by Will Hartridge
In the last two years, breakthroughs in the field of biochemistry and medicine have been frequent and acknowledged by the general public more than ever before. Today, the average person is now well versed in virus and vaccine technologies after a constant bombardment by headlines and press releases. Consequently, after breakthroughs in Covid research have been so publicly acclaimed, it was surprising to see no Nobel prizes this year awarded to this field. However, this year’s prizes are still fascinating and groundbreaking endeavours that have already lead the way into new areas of research and are likely to prompt many new discoveries to come.
For most of our five (realistically many more) senses, their biochemical mechanisms are already known and extensively studied, such as that of vision. However, until recently the sense of touch has remained largely a mystery. The Nobel prize in Medicine and Physiology this year was awarded jointly to Ardem Patapoutian and David Julius for the discovery of two sensory mechanisms: for heat and pressure.
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Firstly, Patapoutian and his lab at Scripps Research discovered two proteins, Piezo1 and Piezo2, responsible for the sensing of pressure- a fundamental indicator of stimuli and internal processes all around the body. This was discovered using a line of cultured cells that, when pressure was applied, electrical signals could be measured. 72 genes in these cells were inactivated one after another until a state was identified where the cells did not respond to pressure- hence the genes turned off in this state were responsible for the Piezo1 and 2 proteins. So how do these proteins sense pressure? They are embedded in the cell membrane and without stimulus, are bent in shape. However, when pressure is applied, an increase in tension of the surrounding membrane causes the protein to flatten out. This large mechanical change causes its central channel to open, allowing charged ions to flow through the membrane, which causes a change in electrical charge and induces a cascade of events to translate this signal into meaningful cellular responses.
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This discovery is a fascinating insight into the inner workings of the human body but also has wide-reaching medical implications. These proteins are not just used for touch- in fact, their pressure sensing abilities allow for involvement in a wide range of physiological processes including blood pressure, bladder control, respiration, tissue growth and proprioception- the body’s ability to sense its own limbs and movements. Therefore all of these processes are potential targets for treating detrimental conditions. For example, in patients with mutations that cause a non-functional Piezo 2, a loss of coordination and struggle learning to walk is common and is often attributed to muscle dysfunction or motor neuron diseases by doctors. Now, knowing Piezo 2 is the true cause of these struggles can provide emotional clarity to the patient and prevent unnecessary treatment for a disease they don’t have. Another potential area of research is treating tactile allodynia- a condition where any touch on the skin causes pain. No cures currently exist, so targeting the Piezo proteins could be a way of blocking the sense of pressure that triggers this pain, however, due to the wide-ranging functions of these proteins in the body, treatments would need to be topical to the affected area to prevent a multitude of undesirable effects. Finally, Piezo1 is also present in red blood cells and the immune system, a fact that is promising for research in malaria treatments.
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The other discovery this prize was awarded for was by Julius and his team in the late 1990s- who identified the gene and protein responsible for heat sensing, called TRPV1. This was carried out by using capsaicin: a molecule present in chilli peppers responsible for their burning sensation, which targets the same proteins responsible for sensing temperature. A search for the responsible genes was carried using a cell line and inactivating genes one by one until they did not respond to capsaicin, much like the experimental technique used by Patapoutian. Like Piezo1 and 2, TRPV1 is also an ion channel that opens in response to stimulus (in this case, a temperature above 43°C) to induce a change in electric charge across the cell membrane.
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Finally, a similar methodology was then later used independently by both Nobel laureates to identify another temperature receptor responsible for sensing cold temperatures- TRPM8. This time menthol was used- the chemical responsible for the cold sensation of mint.
Sources:
https://www.nobelprize.org/prizes/medicine/2021/press-release/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062430/
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