Ayurvedic understanding and modern Chronobiology

With the Nobel Prize for Medicine or Physiology having been announced, there is a lot to rejoice, not just for the scientific community but for the common man also, because it helps us to develop a better understanding of how our body works. This year’s prize is shared among American scientists Jeffrey C Hall, Michael Rosbash and Michael W Young for their work on “molecular mechanisms controlling circadian rhythms”. This would be great news for researchers and students of Ayurveda, the Indian science of health, as it will directly resonate with what they know about the relation between the human system and the nature. Such findings give researchers of Ayurveda concrete modern frameworks to communicate their knowledge on global platforms. With chronobiology gaining prominence after these laureates’ work, it would be relevant at this time to draw parallels with what is mentioned in Ayurveda and the prize winning research. According to news articles and the summary provided in the official Nobel Prize website, some of the key findings of the research are as follows:

1. The gene that controls the daily biological/circadian rhythm responds to light by degradation of the protein accumulated in the cell during nights.
2. Hence, our inner clock adapts our physiology to the dramatically different phases of the day with great precision.
3. There are also indications that chronic misalignment between our lifestyle and the rhythm dictated by our inner time-keeper is associated with increased risk for various diseases.

Circadian Rhythm And Well-being

This Nobel Prize winning research work is based on the circadian rhythm, which refers to biochemical oscillators that respond to solar cycles. To quote Sir Paul Nurse, 2001 Laureate, “All plant and also animal behaviour is determined by the light-dark cycle. We on this planet are slaves to the sun”. Jeffrey Hall and Michael Rosbash discovered that PER, the protein encoded by period, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm.

It is striking to note how Ayurveda establishes the link between the revolution-rotation of the earth and human health. According to Ayurveda, the different tridoshas (the three humors: Vata, Pitta and Kapha, in the body that need to be balanced for perfect health), are predominant during different times of the day. For instance, Pitta Dosha which controls digestion, metabolism and energy production is high between 10am and 2pm. Pitta ensures the availability of energy to perform various activities. This very well correlates with the high alertness, best co-ordination and fastest reaction times shown in the illustration below. Research works on circadian rhythm from the perspective of Ayurveda correlate the time of the day and hormonal activity, very similar to the degeneration of protein with the day as discovered by the laureates. For example, Kapha dosha is predominant in early phase of the day. Most of the hormones are at the peak level in the morning and they decline with the time and are lowest at the evening time.

Time Of Drug Administration

According to The Guardian’s article, “There is some evidence that treatment of disease can be influenced by circadian rhythms too. People have reported that whenyou have surgery or when you have a drug can actually influence things. It’s still not clear, but there will almost certainly be some implications for the treatment of disease too.” This means that the time of the day when a medicine is had most likely influences its impact on the human body.

Ayurveda talks of bhaishajya kaala, which refers to the appropriate time for administering the aushada (medicine). Few research works on Ayurveda, published by Indian researchers, detail the impact of time of drug administration on the treatment of disease. Their research work mentions, “Kapha kaala is one-third part of the day, and later half of this one-third part is Kapha udreka gata kaala (past the excessive kapha). The medicine is administered in the empty stomach when the koshtha (digestive tract) is devoid of Kapha utklesha (aggravated kapha). Because if there is Kapha utklesha, the medicine will not come in contact with agni (digestive fire), and will not be digested properly and effect will be either delayed or reduced. Hence, medicine is administered only after the Kapha udreka is over”.

Lifestyle And Rhythm Dissonance

The key implication of the laureates’ work is that misalignment with the rhythm can cause health issues. It is fascinating to note how Ayurvedic texts address such misalignments caused by dissonance in a systematic manner and prescribe numerous preventive regimes. Dinacharya, an ayurvedic concept, maps the light and dark cycle of the day to human activities. Several Ayurvedic texts detail the list of activities that one can perform during different times in the day for robust health. Ayurveda in fact goes beyond the daily cycles, and elucidates the role of the changing seasons as well.

The first few chapters of the various samhitas (of Ayurveda) are dedicated to ritucharya, which talk about the relationship between human health and seasonal changes (which are caused by the revolution of the earth and tilt of the earth’s axis). Charaka samhita, for instance says, “Tasya shitadiya ahaarbalam varnascha vardhate. Tasyartusatmayam vaditam chestaharvyapasrayam,” meaning ‘knowing the suitable diet and regimen for every season and practicing accordingly enhances the health of a person’.

Hall, Rosbash and Young’s work furthers the research on the chronobiology by identifying specific genes at work. According to the Independent, “The work didn’t reveal any tips for regulating our own circadian rhythm or improving sleep, said experts. But it was a reminder of the importance of doing so …”. Their phenomenal research work has left us at an important juncture, where solutions need to be explored. Interdisciplinary and integrative research that blends insights from Ayurveda and modern medicine could probably offer solutions.

Circadian clock

Ayurvedic clock

https://swarajyamag.com/science/this-years-nobel-prize-in-medicine-puts-fresh-focus-on-ayurveda

Nobel Prize Lectures by 2017 Nobel prize winners for their work in elucidating clock mechanism

Michael W. Young - Nobel Lecture

Time Travels: A 40 Year Journey from Drosophila's Clock Mutants to Human Circadian Disorders

Michael Rosbash - Nobel Lecture

The Circadian Clock, Transcriptional Feedback and the Regulation of Gene Expression

Jeffrey C. Hall - Nobel Lecture

The Little Flies: Multifaceted Basic Research Coming Out Better than Intended

Lectures delivered on 7 December 2017 at Aula Medica, Karolinska Institutet in Stockholm.

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/rosbash-lecture.html

Nobel prize award ceremony - 10th December 2017

Functioning of our inner clock

Most living organisms anticipate and adapt to daily changes in the environment. During the 18th century, the astronomer Jean Jacques d'Ortous de Mairan studied mimosa plants, and found that the leaves opened towards the sun during daytime and closed at dusk. He wondered what would happen if the plant was placed in constant darkness. He found that independent of daily sunlight the leaves continued to follow their normal daily oscillation Plants seemed to have their own biological clock.

Other researchers found that not only plants, but also animals and humans, have a biological clock that helps to prepare our physiology for the fluctuations of the day. This regular adaptation is referred to as the circadianrhythm, originating from the Latin words circa meaning "around" and diesmeaning "day". But just how our internal circadian biological clock worked remained a mystery.

During the 1970's, Seymour Benzer and his student Ronald Konopka asked whether it would be possible to identify genes that control the circadian rhythm in fruit flies. They demonstrated that mutations in an unknown gene disrupted the circadian clock of flies. They named this gene period. But how could this gene influence the circadian rhythm?

This year's Nobel Laureates, who were also studying fruit flies, aimed to discover how the clock actually works. In 1984, Jeffrey Hall and Michael Rosbash, working in close collaboration at Brandeis University in Boston, and Michael Young at the Rockefeller University in New York, succeeded in isolating the period gene. Jeffrey Hall and Michael Rosbash then went on to discover that PER, the protein encoded by period, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm.

The next key goal was to understand how such circadian oscillations could be generated and sustained. Jeffrey Hall and Michael Rosbash hypothesized that the PER protein blocked the activity of the period gene. They reasoned that by an inhibitory feedback loop, PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm 

The figure shows the sequence of events during a 24h oscillation. When the period gene is active, period mRNA is made. The mRNA is transported to the cell's cytoplasm and serves as template for the production of PER protein. The PER protein accumulates in the cell's nucleus, where the period gene activity is blocked. This gives rise to the inhibitory feedback mechanism that underlies a circadian rhythm.

The model was tantalizing, but a few pieces of the puzzle were missing. To block the activity of the period gene, PER protein, which is produced in the cytoplasm, would have to reach the cell nucleus, where the genetic material is located. Jeffrey Hall and Michael Rosbash had shown that PER protein builds up in the nucleus during night, but how did it get there? In 1994 Michael Young discovered a second clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. In elegant work, he showed that when TIM bound to PER, the two proteins were able to enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop.

Simplified illustration of the molecular components of the circadian clock.

Such a regulatory feedback mechanism explained how this oscillation of cellular protein levels emerged, but questions lingered. What controlled the frequency of the oscillations? Michael Young identified yet another gene, doubletime, encoding the DBT protein that delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-hour cycle.

The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms. A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day. Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.

The circadian clock anticipates and adapts our physiology to the different phases of the day. Our biological clock helps to regulate sleep patterns, feeding behavior, hormone release, blood pressure, and body temperature.

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html 

Nobel prize in medicine 2017 for biological clock research

2017-10-02

The Nobel Assembly at Karolinska Institutet has today decided to award

the 2017 Nobel Prize in Physiology or Medicine

jointly to

Jeffrey C. Hall, Michael Rosbash and Michael W. Young

for their discoveries of molecular mechanisms controlling the circadian rhythm

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html

Links between gut bacteria, weight gain and circadian rhythm

The obesity epidemic is one of the fastest growing threats to public health. More than 70 percent of American adults are currently overweight or obese, with other countries catching up quickly. This is putting our population at higher risk of a wide variety of preventable diseases. Despite a multi-billion dollar diet industry, we continue to get larger and larger. Could this really be entirely due to our unhealthy diets? New research on gut bacteria and weight gain suggests that this dangerous trend is not just due to our food choices, but to changes in our gut bacteria.

Several major studies have linked gut bacteria and weight gain. Mice fed high-calorie diets are more likely to gain weight when they have certain imbalances of gut bacteria. Humans, similarly, are more likely to be obese when they have high levels of specific gut bacteria such as Firmicutes. Our microbiome is an integral part of our health, so these imbalances can also lead to vitamin malabsorption, fatigue, depression and a wide variety of common conditions.

This is significant because the balance of human GI bacteria, also known as our microbiome, is rapidly changing. Cultures that eat a lot of whole grains and vegetables have very different kinds of bacteria in their intestines. As our eating habits change, our gut bacteria are rapidly changing in response. Our food choices do not just add to the number of calories we eat, but also the way these calories are processed. But how can gut bacteria cause weight gain and even obesity? The circadian rhythm of the GI tract may be the link.

Like all organ systems, our GI tract has a distinctive circadian rhythm. This rhythm is partially set by external factors, especially what times we eat. This, in turn, affects gut bacteria. Bacteria, like humans, partially set their internal clocks by what times they are most active. When we eat, they also must “eat.”

Changing our mealtimes or our sleep-wake cycles can dramatically alter the circadian rhythms of bacteria in our GI tract. Some bacteria flourish under these changes and can quickly become the predominant bacteria in our intestines when we rapidly change our sleep-wake cycles. In turn, these bacteria appear to contribute to weight gain and obesity. Until recently, this was believed to be the reason for the link between jet lag and weight gain. However, new research suggests that the bacteria themselves may affect our intestinal circadian rhythms as much as our internal clocks affect them.

Researchers studied how a high-fat diet affected two populations of mice: one with a typical microbiome and one bred to have no GI bacteria at all. The ones with no GI bacteria handled their unhealthy diet much better than the other group. When researchers looked closer at the data, this appeared to be due to an intestinal protein called NFIL3.

Mice that had a normal microbiome had higher levels of a protein called NFIL3. NFIL3 is an important cue for the intestines, telling them how much fat to absorb. It is released in a cyclic manner, which helps our circadian rhythm to regulate food intake. Mice with no bacteria produce extremely low levels of NFIL3 on a cyclic basis and thus absorb very little fat even when eating a very high-fat diet. Gut bacteria appear to somehow stimulate NFIL3 production regardless of the time of day, effectively hijacking the circadian rhythm of the intestinal tract. This indiscriminate absorption of fat may, in turn, be one of the mechanisms by which some gut bacteria cause weight gain.

Maintaining a healthy and diverse microbiome is key to whole-body health and a reasonable weight. If you are struggling to develop healthy intestinal bacteria, consider the following strategies:

• Eat a great deal of fiber, especially from plant foods such as whole grains, fruits and vegetables.
• Refuse refined and processed foods such as white sugar that encourage the growth of less healthy bacteria.
• Enjoy fermented foods such as yogurt and sauerkraut.
• Use fewer antacids and other medications that interfere with gut bacterial health.
• Keep your sleep-wake cycles steady, as these can affect your bacterial balance.
• Consider taking a daily probiotic supplement to keep a steady intake of beneficial bacteria.

These simple changes can change your microbiome in positive ways by seeding your intestines with the right kind of bacteria while discouraging the growth of bacteria that contribute to obesity.

For many Americans, our diets have led to a vicious cycle. Our dysregulated circadian rhythm leads to changes in bacteria, which, in turn, further affect our circadian rhythm. This can lead to obesity and other dangerous health conditions. However, there is hope. There are ways to achieve balance in your gut bacteria and thus change the way your body metabolizes food, stopping the cycle once and for all.

https://www.chronobiology.com/gut-bacteria-can-hijack-intestinal-circadian-rhythm-causing-weight-gain/

Project work for UG/PG life science students for academic year 2017-18

Third batch of  Project work for UG/PG life science students for academic year 2017-18 has been started from 19th August 2017.

Late registration is allowed till first week of September.

Register at: http://goo.gl/forms/rHi8gypfxGyzQ03C2

Chronobiology outreach programs for all age groups and background

Select the programs / workshops suitable for you

Most of the programs start every year in August. Can be personalized if sufficient number of participants are avaialble.

1) Project work for higher secondary school children

- Observation of cyclic phenomenon in nature

- Appreciating all living matter undergoing rhythmicity

- Report writing on cyclic activities in humans

2)  Project work for UG / PG life science students

- Chronotype analysis of predefined population

- Statistical analysis of biological rhythmic data

- Report writing on data analysis and interpretation

3) Workshop for life science teachers

- Lecture series on basics of chronobiology

- Designing of experiments in chronobiology

- Incorporation on chronobiology in curriculum

4) Workshop for professionals with odd work schedule 

     [IT professionals/shift workers/frequent flyers]

- Lecture series on basics of biological clock

- Guidance on synchronizing external / internal clock

- Circadian rhythm in health and disease

5) Consultancy for patients with metabolic disorders

- Chronotype analysis and counseling

- Clock genes analysis and counseling

- Chronome analysis