Nobel Prizes 2017

The Nobel Prizes were handed out recently in the areas of Chemistry, Physics, Physiology or Medicine, Literature, and Peace. The story of the prizes, first given out in 1901, is one of those accounts you might have heard from a trivia poseur and vehemently looked up Wikipedia after to see how true it was. Or probably not. Anyway, so Alfred Nobel a big boy scientist in Sweden in the late 1800s was a chemist, engineer, inventor, master of all trades sort of guy and is perhaps best known for the discovery of dynamite. In 1888, Alfred’s brother Ludvig died and a blunderous report in a French newspaper that mistakenly thought it was Alfred that had died posted the not-so-passive-aggressive obituary, “Le marchand de la mort est mort” (“The merchant of death is dead”). A grief-stricken Alfred reckoned he didn’t want to be remembered in this way and decided to make a positive contribution to society, how noble. Fast-forward eight years and after Alfred Nobel finally popped his clogs in 1896, authorities in Sweden and Norway couldn’t believe themselves when he bequeathed almost all of his tremendous wealth to forming the prizes to honour people who have contributed the “greatest benefit on mankind” in the 6 aforementioned areas.

This year’s prize in Chemistry went to Jacques Dubochet, Joachim Frank and Richard Henderson “for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution”.

A picture can give us incredible insight into something. Many breakthroughs in science has been due to the ability to see beyond our human capabilities, beyond the naked eye. In the field of biochemistry, it has been almost the hardest to depict any of life’s molecular machinery as the intense compositions of biomolecules have previously been too intricate and small for even technology to view with resolution. Cryo-electron microscopy turned this on its head. Scientists are now able to freeze biomolecules mid-movement and visualise never-before-seen processes and interactions of biomolecules, which revolutionises both the basic understanding of life’s chemistry and the development of pharmaceuticals.

It wasn’t until 1990, that Richard Henderson proved the sublime potential for electron microscope technology. They were previously believed to only be suitable for imaging dead matter as the power of the electron basically fried any living matter being viewed. Luckily for everyone, Henderson generated a three-dimensional image of a protein at atomic resolution, and the protein lived to tell the tale.

At the same time as Henderson was doing his researcher another g, Jaochim Frank was fiddling around with electron microscopes too, making the technology generally applicable. Spanning the decade after 1975, Frank developed a mechanism which aided the image processing. He overlaid all the fuzzy two-dimensional images allowing for a much sharper three-dimensional structure to be seen.

Jacques Dubochet came along shortly after the two lads and added water to electron microscopy. Liquid water evaporates in the electron microscope’s vacuum causing the biomolecules  to collapse. Dubochet changed things up by vitrifying water meaning he cooled water so rapidly that it solidified in its liquid form around a biological sample, allowing the biomolecules to retain their natural shape even in a vacuum.

It took more than 30 years after these discoveries to fully optimise the electron microscope with the desired atomic resolution being reached in 2013. Researchers are now consistently able to produce three-dimensional structures of biomolecules. In the past few years, scientific literature has been filled with images of everything from proteins that cause antibiotic resistance, to the surface of the Zika virus. The future of the field of biochemistry is about to blow up in a big way. Watch this space.

The Nobel Prize in Physics 2017 was divided; one half awarded to Rainer Weiss, the other half jointly to Barry C. Barish and Kip S. Thorne “for decisive contributions to the LIGO detector and the observation of gravitational waves”.

Gravitational waves, which were first predicted by Albert Einstein over 100 years in his staggering work on the theory of general relativity. Until now,  the majority of Einstein’s work in this area was couldn’t be proven. This all changed on the 14 September 2015, when LIGO, the Laser Interferometer Gravitational-Wave Observatory, observed the universe’s gravitational waves for the first time. To put this into perspective, even the great Einstein didn’t these waves could be observed. This could’ve been due to timing, it only took the waves 1.3 billion years to reach the LIGO detector.

The signal, created by a collision of two black holes, was extremely weak when it reached Earth, but is already promising a revolution in astrophysics. Gravitational waves are an entirely new way of observing the most violent events in space and testing the limits of our knowledge.

LIGO is a collaborative project with over one thousand researchers from more than twenty countries. Together, they have worked and culminated a vision that is almost half a century old. Pioneers Rainer Weiss and Kip S. Thorne, together with Barry C. Barish, the scientist and leader who brought the project to completion, ensured that four decades of effort led to gravitational waves finally being observed.

In the mid-1970s, Rainer Weiss had already analysed possible sources of background noise that would disturb measurements, and had also designed a detector, a laser-based interferometer, which would overcome this noise. Early on, both Kip Thorne and Rainer Weiss were firmly convinced that gravitational waves could be detected and bring about a revolution in our knowledge of the universe.

Gravitational waves spread at the speed of light, filling the universe, as Albert Einstein described in his general theory of relativity. They are always created when a mass accelerates, like when an ice-skater pirouettes or a pair of black holes rotate around each other. Einstein was convinced it would never be possible to measure them. The LIGO project’s achievement was using a pair of gigantic laser interferometers to measure a change thousands of times smaller than an atomic nucleus, as the gravitational wave passed the Earth.

So far all sorts of electromagnetic radiation and particles, such as cosmic rays or neutrinos, have been used to explore the universe. However, gravitational waves are direct testimony to disruptions in spacetime itself. This is something completely new and different, opening up unseen worlds. A wealth of discoveries awaits those who succeed in capturing the waves and interpreting their message.

The Physiology or Medicine award this year was jointly bestowed upon Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythm”.

Living organisms, including humans, have an internal, biological clock that aids to anticipate and adapt to the usual daily rhythm.  Jeffrey C. Hall, Michael Rosbash and Michael W. Young wanted to know what made us tick, so to speak. This circadian rhythm, works in conjunction with the earth’s revolution and these dashing fellows looked at this worked in plants, animals and humans.

Using fruit flies (Drosophila melanogaster) as a model organism, this year’s Nobel laureates isolated a gene that controls the normal daily biological rhythm. 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 gene responsible for fly circadian rhythm, period.

They showed that this gene encodes a protein, PER, that accumulates in the cell during the night, and is then degraded during the day. This more than suggested that PER protein levels oscillate over a 24-hour cycle, synchronising with the circadian rhythm.

Subsequently, they identified additional protein components of this machinery, exposing the mechanism governing the self-sustaining clockwork inside the cell. This research was furthered and other multi-cellular organisms, including humans, have a similar system.

The next key goal was to understand how such circadian oscillations could be generated and sustained. Hall and Rosbash hypothesised 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 tantalising, 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, 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 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 synchronise the clock.

The biological clock is involved in many aspects of our complex physiology. We now know that all multi-cellular organisms, including humans, utilise 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.

Orla Daly – Science Editor

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