18 Oct 2021
Issue #79: The second Nobel year in the time of COVID-19: Medicine
Written by Nobel Laureate Professor Peter Doherty
The average time between making a discovery and being recognised by a Nobel Prize is now about 30 years so, while some may have expected that the mRNA vaccine breakthrough might figure for 2021, that absence was hardly a surprise. Alfred Nobel’s will made way back before his death in 1896 stipulated that the science prizes should be awarded for work done within the past year. But it takes time for discoveries to be evaluated and confirmed, or for any substantial problems to emerge. The various science Nobel Committees are very conservative, and they don’t want to make a mistake.
So, how does this year’s Nobel medicine prize (announced 4 October) to David Julius of the University of California, San Francisco, and Ardem Patapoutian of Scripps Research, La Jolla, California ‘for their discoveries of receptors for temperature and touch’, relate to COVID-19? They are being recognised for the identification of transmembrane ion channel proteins (with names like TRPV1, TRPM8 or Piezo) that, when subject to temperature signals – Julius used the chemical capsaicin (from Chili pepper) for heat and menthol for cold – or physical pressure (Patapoutian) open to allow cations (Ca2+, Na+. K+) from the extracellular fluid to flow into a nerve cell and generate an electrical signal. Experimentally, both groups detected that electrical pulse using the patch clamp (of a detector, onto cell membrane) technique that earned the 1991 Nobel medicine prize for Bert Sakman and Erwin Neher and is widely used across biology.
Technically, our two ‘somatosensory’ Nobelists used the exact opposite approaches to identify the individual ‘gateway’ proteins. Julius extracted the genes (made a cDNA library) from temperature-sensitive, cultured nerve cells (neurons) then, one by one, expressed the DNA sequences encoding the likely proteins in a temperature-insensitive cell line. Patapoutian took a pressure-sensitive cell line and progressively ‘silenced’ the genes for the possible ion channel proteins. Such are the marvels of modern molecular science!
The ion channel proteins they identified are positioned at the tips of the long processes (axons) that extend down to the skin from temperature or pressure reactive neurons located in the dorsal root ganglia (DRG) of the spinal cord. Triggered by a heat, cold or pressure stimulus at the skin surface that causes one or other ion channel protein to open, the electrical signals travel up the axons (by sequential electrical depolarisation of the axonal membrane) to the neuronal cell bodies in the DRG ‘relay station’. Our response can be immediate, depending on direct synaptic connection to motor neurons as a ‘reflex arc’ in the spinal cord, or sent upwards via sensory interneurons to register the consciousness of heat, cold or touch in the brain.
Struggling a bit with that? Me too: The following may be unfamiliar if you’re part of the generation that’s only ever used an iPhone, but you’ve likely seen period movies where people pick up a telephone handset with a cord attached. Just think of the nerves (axons) as the telephone lines connecting repeater or receiving/transmitting stations (the neuronal bodies) in a ‘hard wired’ system, and the opening of a particular ion channel as an ‘operator’ pressing different hot, cold or pressure buttons that send the electrical signal onwards and upwards. That might be intercepted along the way by a rapid response ‘motor’ unit (the reflex arc) or sent on to be interpreted by ‘central command’ (the conscious or unconscious brain) that issues ‘appropriate’ orders. Those skin sensors may give us a local signal that tells us we’ve touched something hot, or a general sense of heat as we move outdoors on a summer day. The result can be the activation of motor neurons innervating the muscles that take our hand way from an inadvertent brush with a hot engine, or the dilation of peripheral blood vessels and the activation of sweat glands to facilitate skin cooling (by evaporation) in warm air. With an infection like COVID-19, if we don’t have a thermometer to hand, we might try to assess whether someone is feverish by touching the back of our hand to their forehead.
Other thermosensitive neurons located in the ‘control centre’ of the hypothalamus, which sits just above the brain stem, measure the ‘environment within’ by taking the temperature of the blood. Fever is, of course, characteristic of most infections, with ‘pyrogenic’ cytokines like interleukin 1 (IL-1) beta, IL-8 and tumor necrosis factor (TNF) alpha circulating in the blood from sites of infection to interact directly with the hypothalamus, which will in turn relay information to other regions of the brain. Such effects will obviously be part of COVID-19, with fever and malaise being ‘nature’s way of telling us to slow down’!
Way back (#22), we discussed anosmia, the loss of sense of smell characteristic of early infection with, particularly, the SARS-CoV-2 alpha variant. Beyond that, some COVID-19 patients experience a sensory deprivation called ‘chemethesis’, an inability to detect hot chilies or cool peppermints. The interaction of SARS-CoV-2 with brain and neuronal function can be profound, and there’s a great deal that we don’t understand. Without knowing what’s happening, how do we treat the ‘brain fog’, unexplained muscle pains and so forth that are especially characteristic of Long COVID? Next week, we’ll continue with a somewhat different, though related, face of complexity as we discuss the 2021 Physics Nobel.