Biological Clocks and Rhythms

Nobel Prize and Discovery

In physiology and medicine, three individuals received the Nobel Prize for their discovery of the biological clock in organisms, including humans and plants. This discovery marked a significant advancement in understanding the internal mechanisms governing life's cycles.

Historical Context

The understanding of biological clocks dates back centuries, with initial observations hinting at their existence.

Key Publications

Key research was published in journals like CELL, Nature, and Science. A publication in CELL from October 1984 detailed work in Drosophila (fruit flies), identifying aspects of what later was understood as the biological clock. These publications often include graphical abstracts simplifying complex processes.

Overview of Circadian Rhythms

Circadian rhythms involve a transcriptional program that tunes organisms to the cycles of Earth. The lecture will cover:

Physiology of rhythms.
Terminology.
Molecular clock mechanisms.
Research examples.
Disturbances (e.g., jet lag).
Chronopharmacology (timing of drug administration).
Impact of exercise and eating patterns.

Basic Principles of Life on Earth

Life on Earth is influenced by the Earth's rotation and orbit around the sun. The Earth's approximately 24-hour rotation and annual orbit cause daily and seasonal rhythms. These rhythms are foundational to life's evolution and the biological clock.

Circadian Rhythms

Circadian rhythms, derived from Greek or Latin, with "circa" meaning about and "dia" meaning day, are approximately 24-hour cycles influenced by the Earth's rotation. Human activities align with these rhythms, reflecting evolutionary priming for environmental changes to maintain homeostasis.

Types of Biological Rhythms

Various biological rhythms and cycles exist:

Tidal cycles: Influenced by the moon's gravitational pull.
Circadian rhythms: Daily rhythms.
Trichnient rhythms: Monthly rhythms like the menstrual cycle.
Annual rhythms: Seasonal changes.

Clock Genes in Life Forms

Most life forms possess clock genes. Examples include:

Plants: Sunflowers move with the sun.
Fruit flies: Where the clock was discovered.
Molds: Exhibit internal clocks.
Nocturnal animals: Rodents active at night.
Humans: Active during the day.

These rhythms are dictated by molecular-level clocks, imprinted by genes.

Advantages of Biological Clocks

Biological clocks enable organisms to anticipate predictable environmental changes, such as temperature, tides, light, and food availability. This allows for efficient resource use, e.g., birds laying eggs in spring, and hibernation.

Predictive vs. Reactive Mechanisms

Biological clocks are predictive, not reactive. Plants inherently anticipate light and dark, unlike reactive feedback mechanisms where one protein reacts to another.

Early Evidence of Biological Clocks

In the 1700s, a Frenchman observed leaves opening during the day and closing at night. Even in complete darkness, the plant maintained this rhythm, demonstrating an internally generated mechanism encoded in genes.

Rodent Activity Patterns

Rats are nocturnal animals, active at night to avoid predators. This activity can be tracked on a double plot showing time versus days, with black boxes indicating wheel spins.

Terminology of Rhythms

Period: Time required for a full cycle.
Phase: A part of the period, the morning.
Amplitude: Change between the highest and lowest points.
Aqua phase: The maximum point.
True: The lowest point.

Phase Advance and Delay

Phase delay: Traveling west from Europe to The States.
Phase advance: Traveling east from Europe to Asia.

Phase advance is typically more difficult for the body to adjust to.

Glossary of Chronobiological Terms

Circadian rhythm: Approximately 24-hour rhythm.
Ultradeon rhythms: Shorter rhythms.
Infra diem: Slightly longer.
Diurnal rhythms: During the day.
Nocturnal: Active at night.
Free running rhythm: Rhythm in the absence of external cues; genetically encoded.

Entrainment and Zeitgebers

Rhythms can be entrained to Zeitgebers (time givers). Light is the most powerful Zeitgeber, but exercise, food timing, and melatonin also play a role.

Experimental Evidence

Studies with mice show that in constant darkness, animals begin their activity later each day, indicating a free running rhythm longer than 24 hours. Human examples include individuals in caves who lose track of time due to altered perceptions.

Phase Shifts in Rats

Rats in complete darkness may display a phase shift, running earlier each day. This shift depends on the organism and individual, explaining differences like morning versus evening preferences.

Light Pulses and Clock Resetting

Light pulses can reset biological clocks. Even short light exposures can restore rhythms, demonstrating the potency of light, especially blue light, in adapting the clock.

Suprachiasmatic Nucleus (SCN)

The SCN, located above the optic chiasm, serves as the central biological clock. Composed of two small groups of cells, it drives rhythms and physiology. The main trigger for the SCN is light.

Mechanism of Light Detection

Melanopsin, a photopigment in specialized ganglion cells, detects light. This information is relayed to the central nervous system via the retinal hypothalamic tract. Neurotransmitters like glutamate and PACAP activate the SCN.

Role of Vasopressin

Vasopressin (antidiuretic hormone) is found in 30% of SCN cells, suggesting its function in water homeostasis and as a neurotransmitter.

SCN Activity

The SCN is very active during the day and less active at night, triggered by light. Electrical activity measurements show rapid firing in the presence of light and slower activity in darkness.

Retinal Axillary Tracts

Light enters through retinal axillary tracts to the SCN, which then signals the hypothalamus and travels through the superior cervical ganglion to glands, producing melatonin.

Melatonin

Melatonin is a crucial hormone in regulating day-night rhythms. It feeds back to the SCN, and its production is sensitive to light exposure.

Molecular Mechanisms in the SCN

Light triggers neurotransmitter release and calcium influx, activating clock genes that make clock proteins and regulate rhythms. Adenosine Diuretic Hormone (ADH) or AVP along with Yaba, inhibit the communication to paraventricular nucleus (PVN).

In darkness, ADH and Yaba, PVN is activated, norepinephrine is released, which activates the pineal gland, leading to melatonin production.

Oscillations

Per and Cry are clock genes regulated by Clock and Bmal which drive transcription which creates the Purr and Cry protein. Which has a negative feedback and controls itself, this is regulated tightly.

Experimental Evidence and SCN

Neurons from the SCN maintain rhythmicity even when cultured in a lab. Destroying the SCN disrupts activity patterns, blood pressure regulation, and other physiological rhythms.

Clock Control Genes

Clock control genes constitute 10% of the genome, regulating metabolism in various tissues. Research at Maastricht focuses on the timing of exercise and food intake.

Circadian Rhythms on Exercise

Rodents put on a treadmill later in their active period (night) ran longer because they had more liver glycogen and stable blood glucose.

Chronopharmacology

Symptoms of diseases vary throughout the day. Asthma symptoms typically occur at night, prompting timed medication before bed.

Modern Day Society

Light emitted from devices alters melatonin secretion, exercise should be done during the day and not at night because it will increase levels making it harder to sleep. There is an increased risk of cancer and immunological disorders heart disease and depression-like symptoms.

Jet Lag

Eastward travel is more severe.
Working with light and blue lights. One can also take melatonin as it's counter medicine.

Food Intake

Intermittent fasting and timing of food can have huge impact on your body as calories that are broken down on timing for example late at night the body doesn't accept because it's ready for rest and not to breakdown calories.

Nobel Prize and Discovery

In 2017, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young were awarded the Nobel Prize in Physiology or Medicine for their groundbreaking discoveries of molecular mechanisms controlling the circadian rhythm. Their work elucidated how biological clocks function in organisms, including humans and plants, marking a pivotal advancement in understanding the internal mechanisms governing life's cycles. These mechanisms influence numerous physiological processes, such as sleep-wake cycles, hormone release, and metabolism.

Historical Context

The understanding of biological clocks dates back centuries, with early observations hinting at their existence. Initial studies involved observing plant movements and sleep patterns in animals, laying the groundwork for modern chronobiology.

Key Publications

Key research has been published in high-impact journals such as CELL, Nature, and Science, detailing the intricate molecular pathways of circadian rhythms. A seminal publication in CELL from October 1984 reported findings in Drosophila (fruit flies), identifying crucial aspects of what was later understood as the biological clock. These publications often include graphical abstracts simplifying complex processes and detailed methodologies.

Overview of Circadian Rhythms

Circadian rhythms involve a complex transcriptional program that tunes organisms to the cycles of Earth. The lecture will cover:

Physiology of rhythms:
- Detailed examination of physiological processes governed by circadian clocks.
- Discussion of how these rhythms affect various organ systems.
Terminology:
- Clear definitions of key terms such as period, phase, amplitude, and Zeitgeber.
- Explanation of how these terms are used in chronobiological research.
Molecular clock mechanisms:
- Comprehensive overview of the genes and proteins involved in circadian clocks.
- Explanation of feedback loops and regulatory pathways.
Research examples:
- Case studies demonstrating the impact of circadian rhythms on health and disease.
- Discussion of experimental designs used to study circadian rhythms.
Disturbances (e.g., jet lag):
- Exploration of factors that disrupt circadian rhythms, such as jet lag and shift work.
- Strategies for mitigating these disruptions.
Chronopharmacology (timing of drug administration):
- Principles of chronopharmacology and its applications in optimizing drug efficacy.
- Examples of drugs with time-dependent effects.
Impact of exercise and eating patterns:
- Discussion of how exercise and eating patterns can influence circadian rhythms.
- Recommendations for aligning lifestyle with natural rhythms.

Basic Principles of Life on Earth

Life on Earth is deeply influenced by the Earth's rotation and its orbit around the sun. The approximately 24-hour rotation and the annual orbit cause daily and seasonal rhythms, which are foundational to life's evolution and the development of the biological clock. These rhythms drive adaptations in physiology and behavior across all living organisms.

Circadian Rhythms

Circadian rhythms, derived from Greek or Latin with "circa" meaning about and "dia" meaning day, are approximately 24-hour cycles influenced by the Earth's rotation. Human activities are intricately aligned with these rhythms, reflecting evolutionary priming for environmental changes to maintain homeostasis. Disruptions can lead to various health issues, underscoring the importance of understanding and maintaining these rhythms.

Types of Biological Rhythms

Various biological rhythms and cycles exist:

Tidal cycles: Influenced by the moon's gravitational pull, affecting marine life and coastal ecosystems.
Circadian rhythms: Daily rhythms that govern sleep-wake cycles, hormone secretion, and metabolism.
Trichnient rhythms: Monthly rhythms like the menstrual cycle in females, influencing reproductive physiology.
Annual rhythms: Seasonal changes affecting migration patterns, reproductive behavior, and hibernation.

Clock Genes in Life Forms

Most life forms possess clock genes that regulate their internal rhythms. Examples include:

Plants: Sunflowers move with the sun, optimizing light capture.
Fruit flies: Where the clock was initially discovered, providing insights into genetic mechanisms.
Molds: Exhibit internal clocks that influence growth and reproduction.
Nocturnal animals: Rodents active at night, avoiding predators and optimizing resource use.
Humans: Active during the day, with physiological processes aligned accordingly.

These rhythms are dictated by molecular-level clocks, imprinted by genes such as Per, Cry, Clock, and Bmal.

Advantages of Biological Clocks

Biological clocks enable organisms to anticipate predictable environmental changes, such as temperature fluctuations, tidal movements, light availability, and food sources. This allows for efficient resource use, e.g., birds laying eggs in spring when food is abundant, and animals undergoing hibernation to conserve energy during winter.

Predictive vs. Reactive Mechanisms

Biological clocks are predictive, not reactive. Plants inherently anticipate light and dark, unlike reactive feedback mechanisms where one protein reacts to another. This predictive nature optimizes physiological processes and behavior.

Early Evidence of Biological Clocks

Rodent Activity Patterns

Rats are nocturnal animals, active at night to avoid predators. This activity can be tracked on a double plot showing time versus days, with black boxes indicating wheel spins. Advanced tracking methods provide detailed insights into activity levels and patterns.

Terminology of Rhythms

Period: Time required for a full cycle, measured in hours.
Phase: A part of the period, such as the morning or evening.
Amplitude: Change between the highest and lowest points, reflecting the intensity of the rhythm.
Aqua phase: The maximum point or peak of activity.
True: The lowest point or trough of activity.

Phase Advance and Delay

Phase delay: Traveling west from Europe to The States, requiring adjustment to a later time zone.
Phase advance: Traveling east from Europe to Asia, requiring adjustment to an earlier time zone.

Phase advance is typically more difficult for the body to adjust to due to the inherent asymmetry of circadian rhythms.

Glossary of Chronobiological Terms

Circadian rhythm: Approximately 24-hour rhythm.
Ultradeon rhythms: Shorter rhythms with a period of less than 24 hours.
Infra diem: Slightly longer rhythms with a period slightly more than 24 hours.
Diurnal rhythms: Rhythms that occur during the day.
Nocturnal: Active at night.
Free running rhythm: Rhythm in the absence of external cues; genetically encoded and reflecting the natural period of the clock.

Entrainment and Zeitgebers

Rhythms can be entrained to Zeitgebers (time givers). Light is the most powerful Zeitgeber, but exercise, food timing, and melatonin also play a role. Social cues and temperature can also act as Zeitgebers.

Experimental Evidence

Phase Shifts in Rats

Rats in complete darkness may display a phase shift, running earlier each day. This shift depends on the organism and individual, explaining differences like morning versus evening preferences. Genetic factors and environmental conditions can influence phase shifts.

Light Pulses and Clock Resetting

Light pulses can reset biological clocks. Even short light exposures can restore rhythms, demonstrating the potency of light, especially blue light, in adapting the clock. The timing, intensity, and wavelength of light pulses are critical for effective resetting.

Suprachiasmatic Nucleus (SCN)

The SCN, located above the optic chiasm, serves as the central biological clock. Composed of two small groups of cells, it drives rhythms and physiology. The main trigger for the SCN is light, which synchronizes the internal clock with the external environment.

Mechanism of Light Detection

Role of Vasopressin

Vasopressin (antidiuretic hormone) is found in 30% of SCN cells, suggesting its function in water homeostasis and as a neurotransmitter. It plays a critical role in regulating urine production and blood pressure.

SCN Activity

The SCN is very active during the day and less active at night, triggered by light. Electrical activity measurements show rapid firing in the presence of light and slower activity in darkness. This diurnal variation in activity is fundamental to circadian regulation.

Retinal Axillary Tracts

Light enters through retinal axillary tracts to the SCN, which then signals the hypothalamus and travels through the superior cervical ganglion to glands, producing melatonin. This pathway ensures that light information is accurately transmitted to the brain.

Melatonin

Melatonin is a crucial hormone in regulating day-night rhythms. It feeds back to the SCN, and its production is highly sensitive to light exposure. Melatonin promotes sleep and regulates various physiological processes, including immune function and blood pressure.

Molecular Mechanisms in the SCN

In darkness, ADH and Yaba, PVN is activated, norepinephrine is released, which activates the pineal gland, leading to melatonin production.

Oscillations

Per and Cry are clock genes regulated by Clock and Bmal which drive transcription which creates the Purr and Cry protein. Which has a negative feedback and controls itself, this is regulated tightly.

Experimental Evidence and SCN

Neurons from the SCN maintain rhythmicity even when cultured in a lab. Destroying the SCN disrupts activity patterns, blood pressure regulation, and other physiological rhythms. These experiments underscore the SCN's central role in circadian regulation.

Clock Control Genes

Clock control genes constitute 10% of the genome, regulating metabolism in various tissues. Research at Maastricht focuses on the timing of exercise and food intake to optimize metabolic health.

Circadian Rhythms on Exercise

Rodents put on a treadmill later in their active period (night) ran longer because they had more liver glycogen and stable blood glucose. This highlights the importance of aligning exercise with natural circadian rhythms to enhance performance and metabolic benefits.

Chronopharmacology

Symptoms of diseases vary throughout the day. Asthma symptoms typically occur at night, prompting timed medication before bed. Chronopharmacology aims to optimize drug efficacy by considering the timing of administration in relation to circadian rhythms.

Modern Day Society

Jet Lag

Eastward travel is more severe due to the difficulty in advancing the circadian clock.
Working with light and blue lights to reset the clock.
One can also take melatonin as it's counter medicine to help adjusting the sleep patterns.