2017 Nobel Prize in Physiology or Medicine: Hall, Rosbash, and Young Discover the Gears of the Body's Clock
What You'll Learn in This Article
The 2017 Nobel Prize in Physiology or Medicine was awarded to three American scientists who elucidated the molecular clock of circadian rhythm β how our bodies maintain a 24-hour cycle even without external cues. Jeffrey Hall and Michael Rosbash at Brandeis University first cloned the Period (PER) gene in fruit flies in 1984. Michael Young at Rockefeller University discovered subsequent genes such as Timeless (TIM) and Doubletime (DBT) in the 1990s. The combined discoveries of the three laboratories revealed that the body's clock is a self-oscillating oscillator operating with a negative feedback loop, which forms the molecular basis of rhythms in sleep, metabolism, hormones, immunity, and cognition. The practical discussions of today, such as jet lag, health risks of night shifts, and chronotherapy, are all based on this discovery.
Beyond Common Sense: The Body's Clock is Made by Genes, Not the Sun
The common belief that "our body's 24-hour cycle is due to sunlight" is only half true. In reality, even when humans are isolated in complete darkness or under constant light, a rhythm of approximately 24 hours is maintained. Sleep, body temperature, hormone secretion, and cognitive performance all continue with their own rhythm, independent of external stimuli. This means that there is a self-oscillating oscillator within the body, and until the late 20th century, the nature of this oscillator remained a mystery.
The three laureates revealed the molecular circuitry of this oscillator. A few clock genes create a negative feedback loop that regulates each other, generating a self-oscillating rhythm of approximately 24 hours. During the day, PER protein is synthesized and accumulates at night. During the night, PER inhibits the transcription of its own gene, stopping its own production. When PER is degraded, the gene is turned on again, and a new cycle begins. This self-regulating loop creates a cycle of approximately 24 hours.
In terms of a CS framework, this is a natural counterpart to hardware clock oscillators. Just as a crystal oscillator creates a clock cycle through self-oscillation, clock genes and their proteins create a 24-hour cycle through self-oscillation. All other rhythms in the body β sleep-wake cycles, cortisol rhythms, body temperature rhythms, and digestive rhythms β are synchronized with this master clock. Sunlight is just an external synchronization signal that forces the clock to reset, not the clock itself.
The Zeitgeist: The Beginning of the Candlelight Government and the Explosion of #MeToo
In 2017, South Korea began with the results of candlelight vigils. On March 10, the Constitutional Court confirmed the impeachment of President Park Geun-hye, and on May 9, Moon Jae-in was elected in a snap election and inaugurated on May 10. This marked the beginning of the "candlelight government," with prosecution reform, clearing out corruption, and income-led growth as the government's priorities. In December, a task force reviewing the agreement on the comfort women issue announced its findings, creating a new variable in Korea-Japan relations.
At the same time, China's "Thaad retaliation" (restrictions on Korean culture) continued, severely impacting the K-pop, drama, and tourism industries. Lotte faced significant difficulties in its Chinese operations due to providing the Thaad site. North Korea's missile tests increased sharply, reaching the highest level of tension between the US and North Korea, and Trump and Kim Jong-un continued to exchange harsh statements.
In the world, Trump's first year in office began. He continued to take actions that challenged previous international norms, such as announcing the withdrawal from the Paris Agreement in June, threatening the Iran nuclear deal, and issuing anti-immigration executive orders. On October 1, the Las Vegas mass shooting resulted in 59 deaths, becoming the deadliest mass shooting in US history and reigniting the debate over gun control.
In October, the New York Times published an exposΓ© on Harvey Weinstein's sexual harassment scandal, and the #MeToo movement spread around the world. Sexual harassment allegations continued to surface in various fields, including film, media, and politics, and this is recorded as a decisive turning point in the women's rights movement of the late 21st century.
In the tech world, the iPhone X was released in November, opening a new standard for smartphone interfaces with Face ID and the removal of the home button. In December, Bitcoin exceeded $20,000, marking the beginning of the first major cryptocurrency boom. In October, DeepMind released AlphaGo Zero, unveiling a system that became the strongest in the world through self-learning without human game data, opening a new horizon for reinforcement learning.
In the scientific community, this award was an interesting story about generations. All three laureates began their fruit fly genetics in the 1970s, and they were people who had devoted more than 40 years to this one topic. In an era when the Nobel Prize is likely to shift to other topics, they are often cited as an example of people who devoted their lives to a single problem.
The Narrative: Fruit Flies and 40 Years, the Gears of Three Laboratories
Seymour Benzer is a key figure in this story. In the early 1970s, his lab at Caltech opened the door to fruit fly behavioral genetics. His student, Ron Konopka, screened for three types of fruit fly mutants with abnormal periods β short period, long period, and arrhythmic β in 1971. It was confirmed that all three mutants were different variations of a single gene, called Period (per), but the technology to actually clone the gene did not exist, and its identity remained a mystery for more than 10 years.
Jeffrey Hall (1945β) was born in New York, USA. He received his Ph.D. from Benzer's lab at Caltech and settled at Brandeis University. Michael Rosbash (1944β) was born in Kansas City, USA. He began his research at Rosbash's lab at Brandeis University. The two were colleagues at the same university and began collaborating.
Michael Young (1949β) was born in Miami, USA. He received his Ph.D. from the University of Wisconsin and established his own lab at Rockefeller University, where he spent his life.
From the early 1980s, the three laboratories began a competition to actually clone the per gene. Genetics can roughly indicate the location of a gene, but to obtain the actual sequence of the gene, it is necessary to clone the gene by physically extracting it from a DNA library. In 1984, Hall and Rosbash's team at Brandeis and Young's team at Rockefeller cloned the per gene almost simultaneously, and the two papers were published together.
However, the per gene alone could not explain the clock. As observations accumulated that PER protein levels were low during the day and high at night, the question became: what mechanism creates this oscillation? In the early 1990s, Hall and Rosbash's team reported that PER inhibits the transcription of its own gene. In other words, it is a negative feedback loop that regulates itself. This observation confirmed the basic architecture of the clock circuit.
Young's lab discovered subsequent components. In 1994, the Timeless (TIM) gene β a partner protein that binds to PER and stabilizes it. In 1998, Doubletime (DBT) β a kinase that regulates the timing of PER degradation by phosphorylating it. With these components, the fine gears of the clock circuit began to fall into place. PER synthesis during the day β PER-TIM binding and stabilization at night β PER-TIM moving to the nucleus and inhibiting its own transcription β PER degradation and release of inhibition β a new cycle was revealed.
Subsequently, a similar group of genes was found in mice. In humans, there are clock genes such as PER1, PER2, PER3, CRY1, CRY2, BMAL1, and CLOCK, and they form a surprisingly similar circuit to that of fruit flies. The suprachiasmatic nucleus (SCN) in the human brain is the master clock, and the SCN neurons maintain their self-oscillation through this clock gene circuit. Almost all cells in the body also have their own clock and are synchronized with the SCN.
Key Achievements: The 24-Hour Oscillator in a CS Framework
If you were to draw the molecular circuit of the circadian clock as a pipeline, it would look like this:
- Morning phase: The CLOCK-BMAL1 heterodimer binds to the promoter of the PER and CRY genes in the nucleus, activating their transcription. PER and CRY proteins begin to be synthesized slowly in the cytoplasm.
- Evening phase: PER and CRY proteins accumulate in the cytoplasm. At this time, DBT (casein kinase 1) begins to phosphorylate PER, starting a countdown to degradation. However, if TIM or CRY binds, this degradation is delayed, and accumulation continues.
- Night phase: The PER-CRY complex moves to the nucleus and binds to CLOCK-BMAL1, inhibiting the transcription of its own gene. Closure of the negative feedback loop. This state is maintained for several hours.
- Dawn phase: PER and CRY begin to degrade due to phosphorylation and accumulation. As the inhibition gradually decreases, CLOCK-BMAL1 is reactivated, and a new cycle begins.
The nature of this circuit is a self-delayed oscillator with negative feedback. The key principle is the time delay between transcription, translation, and degradation. Even if a gene is turned on, it takes several hours for the protein to be produced, accumulate, and degrade, and this delay determines the period of the oscillation. In the language of CS, this is a delay-based oscillator or a relaxation oscillator β exactly corresponding to the old design principle of hardware clock circuits.
Light-induced synchronization is the mechanism that tunes this system. When morning sunlight reaches the retina, a signal is sent to the SCN, and this signal induces the CRY protein to become active, adjusting the phase of the clock. This is why artificial light in the late evening can disrupt this synchronization.
However, it is important to note the limitations of this analogy. Unlike a pure hardware oscillator, the molecular clock has significant noise and flexibility. Individual cell clocks are not very accurate, but the thousands of neurons in the SCN synchronize with each other to create a stable master clock. In addition, this clock has the flexibility to adjust its phase in response to various environmental signals, such as temperature, sleep, diet, and exercise, which is not found in a pure deterministic hardware clock.
Why It Matters: Sleep Medicine, Chronotherapy, and the Dangers of Night Shifts
First, it laid the molecular foundation for sleep medicine. It was discovered that familial advanced sleep phase syndrome is caused by a specific mutation in the human PER2 gene, which provided definitive proof that human sleep patterns are regulated at the genetic level. Subsequently, it was confirmed that several other sleep disordersβsuch as delayed sleep-wake phase disorder and irregular sleep-wake rhythm disorderβare associated with mutations in clock genes.
Second, it led to the clinical application of chronotherapy. Observations accumulated that the efficacy and side effects of drugs vary significantly depending on the time of day they are administered. For example, various anticancer drugs, antihypertensive drugs, and anti-inflammatory drugs have a more favorable benefit-risk ratio when administered at specific times of the day. This is due to the rhythm of the target tissue's own clock and drug metabolism. Since the early 21st century, chronotherapy has been treated as a formal variable in several clinical trials, and some guidelines already reflect this.
Third, it provided a molecular understanding of the health risks of night shifts. In 2007, the WHO IARC classified night shift work as a Group 2A carcinogen (possibly carcinogenic to humans). Epidemiological observations have accumulated showing that night shift workers have an increased risk of breast cancer, prostate cancer, cardiovascular disease, and metabolic syndrome, and it is now understood that this risk comes from the continuous disruption of the clock gene rhythm. This has also influenced discussions on social labor policies.
Fourth, it disseminated practical knowledge for managing jet lag. It takes about one day per time zone for the body's master clock to adapt to a new time zone, and during this process, cognitive performance, sleep quality, and digestive function are impaired. It has been confirmed through several studies that interventions such as melatonin supplementation, adjusting the timing of light exposure, and adjusting meal times can accelerate adaptation to jet lag, and international travelers and professional sports teams are using this.
Fifth, it revealed a strong connection with metabolic and cardiovascular health. The molecular basis for the observation that intermittent fasting or time-restricted eating is effective in improving metabolic health lies in the clock system. Each cell in the liver, muscle, and adipose tissue has its own clock, and this clock regulates the expression of metabolic genes in a time-of-day-dependent manner. The perspective is that when meal times are out of sync with this rhythm, metabolism is disrupted.
Sixth, it highlighted the relationship between aging and the decline of the clock system. Several studies have confirmed that as people age, the amplitude of clock genes in the SCN decreases and the phase becomes disrupted. Some of the sleep disorders, metabolic decline, and cognitive decline in old age are associated with this decline in the clock system, and targeting the clock system is becoming a new research direction for anti-aging interventions.
The story that started with three short- and long-period mutants in fruit flies has become the root of our understanding of human sleep, metabolism, and health after 40 years of experimentation. The condensed point of this award is that we already have a clock inside our bodies, and now we know the names of its gears.
β Previous: 2016 Nobel Prize in Physiology or Medicine β Next: 2018 Nobel Prize in Physiology or Medicine