Genes that Regulate Sleep and Circadian Rhythms – Lecture by Nobel Laureate Michael Young

TL;DR

Genes control circadian rhythms by building internal biological clocks whose mutations can stop rhythmicity or change its timing. In fruit flies, three mutations affecting one functional gene produced arrhythmic behavior or cycles of 19 and 28 hours, while rodent experiments identified the suprachiasmatic nucleus as a key clock tissue. Read on to see how plants, bees, butterflies, rodents, and flies reveal the mechanisms and practical value of biological timing.

Transcript

[Applause] right what a great audience and so many young faces this is what I came for to visit you who represent the future science this is not my first trip to China it's my first trip to this part of China but I've been coming here over the years my first trip was to Beijing to the National Institutes of life sciences and I made the mistake of b... Read More

Key Insights

• Circadian rhythms are internally generated cycles that continue when external timing signals are removed. A rodent kept in constant darkness maintained a predictable activity and rest pattern, but its cycle was not exactly 24 hours, supporting the existence of an internal biological pacemaker.
• The Colorado four o'clock uses rhythmic flower opening to coordinate with a nocturnal hawk moth. Its blooms remain closed during the hotter daytime and open at night, making pollination possible while potentially reducing the water cost associated with keeping petals open.
• Honeybee waggle dances communicate both food distance and direction. The duration of the central crossing indicates distance, while its orientation relative to vertical represents the food's direction in relation to the Sun's position above the horizon.
• Honeybees compensate for the Sun's movement while dancing for hours inside a dark hive. A forager gradually changes the dance orientation without returning outside to recheck the Sun, thereby preserving an accurate directional signal as the Sun's position changes.
• Monarch butterflies use a time-compensated Sun compass during migration. The clocks involved in this timing are located in their antennae, because painting the antennae black causes the butterflies to become disoriented and unable to maintain their migration route.
• The suprachiasmatic nucleus is a metabolically cycling region of the rodent hypothalamus. It shows greater metabolic activity during the day than at night, and its surgical removal eliminates the organized activity and rest rhythm observed in intact animals.
• Transplanting donor suprachiasmatic nucleus tissue can restore rhythms after the recipient's corresponding tissue has been surgically removed. This result identifies the nucleus as a tissue locus capable of driving rhythmic behavior and containing essential biological clock mechanisms.
• Fruit fly clock mutations can abolish rhythmicity or alter cycle length. Three mapped mutations produced arrhythmic behavior, a 19-hour period, or a 28-hour period, and preliminary mapping indicated that all affected one functional gene on the fly's X chromosome.

Questions & Answers

Q: How do genes control sleep and circadian rhythms?

Fruit fly experiments showed that mutations in a single functional gene could eliminate circadian rhythmicity or change the clock's period. The three mapped mutations produced arrhythmic behavior, a 19-hour cycle, or a 28-hour cycle, demonstrating that one gene can stop or retune biological timing.

Q: What is a circadian rhythm?

A circadian rhythm is an internally generated biological cycle with a period close to, but not necessarily exactly, 24 hours. Rodents maintained predictable activity and rest patterns in constant darkness, showing that the rhythm came from an internal pacemaker rather than an external time signal.

Q: Why does the Colorado four o'clock open its flowers at night?

The Colorado four o'clock opens when its nocturnal hawk moth pollinator is active and closes during the hotter daytime. Because opening its petals requires water to be transferred from the rest of the plant into the flowers, this timing may preserve water while making pollination possible.

Q: How does a honeybee waggle dance communicate a food source's location?

The waggle dance follows a figure-eight pattern and communicates both distance and direction. The time spent crossing the center indicates the food's distance, while the crossing's angle relative to vertical represents its direction in relation to the Sun.

Q: How do honeybees compensate for the Sun moving while they dance inside a dark hive?

A foraging honeybee can dance for hours inside the dark hive without returning outside to check the Sun. It gradually changes the dance's orientation to predict the Sun's new location, preserving an accurate directional signal through an internal timing system.

Q: Where is the migration clock located in monarch butterflies?

The clocks supporting the monarch butterfly's time-compensated Sun compass are located in its antennae. When researchers painted the antennae black, the butterflies became disoriented and could no longer maintain their migration route.

Q: What evidence shows that rodents have an internal biological clock?

A rodent kept in constant darkness with food continuously available continued to show a regular pattern of running-wheel activity and rest. Because the cycle persisted but was not exactly 24 hours, the experiment supported the existence of an internal circadian pacemaker.

Q: What role does the suprachiasmatic nucleus play in circadian rhythms?

The suprachiasmatic nucleus is a region of the rodent hypothalamus that cycles metabolically, with greater activity during the day than at night. Removing it eliminates organized activity and rest rhythms, while transplanting donor tissue can restore them, identifying it as a key tissue locus for the biological clock.

Summary

In this video, the speaker discusses the genetic control of circadian rhythms and its intersection with sleep and other physiological properties. They provide examples of circadian rhythms found in plants and animals, such as the opening and closing of flowers and the dance language of honeybees. The speaker explains the discovery of clock genes in fruit flies and how these genes work together to regulate circadian rhythms. They discuss the importance of these clocks in various organs and the implications for medical treatments. Finally, they present a case study of a sleep disorder called delayed sleep phase disorder and how a mutation in the cryptochrome 1 gene is associated with this disorder.

Questions & Answers

Q: What is the significance of circadian rhythms?

Circadian rhythms are biological processes that occur on a roughly 24-hour cycle, and they are found in many organisms. These rhythms are essential for synchronizing an organism's internal processes with the external environment, such as the day-night cycle. They regulate various physiological functions, including sleep/wake patterns, hormone release, digestion, metabolism, and gene expression.

Q: Can you provide an example of a circadian rhythm in plants?

Yes, one example is the circadian rhythm of flowering in plants. Some plants, like the mirabilis plant, have their flowers open at night and close during the day. This rhythm allows them to conserve water during the hot daytime and attract pollinators, such as nocturnal moths, during the night when they are active.

Q: How do honeybees communicate the location and distance of food to other bees?

Honeybees communicate the location and distance of food through a dance language. They perform two different types of dances: the round dance and the waggle dance. The round dance indicates that food is close to the hive, but it does not provide specific directions. The waggle dance, on the other hand, indicates the direction and distance of food. The direction is represented by the angle the bee forms during the figure-eight pattern, and the distance is represented by the time it takes the bee to complete the cross-over in the figure-eight.

Q: How does the circadian clock work in mammals?

In mammals, the circadian clock is located in a region of the brain called the suprachiasmatic nucleus (SCN). The SCN contains specialized cells that generate a 24-hour rhythm. These cells receive light input from the eyes, allowing them to synchronize with the external light-dark cycle. The clock genes period and timeless play a crucial role in this process. They are activated by transcription factors called clock and cycle, and their protein products inhibit the activity of clock and cycle themselves. This negative feedback loop generates the 24-hour oscillations of the clock.

Q: What is the significance of the discovery of clock genes in fruit flies?

The discovery of clock genes in fruit flies, known as Drosophila, was a major breakthrough in the study of circadian biology. These genes, including period and timeless, were found to be essential for regulating the fruit flies' circadian rhythms. Mutations in these genes led to altered sleep-wake cycles, providing strong evidence for their involvement in circadian rhythm regulation. This finding highlighted the importance of genetic control in circadian rhythms and paved the way for further research in other organisms.

Q: How do the clock genes period and timeless interact in circadian rhythm regulation?

In fruit flies, the period and timeless genes are coordinated by two transcription factors, clock and cycle. These transcription factors activate the transcription of both period and timeless genes, leading to the production of their corresponding RNA and protein products. The period and timeless proteins, when combined, form a complex that can enter the nucleus of cells and inhibit the activity of clock and cycle. This inhibition helps regulate the timing of gene expression and the oscillation of circadian rhythms.

Q: What is the significance of peripheral clocks in the body?

Peripheral clocks refer to the presence of circadian rhythms in various organs and tissues outside of the central pacemaker in the brain. These peripheral clocks allow different parts of the body to synchronize their activities with the central pacemaker and coordinate their functions. It enables different organs to anticipate and respond to environmental cues and maintain proper timing for specific physiological processes, such as digestion, metabolism, and hormone release. The synchronization between central and peripheral clocks is crucial for overall health and well-being.

Q: How do clocks in peripheral organs interact with each other and the central pacemaker?

The clocks in peripheral organs communicate with each other and with the central pacemaker in a coordinated manner. The central pacemaker, located in the brain, provides timing cues to peripheral organs through neural and hormonal signals. However, peripheral clocks can also operate independently and adapt to local signals, such as feeding patterns. Studies have shown that conflicting signals, such as a discrepancy between the timing of light exposure and feeding, can result in the desynchronization of peripheral clocks. This highlights the complex interaction between central and peripheral clocks in maintaining overall circadian rhythmicity.

Q: What sleep disorder did the speaker discuss in the video?

The speaker discussed delayed sleep phase disorder (DSPD), which is a sleep disorder characterized by a persistent delay in the timing of the major sleep episode. Individuals with DSPD have a natural tendency to go to bed and wake up later than what is considered typical. This delay can cause difficulties in aligning their sleep-wake schedule with societal norms and can lead to insomnia, daytime sleepiness, and impaired functioning. The speaker presented a case study of a family with DSPD and identified a mutation in the cryptochrome 1 gene associated with this disorder.

Q: How does the mutation in the cryptochrome 1 gene affect sleep patterns?

The mutation in the cryptochrome 1 gene found in individuals with delayed sleep phase disorder (DSPD) alters the function of the cryptochrome protein, which is involved in regulating the circadian clock. The truncated form of the protein resulting from the mutation has a different interaction with other proteins in the clock machinery. This altered interaction affects the inhibitory properties of the period-cryptochrome complex, which disrupts the normal regulation of gene expression and the timing of sleep-wake cycles. This leads to a persistent delay in the timing of sleep onset and wake times seen in individuals with DSPD.

Takeaways

The study of circadian rhythms and clock genes has provided significant insights into the genetic control of biological clocks and their regulation of various physiological processes. Circadian rhythms are crucial for synchronizing an organism's internal processes with the external environment, and disruptions in these rhythms can lead to sleep disorders and other health issues. Clock genes, such as period and timeless, play a central role in regulating circadian rhythms in fruit flies and other organisms. These genes work together in a complex molecular process to generate rhythmic behavior and control gene expression patterns. Clocks are also found in peripheral organs, enabling the coordination of various physiological functions. The discovery of mutations in clock genes associated with sleep disorders, like delayed sleep phase disorder, highlights the importance of understanding the genetic basis of circadian rhythms for the development of targeted therapies. Additionally, the widespread influence of circadian rhythms on gene expression and drug targets emphasizes the need for considering the timing of treatments in medical interventions.

Summary & Key Takeaways

• Circadian clocks help organisms coordinate behavior with predictable environmental conditions. The Colorado four o'clock opens its flowers when its nocturnal pollinator is active and closes them during hotter daylight hours. This timing may preserve water because opening petals requires water to be transferred from the rest of the plant into the flowers.

• Honeybees use an internal clock to keep their waggle dance aligned with the changing position of the Sun while remaining inside a dark hive for hours. Monarch butterflies also use a time-compensated Sun compass. Experiments that blackened their antennae disrupted orientation, indicating that the clocks supporting migration are located in the antennae.

• Rodents maintain predictable activity and rest cycles in constant darkness, demonstrating the operation of an internal circadian pacemaker. The suprachiasmatic nucleus is a key tissue locus for these rhythms. Fruit fly mutations further showed that a single functional gene can eliminate rhythmicity or change the cycle from nearly 24 hours to 19 or 28 hours.