Chile and the Nobel Prize

On December 10, the Nobel Prize in Physiology and Medicine was awarded to David Julius and Ardem Patapoutian, for the work they carried out thanks to which we now understand more clearly how we communicate with the environment. They identified receptors for temperature and touch, respectively.

I vividly remember when Julius’ work was published in the journal Nature in 1997. What he discovered was a membrane channel in neurons that he named TRPV1, as it is the first identified channel of this family that is known as the “Transient Potential Vanilloid Receptor “, Which means that they are membrane channels that generate an electrical potential when they are stimulated with vanilloid agonists. Vanilloids are chemical compounds whose structure contains a vanillyl-type ring, within which is nothing less than capsaicin. What Julius did was discover the receptor in neurons that is stimulated by this compound, capsaicin, which is what gives us the spicy sensation of chili. The cover of Nature on that occasion, which was also the day of the doctor, October 23, 1997, precisely had a photograph of various chili peppers.

The article caught my attention then for two reasons. The methodology that Julius used to identify the receptor was the same that I had used years ago, under the mentorship of Steven Hebert at Harvard, to identify the gene that encodes the NaCl cotransporter in the kidney (PNAS, 1993) and the one that encodes for a membrane receptor, whose ligand is calcium and which allows cells to respond to different concentrations of this ion in the environment, that is, another form of communication with the environment. We named this receptor the calcium sensing receptor (Nature 1993). The methodology is what is known as cloning by functional expression, which consists of starting from the messenger RNA of the cells of interest and transfecting it into other cells, mammalian or frog oocytes, to search for the function of the protein of interest and thus, use that assay to systematically analyze a complementary DNA library until a unique clone is found that contains the gene for that protein.

In the case of TRPV1, what Julius measured was the electrical current generated in cells transfected with mRNA from neurons of the dorsal ganglion when stimulated with capsaicin, and thus, he followed this function until the gene was identified. I clearly remember the figure in the article in which the magnitude of the response induced by pure capsaicin was similar to that observed with an extract of habanero pepper and much lower than that obtained with poblano pepper, which gave a molecular explanation to the degree of “hotness ”Of the different chili peppers studied. Julius had found the molecular mechanism by which chili peppers sting and I thought – heck, the methodology was identical to the one I used. Being Mexican, how I would have liked to do this job.

But the Nobel Prize was not awarded for discovering the recipient of the chili, but for an observation that was unexpected and that reminds us again and again of the importance of doing basic science. TRPV1, in addition to responding to capsaicin, is also activated by high temperature and, therefore, they had discovered the molecular mechanism by which mammals perceive heat and with this, they also explained the phenomenon, known to all, why the physiological response to eating chili is similar to that obtained in hot weather: vasodilation and sweat that makes our skin red and serves to wet it, cool it and thus lose heat. Mice intentionally knocked out of the TRPV1 gene stopped responding to capsaicin and heat in this way.

Subsequently, Julius and Patapoutian independently discovered cold receptors, using peppermint as the stimulating agent, and Patapoutian discovered receptors by touch. Patapoutian was born in Beirut and came to the United States with his family in his late teens fleeing the war in Lebanon. He is thus one of the immigrants so hated by President Trump, who teaches us that when you think that everything is lost in life, you do not know what may come next, when you insist on work and study.

The award of the Nobel Prize for this work fills me with nostalgia because I participated in a work whose researcher could have received it. With the molecular identification of the calcium receptor sensor (Nature, 1993), as I said, with an identical methodology, we discovered the mechanism by which cells detect how much calcium is in the extracellular medium and respond accordingly, which came to explain to multiple phenomena in diversity of organs. For example, the mechanism by which parathyroid hormone secretion is regulated by calcium in the blood or the mechanism by which fish know whether they are in fresh or salt water. What they sense in calcium. The discovery of this sensor made it possible to demonstrate that this gene causes diseases in humans and to develop drugs, such as cinacalcet, which we use today in clinical practice. My mentor Steve proposed this project to me one cold Boston afternoon and two years later we had succeeded. Unfortunately, Steve died prematurely, at 61 years of age, one night in 2008 during sleep, without having had any risk factors for cardiovascular disease, or previous manifestations. Had he not died, I am sure Steve Hebert would have received the Nobel Prize for teaching us how cells communicate with the environment, just as Julius and Patapoutian taught us how humans perceive the environment.