Life on Earth is adapted to the rotation of our planet. For many years we have known that living organisms, including humans, have an internal, biological clock that helps them anticipate and adapt to the regular rhythm of the day. But how does this clock actually work? Jeffrey C. Hall, Michael Rosbash and Michael W. Young were able to peek inside our biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth’s revolutions.

Using fruit flies as a model Honored for their discoveries of molecular mechanisms controlling the circadian rhythm organism, this year’s Nobel laureates isolated a gene that controls the normal daily biological rhythm. They showed that this gene encodes a protein that accumulates in the cell during the night, and is then degraded during the day. Subsequently, they identified additional protein components of this machinery, exposing the mechanism governing the self-sustaining clockwork inside the cell. We now recognize that biological clocks function by the same principles in cells of other multi-cellular organisms, including humans.

With exquisite precision, our inner clock adapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behavior, hormone levels, sleep, body temperature and metabolism. Our wellbeing is affected when there is a temporary mismatch between our external environment and this internal biological clock, for example when we travel across several time zones and experience “jet lag”. There are also indications that chronic misalignment between our lifestyle and the rhythm dictated by our inner timekeeper is associated with increased risk for various diseases.

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 (See figure). 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.

Identification of a clock gene

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.

A self-regulating clockwork mechanism

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 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.

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, double time, 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 paradigm-shifting discoveries by the laureates established key mechanistic principles for the biological clock. During the following years other molecular components of the clockwork mechanism were elucidated, explaining its stability and function. For example, this year’s laureates identified additional proteins required for the activation of the period gene, as well as for the mechanism by which light can synchronize the clock.

Keeping time on our human physiology

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 circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.

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InnoHEALTH Volume 1 Issue 1 (July to September 2016) – https://goo.gl/iWAwN2 
InnoHEALTH Volume 1 Issue 2 (October to December 2016) – https://goo.gl/4GGMJz 
InnoHEALTH Volume 2 Issue 1 (January to March 2017) – https://goo.gl/DEyKnw 
InnoHEALTH Volume 2 Issue 2 (April to June 2017) – https://goo.gl/Nv3eev
InnoHEALTH Volume 2 Issue 3 (July to September 2017) – https://goo.gl/MCVjd6
InnoHEALTH Volume 2 Issue 4 (October to December 2017) – http://amzn.to/2B2UMLw
InnoHEALTH Volume 3 Issue 1 (January to March 2018) – https://goo.gl/fksdQx

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Mammography continues to be the only screening test proven to decrease mortality from breast cancer. However, 2D mammography is less accurate in women with dense breasts for whom cancer may be masked by overlapping breast tissue. When a 2D mammogram detects an area of concern, radiologists further investigate with a diagnostic mammogram, ultrasound or biopsy. Looking at the same breast tissue in 3D, the radiologist may now be able to see that the abnormality on 2D mammogram in fact represents normal breast tissue. This avoids further investigation in large number of patients undergoing routine screening.

3D mammography or Tomosynthesis is a special kind of mammogram that uses several low dose x-rays obtained at different angles to create multiple images or “sequential slices” that step through the breast tissue and allows radiologists to see more clearly. The breast is positioned and compressed in the same way as for a 2D mammogram but the x-ray tube moves in a circular arc around the breast. It takes less than 10 seconds for the scan. The information from the x-rays is sent to a computer, which produces a focused 3 D digital image of the breast.

There is no organised national or regional breast cancer screening program in India. Naturally, majority of those involved in women’s health are not aware of the available technology and expertise in the field of breast cancer diagnosis. Needless to say, women undergoing screening have little understanding of the tests or the results thereof.

In contrast to the western world, breast cancer incidence is much higher in premenopausal age group (<50 years) in India. As compared to both screen film and Computed Mammograms (older but most widely used technologies), 2D and 3D Digital Mammography has significantly higher accuracy in cancer detection in younger women and in women with dense glandular breasts. This will have large impact on decreasing the number of women undergoing unnecessary recalls or biopsies. It is most important to avoid anxiety in women opting for screening tests. 3D mammography serves as an excellent problem solving tool and reduces misdiagnoses. Contrary to common practice, ultrasound alone has significant limitations as a screening tool and must always be combined with a 2D or 3D Digital Mammogram. The x-ray dose of 3D mammography is comparable to that of a 2D mammogram. Therefore the cumulative dose of the combined screening is still below the FDA regulated limit and found to be safe and effective for patient use.

Incorporating this aspect Cytecare hospital’s breast imaging services are complete with Digital Breast Tomosynthesis (DBT or 3D Mammogram), Full Field Digital Mammogram (FFDM), Stereotactic and Vacuum Assisted Breast Biopsy (VABB).

3D mammography has shown to reduce percentage of missed cancers by 15%. More recent studies show about 30% increased 3D mammography sensitivity and specificity compared to 2D Mammography with a recalls reduction in screening by approximately 40%.

Want to write for InnoHEALTH? send us your article at  magazine@innovatiocuris.com

Read all the issues of InnoHEALTH magazine:
InnoHEALTH Volume 1 Issue 1 (July to September 2016) – https://goo.gl/iWAwN2 
InnoHEALTH Volume 1 Issue 2 (October to December 2016) – https://goo.gl/4GGMJz 
InnoHEALTH Volume 2 Issue 1 (January to March 2017) – https://goo.gl/DEyKnw 
InnoHEALTH Volume 2 Issue 2 (April to June 2017) – https://goo.gl/Nv3eev
InnoHEALTH Volume 2 Issue 3 (July to September 2017) – https://goo.gl/MCVjd6
InnoHEALTH Volume 2 Issue 4 (October to December 2017) – http://amzn.to/2B2UMLw

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