Straight Dope on Medicine: 2021 Nobel Prize in Medicine

Author

Scott Ganser
April 20, 2023

David Julius won the 2021 Nobel Prize in medicine. This was awarded because he discovered our sensors for temperature. Ole Petter Otterson, President of the Karolinska Institut, which selects the winners, introduced the plenary lecture. He said, “the uber goal is to achieve scientific breakthroughs that significantly deepen our understanding of health and disease.”[i]

Touch and temperature are omnipresent senses. We cannot turn them off at will. These sensors convert physical stimuli into electrical pulses, which are conveyed to the brain to allow us to perceive temperature and touch.

Julius unraveled the mystery of capsaicin, a compound found in chili peppers, that induces a burning sensation, to identify a novel sensing protein called trpv1. It not only was a receptor for capsaicin, but doubled as a sensor for heat.

Heat receptors allow us to discern our core body temperature and distinguish pleasant warmth and bitter cold.

Piezo means “pressure” in Greek. This was the mechanoreceptor channel elucidated by Julius’ co-winner, Ardem Patapoutian. These channels endow us with the sense of touch and give us positional understanding of our bodies.

Proprioception[GS1] , or kinesthesia, is the sense that lets us perceive the location, movement, and action of parts of the body. It encompasses a complex of sensations, including perception of joint position and movement, muscle force, and effort.[ii]

Some think of this ability as coordination.

That’s part of it.

Julius is the Chair of the Department of Physiology at UCSF. He was born in Brooklyn, New York. Graduated from M.I.T. Berkeley was where he did his graduate work.

His Nobel speech was entitled, “From Peppers to Peppermint: Insights into Thermal Sensation and Pain.”

Julius has always had an interest in natural products, something that God cooked up, and he wanted to explore how they might help us understand ourselves.

Nociception refers to the central nervous system (CNS) and peripheral nervous system (PNS) processing of noxious stimuli, such as tissue injury and temperature extremes, which activate nociceptors and their pathways. Pain is the subjective experience one feels as a result of the activation of these pathways.[iii]

Nociceptors can run the gamut from detecting external stimuli to internal stimuli, like prostaglandins, which can contribute to pain.

What touched it all off from Julius was capsaicin.

 

 

Capsaicin is used to help relieve a certain type of pain known as neuralgia (shooting or burning pain in the nerves). Capsaicin is also used to help relieve minor pain associated with rheumatoid arthritis or muscle sprains and strains.[iv]

Neuralgia is a pain that comes from the nerves near the surface of your skin.

This product is available in the following dosage forms:

· Cream

· Lotion

· Patch, Extended Release

· Solution

·  

It works by depolarizing the nerve fiber and allowing sodium ions to flow in.

Back in the 1970s, when this was just a theoretical idea, they did not have a clue what a capsaicin receptor might look like.

No idea.

And so they took a “structure-blind identity approach.”

Basically, they looked for the needle in the haystack.

But their needle was regular size.

They took cDNA from central nerve ganglia and introduced those clones into a non-neural cell that is normally capsaicin insensitive like a fibroblast. If you exposed these transformed cells to capsaicin and it allowed calcium to flow into the cell, it was a hit.

GAIN OF FUNCTION.

But for cells. And for capsaicin.

One assumption built into the mix that might have thwarted them would be a structure build by multiple gene products. They needed a single source for their fishing expedition to work.

They got lucky.

What else might this trpv1 vanilloid receptor do?

Detect heat.

Whenever you answer one question, ten more spring up in its place. This is known as the scientific hydra. I just made that up.

Next question:

What about cold sensation?

Conduct another search in a different haystack and see if there is a “mint” or cold receptor.

Lightning struck twice.

TRPM8 arose.

Again, it was an ion channel entity.

Patapoutian is Lebanese. Graduated from UCLA in 1990. After that, he obtained his doctorate from Caltech. Now he is at Scripps.[v]

Touch gathers tactile signals from peripheral tissued like skin and then converts this information to electrical signals which the brain can understand.

Our sense of touch is uncanny. We can distinguish indentations 500 times smaller than the human hair.

Mechanosensation is the flip side of touch in that it informs about pain.

Pain is essential for survival.

Chronic pain falls under the category, “unmet medical need.”

These pain receptors reside in the dorsal root ganglia next to the spinal cord.

How do you know if you are experiencing a gentle breeze, or a cactus pricking your finger?

Cells containing ion channels in your fingertips are activated by physical forces.

In 2010 Patapoutians lab discovered mammalian nonselective cation channels Piezo 1 and 2.

Piezos are very large molecules and traverse membranes, with 38 transmembrane domains.

These channels sit in grooves within the plasma membrane.

Tension or stretch of the membrane activates the channels. The amount and force of deformation matters.