates worked together in one laboratory. Correct: Hall and Rosbash collaborated at Brandeis University, while Young worked independently at Rockefeller University.
• Misconception: The clock mechanism found in fruit flies applies only to insects. Correct: Similar feedback-loop clock genes operate in other multicellular organisms, including humans.
• Misconception: Jet lag happens because of tiredness from travel alone. Correct: Jet lag reflects a mismatch between the body's internal 24-hour clock and the new local time.
• Misconception: The prize was awarded for inventing a treatment for sleep disorders. Correct: The prize recognised discovery of the molecular mechanisms controlling circadian rhythm, not a treatment.

Exam-style questions with model answers

Q1. In which year was the period gene isolated, and by whom? [1 mark]

1. The period gene was isolated in 1984 by Jeffrey Hall and Michael Rosbash at Brandeis University, and independently by Michael Young at Rockefeller University.

Q2. State the official citation for the Nobel Prize in Physiology or Medicine 2017. [2 marks]

1. The prize was awarded "for their discoveries of molecular mechanisms controlling the circadian rhythm", recognising work on how genes and proteins create a roughly 24-hour internal clock in cells.

Q3. Explain the basic feedback loop proposed by Hall and Rosbash for the period gene. [4 marks]

1. Hall and Rosbash proposed that the period gene is transcribed at night into messenger RNA, which is used to build PER protein in the cytoplasm.
2. PER protein gradually accumulates and moves into the cell nucleus.
3. Inside the nucleus, PER blocks the activity of its own period gene, reducing further production of messenger RNA and protein.
4. As PER protein is slowly broken down, the block is removed and the period gene switches on again, so the whole cycle repeats roughly every 24 hours, forming a negative feedback loop.

Q4. What role did Michael Young's discoveries of timeless and doubletime play in completing the clock mechanism? [4 marks]

1. Young found that the PER protein made in the cytoplasm needed help to enter the nucleus, and in 1994 he discovered the timeless gene, whose protein TIM binds to PER.
2. Only the paired PER-TIM complex can enter the nucleus and block the period gene, explaining how PER reaches its site of action.
3. In 1998 Young discovered doubletime, whose protein DBT adds phosphate groups to PER, marking it for breakdown.
4. This controlled breakdown delays PER's build-up, helping the whole cycle settle close to 24 hours instead of running faster or slower.

Q5. Discuss, with examples from the sources, why the discovery of the circadian clock mechanism matters beyond fruit flies. [5 marks]

1. The laureates showed that a protein feedback loop involving genes such as period, timeless and doubletime keeps a roughly 24-hour clock running inside individual cells.
2. Similar clock genes and feedback mechanisms were later found in other multicellular organisms, including plants, animals and humans, showing the principle is widely shared across life.
3. In humans, this internal clock regulates behaviour, hormone levels, sleep, body temperature and metabolism, so disruption of the clock can affect many body systems at once.
4. Travel across time zones causing jet lag is described as a temporary mismatch between the external environment and the internal clock, which explains why adjustment takes several days rather than happening instantly.
5. There are also indications that chronic misalignment between lifestyle and the internal clock is associated with increased risk of various diseases, giving the discovery relevance to public health, shift work and sleep medicine, and opening up circadian biology as an active research field.

Q6. Name the three Nobel laureates in Physiology or Medicine 2017 and their respective affiliations at the time of the award. [2 marks]

1. Jeffrey C. Hall was affiliated with the University of Maine, Michael Rosbash with Brandeis University and the Howard Hughes Medical Institute, and Michael W. Young with Rockefeller University, all in the USA.

Q7. Why was de Mairan's 1729 mimosa experiment important for circadian biology, even though it came long before any gene was identified? [3 marks]

1. De Mairan placed a mimosa plant, whose leaves normally open by day and close at night, into constant darkness.
2. The leaves kept opening and closing on roughly their usual daily timing even without any change in outside light.
3. This suggested for the first time that the daily rhythm came from something inside the organism itself, rather than being a direct reaction to sunlight, an idea the twentieth-century laureates later explained at the molecular level.

Key takeaways

• The 2017 Nobel Prize in Physiology or Medicine honoured Jeffrey C. Hall, Michael Rosbash and Michael W. Young for finding how circadian rhythms work at a molecular level.
• Working with fruit flies, Hall and Rosbash co-isolated the period gene in 1984 at Brandeis University, alongside Michael Young at Rockefeller University.
• The PER protein made from the period gene builds up at night and is broken down during the day, oscillating on a 24-hour cycle.
• PER protein blocking its own gene once inside the nucleus forms a negative feedback loop that keeps the clock self-sustaining.
• Michael Young discovered the timeless gene in 1994 and the doubletime gene in 1998, explaining how PER enters the nucleus and how the cycle's speed is set.
• Similar clock genes operate in other multicellular organisms, including humans, where the clock affects sleep, hormones, temperature and metabolism.
• Jet lag and health risks linked to chronic circadian disruption are practical consequences of this molecular clock mechanism.

Test yourself

What does the word "circadian" mean, and where does it come from?

Circadian comes from the Latin words for "around" and "a day", describing a biological rhythm lasting roughly 24 hours.

Which gene did Hall, Rosbash and Young isolate in 1984?

In 1984 they isolated the period gene, the first gene shown to control a fruit fly's daily circadian rhythm.

What happens to PER protein levels over 24 hours?

PER protein gradually accumulates in the cell during the night and is then broken down during the day, repeating this cycle daily.

Which gene did Michael Young discover in 1994, and what does its protein do?

Michael W. Young works at Rockefeller University in New York, USA, and discovered the timeless gene, whose TIM protein pairs with PER to enter the nucleus.

What role does the doubletime gene's protein, DBT, play in the clock?

DBT adds phosphate groups to PER protein, marking it for breakdown and helping to delay and pace the 24-hour cycle correctly.

Why do travellers experience jet lag after crossing several time zones?

Jet lag happens because the body's internal circadian clock is temporarily out of step with the new local time at the destination.

On what date was the Nobel Prize in Physiology or Medicine 2017 announced?

The prize was announced on 2 October 2017 by the Nobel Assembly at Karolinska Institutet, Sweden.