Nobel Prize lecture: David Julius, Nobel Prize in Physi… — Transcript

Ladies and gentlemen, it's a great pleasure and a privilege to welcome all of you to the 2021 Nobel Lectures in Physiology or Medicine. My name is Ole Petter Ottersen, and the President of Karolinska Institutet.

During the Nobel Week, we celebrate science, and we rejoice at the unique contributions of some exceptional individuals whose discoveries, in the words of Alfred Nobel, have conferred the greatest benefit to humankind. Within physiology or medicine, the ultimate goal is to achieve scientific breakthroughs that significantly deepen our understanding of health and disease.

The discoveries we celebrate this year are stellar examples of such breakthroughs. Today, it's an honor for me to extend my warmest congratulations on behalf of Karolinska Institutet to David Julius and Ardem Patapoutian.

They share the 2021 Nobel Prize in Physiology or Medicine for the discoveries of receptors for temperature and touch.

This morning here in Stockholm, the temperature had dropped to minus 17 degrees Celsius. When I was walking to work, I felt very clearly that we humans, we do have receptors that react to temperature. So it will be very exciting and also I would say very timely to hear more about the important findings of our Nobel laureates today.

Without further ado, I now give the floor to Abdel El Manira, Professor of Neuroscience and a member of the Nobel Assembly, who will introduce this year's laureates. Please, Abdel.

President of the Karolinska Institutet, esteemed laureates, dear colleagues and friends, ladies and gentlemen, on behalf of the Nobel Assembly at the Karolinska Institutet, I welcome you all to the 2021 Nobel Lectures.

I have the great pleasure and honor to introduce this year's Nobel laureates in Physiology or Medicine, Dr. David Julius and Dr. Ardem Patapoutian. They have been awarded this year's Nobel Prize in Physiology or Medicine for their discoveries of receptors for temperature and touch.

The philosopher Immanuel Kant wrote, "All our knowledge begins with the senses, precedes then to the understanding, and ends with reason." Our senses are not only the source of reason, but they are also the essence of our survival. They underpin our interaction with the world around us. This year's Nobel Prize pertains to our ability to sense temperature and touch. These sensations are omnipresent. We cannot switch them off at will. We take them for granted in our daily lives, and yet, the absence of these sensations has the dramatic consequences for our well-being. The question then is, how temperature and touch are sensed and converted into electrical signals in the nervous system? This question remained a mystery until this year's, until the work of this year's Nobel laureates.

They have discovered novel classes of molecular sensors that respond to heat and mechanical pressure. These sensors convert physical stimuli into electrical impulses that are then conveyed to the brain to allow us to perceive temperature and touch. Nature not only provided the mystery, but it also afforded us the tools to solve it. David Julius took advantage of capsaicin, a natural chemical compound found in chili peppers that induces a burning sensation, to identify a novel receptor protein, named TRPV1. Remarkably, David Julius found that TRPV1 is not only a receptor for capsaicin, but it is also a sensor for heat. This was a major breakthrough, leading the way to the unraveling of additional temperature-sensing receptors belonging to the TRP channel family. Each of these receptors is activated over a specific temperature range, and together, they act as a biological thermometer that allows us to control our core body temperature and to distinguish pleasant warmth or a cool breeze from painful heat.

Ardem Patapoutian took advantage of a cell line with inherent sensitivity to mechanical stimulation, and using a painstaking gene silencing experimental analysis, he succeeded in identifying the gene encoding the elusive mechanosensitive channel that he named Piezo, after the Greek word pressure. Piezo channels provide us with the sense of touch, to feel the texture of objects, and to monitor the position of our body in time and space, our sixth sense, called proprioception.

The work of this year's Nobel laureates has unlocked one of the secrets of nature. Their discoveries of receptors for temperature and touch have fundamentally changed our views on the functioning of sensory systems and enhanced our understanding of the complex interplay between the environment and our senses. At this point, reason obliges that I give way to the Nobel laureates, who will now give us a true sense of their seminal discoveries.

The first lecture is on the discovery of receptors for temperature by Dr. David Julius. David Julius is Professor and Chair of the Department of Physiology at the University of California, San Francisco. He holds the Morris Herzstein Chair in Molecular Biology and Medicine. Professor Julius was born in Brooklyn, New York, where he attended public elementary and high schools. He receives his bachelor's degree in Life Sciences from the Massachusetts Institute of Technology in 1977, and obtained his doctoral degree in Biochemistry in 1984 from the University of California, Berkeley, California. University of California, Berkeley, where he worked with Jeremy Thorner and Randy Schekman on peptide hormone processing and secretion in yeast. Professor Julius performed his postdoctoral training in the laboratory of Richard Axel at Columbia University, New York. During this time, he developed novel expression cloning methods, enabling him to identify genes encoding serotonin receptors, and he joined the faculty at the University of California, San Francisco in 1989. David Julius is a member of the National Academy of Sciences, and the National Academy of Medicine, and the American Academy of Arts and Science. David Julius will now deliver his Nobel Lecture entitled, "From Peppers to Peppermints: Insights into Thermosensation and Pain."

Hello from San Francisco. I'd like to begin by thanking the Karolinska Institute and Professor Otterson for hosting this these lectures. Uh and I'd like to thank the Nobel Foundation for their creativity in putting this hybrid celebration of Nobel Week together, which at least allows us to enjoy one another's company in some form, uh during this still challenging pandemic times. And of course, I'd like to thank the Nobel Assembly for uh bestowing this tremendous honor upon me and my co uh laureate Ardem, uh who I am very pleased to share with whom I'm very pleased to share this prize. Uh and in a larger sense, I'd like to thank the Nobel Assembly for recognizing the field of pain and somatosensory research, uh which has um brought great excitement to the field, to our laboratories, to our institutions, uh and even to the many patients around the world who suffer from chronic and persistent pain syndromes. So that's actually a good place to start, because much of what we've uh um our motivation for what much of what we've learned over the last few years has been to ask questions about pain and pain mechanisms and understanding pain.

So pain, of course, is a submodality of somatosensation, the sensation that we colloquially refer to as touch. And uh I often argue that among our five senses, uh um somatosensation and pain is probably the most important for our survival and well-being. Uh and that's because pain serves as a main warning and protective system that tells us when we have or about to experience bodily injury and to initiate appropriate protective reflexes.

Um and in people who in whom this system is rendered inoperable due to genetic mutations or diseases, uh those individuals are at great risk of bodily injury or death.

The problem is, of course, is that uh while pain is incredibly uh useful and necessary as an acute warning system, it often outlives this phase and instead becomes persistent and debilitating. Uh and the goal uh is to understand this switch between acute and chronic pain, uh ultimately with the hope of preventing or reversing that. Now, another challenge I think in the pain field, uh in the long run is to better define different pain syndromes, to ask how chronic pain syndromes differ, cellularly, molecularly, in terms of the circuitry, uh and to understand what the underlying molecular mechanisms are, because I think until we do that, uh we won't be able to adequately treat different pain syndromes.

Um so let me begin by uh by just giving a very brief overview of the pain pathway. Of course, pain like other sensory systems involves the detection of uh peripheral stimuli, environmental stimuli, as well as some endogenous stimuli. Uh and this occurs at the tips of primary afferent or sensory nerve endings, uh that transduce this information then to the central nervous system, first to the spinal cord, uh and ultimately to the brain where we perceive what's happened peripherally as a noxious or painful stimulus.

Uh in my lab, we focused uh um mostly at uh understanding what happens here where pain begins at the periphery, in these primary afferent nerve terminals, uh and uh and which in aggregate are really remarkable cells. And why are they so remarkable? Because they must they they're tasked with the job of being able to detect a wide range of stimuli that include uh physical stimuli like changes in pressure and temperature, which is really sort of the focus of the lectures you'll hear today, uh as well as other things in our environment such as um noxious chemical agents, uh as well as agents that are produced in our body, uh in the as a consequence of uh of tissue or nerve damage. And what's remarkable about these uh sensory nerve endings is that they have uh mechanisms, receptors for sensing each and every component of the so-called inflammatory soup. And of course, the purpose of this is to heighten the sensitivity of the primary afferent nerve terminal as part of the guarding response to tell us when we have uh experienced injury so that we can protect that area. So it really changes the gain of the nerve fiber.

Uh and the goal in my lab and many labs in this uh uh in this area is to understand how all these different stimuli focus in on the primary afferent nerve terminal, including physical stimuli and chemical stimuli, to regulate its excitability under normal conditions and under conditions of following injury.

Now, studying these mechanisms, especially 20 or 25 years ago when we began this, was somewhat challenging because the genetic uh and other tools to uh to identify molecules and mechanisms involved uh were uh were lacking.

And so we turned to an approach, and that is to really exploit natural products and in some sense folk medicine to uh to use uh tools, pharmacological tools from these systems to uh to try and identify and probe mechanisms that are involved in pain sensation. And I sort of refer to this as pharmacology honed by evolution, and I've always been fascinated by this, because studying natural products and folk medicine is really sort of the nexus uh where human behavior, chemistry, uh and neurophysiology come together.

And I think some of the uh examples that have really inspired me and other people in this field uh come from some of the following individuals. For example, Saul Snyder's uh brilliant use of morphine and other opiate uh alkaloids to discover opiate receptors. Um the work of Sir John Vane, who uh explored the role of of aspirin and salicylic acid, uh as a product of the willow bark, uh as which we know as an analgesic and through that route discovered the existence of cyclooxygenases and prostaglandins. Uh and then Raphael Mechoulam in Israel, who uh asked what the psychoactive ingredient in marijuana uh is, and identified THC uh as the active psychotropic component, and then went on to identify endogenous endocannabinoid-like compounds, namely anandamide and 2-AG, through this kind of route. Uh I've always been fascinated by this approach, and I think this has served as inspiration for many of us who uh who have taken this route of exploiting natural products and folk medicine uh as a way to explore endogenous mechanisms of neural signaling or even cardiovascular signaling uh in the in human in human physiology.

Now, um we've uh sort of turned this um coin over on its other side and instead of asking how natural products work uh to deliver analgesic uh relief, we've asked uh how natural products work uh that serve as to induce pain, that serve as irritants. And the granddaddy in this uh field is really capsaicin, the main pungent ingredient in chili peppers. But there are also other plant-derived irritants, including menthol from mint leaves, uh and these compounds, the so-called isothiocyanates and thiosulfinates, that represent the pungent irritants in wasabi, members of the mustard family of plants, allium plants such as onions, uh shallots, garlic, et cetera.

Um now, uh in this regard, there are really two groups when I went back and thought about this, whose work really influenced our approach, specifically in regard to using these plant-derived uh irritants. And one of these is the uh brilliant work of Jancsó and colleagues, together with his wife Aurelia Jancsó-Gábor, uh whose team were really the first to use capsaicin at the University of Szeged in Hungary, uh as a chemical probe for a subset of sensory neurons that uh that turned out to be very important in pain sensation. So they showed uh in the 1950s and 60s that uh exposure of that capsaicin served as a as a very selective excitatory agent for a subset of primary afferent nerve fibers uh that are dedicated to pain sensation, the so-called nociceptors.

Uh and they further showed that exposure of these of sensory neurons to capsaicin, especially at high doses, led to a functional desensitization of these cells, as well as to their ultimately to their uh to their death. Uh and furthermore, they showed that animals uh injected with a bolus of capsaicin would show a very profound decrease in their core body temperature, which is probably why we like to eat hot peppers in hot climates, because it leads to a uh a centrally mediated uh hypothalamically mediated cooling of the body through vasodilation and sweating. But that also uh suggested that whatever the mechanism of capsaicin capsaicin might be on the primary afferent, that this somehow was involved in sensing external temperature and reporting this information to the CNS.

The other group that uh that greatly influenced our work uh was that of uh Yngve Zotterman, uh together with um Herbert Hensel, who did their work actually at the Karolinska Institute. Here's a picture of Zotterman in 1926, speaking with Lord Adrian outside the Karolinska Institute during a physiological conference. Uh and what Hensel and Zotterman showed was that menthol um has a very specific action on a subset of nerve fibers in the cat tongue, uh and that the actions of menthol as an excitatory agent could be suppressed by warming or enhanced by cooling. And together, these observations uh suggested that the psychophysical effects of these natural products are mediated through their selective action on somatosensory nerve fibers.

Uh it also suggested uh later on to many of us that if one could define the molecular targets for these natural products, that this would reveal some important endogenous mechanisms of pain and or temperature sensation.

So later on, uh the focus really uh in in ensuing years was really on understanding how capsaicin works.

In about the 1990s, uh um a number of scientists, particularly at the Sandoz Institute at the University of College London, began to ask how capsaicin works from a biophysical perspective. So they patch-clamped sensory neurons, uh and they had data to suggest that what capsaicin does is to enhance the permeability of the membrane of sensory neurons to uh both mono and divalent cations. And the presumption was that capsaicin acts upon a receptor and or an ion channel that mediates these effects, uh and that the selective actions of capsaicin might uh be a consequence of the expression of such a receptor on these cells.

Although I have to say at this time, there are also uh um uh competing ideas that capsaicin works more non-selectively by integrating into the membrane and somehow forming uh um some kind of a of an ion permeation pore. Um but this set up a number of questions, obviously, in the in the 80s and 90s, uh that hearken back to the questions that were raised by uh Jancsó and by Hensel and Zotterman, and that is, do natural irritants target specific sites on sensory nerve fibers? What's the molecular nature of these putative receptors if they do exist? Uh and and if they do exist, can we use these as molecular tools ultimately to ask if they mark functionally distinct sensory neuron subtypes? In particular, are they good probes for marking subsets of neurons, the presumptive nociceptors that are involved in either temperature or pain sensation? Uh and really the biggest question is what are the endogenous physiological roles for such molecules if they exist? Obviously, we don't have these uh putative receptors in our body just so we can experience the culinary wonders of spices, what are their roles in normal physiological uh um circumstances?

And this really set up uh a what we often refer to as a holy grail of molecular pain research at the time, which was to find the capsaicin receptor.

Uh and this grail was really reached when Mike Caterina joined my lab, he's now at Johns Hopkins Medical Center, uh when he took on the the challenge of cloning uh what we hoped would be a gene encoding the capsaicin receptor. And and he had a very simple approach, which is to take somatosensory neurons from a mouse or a rat, uh and generate a cDNA uh library, expression library from these cells in mass, and then to introduce those these into non-excitable, non-neuronal cells, in this case, so-called HEK 293 fibroblasts. And the idea was that if capsaicin really acted on some kind of a receptor or a channel that increased uh intracellular calcium, uh as as people like uh Humphrey Rang and Stuart Bevan had suggested, that we could detect this with uh the calcium-sensitive dyes developed by the late Roger Tsien. Uh and so what we did was load these cells with these calcium the calcium dye called Fura, introduce capsaicin, and we looked for cells that glowed, which presumably had taken up a cDNA clone that allowed them to express a receptor that rendered them sensitive to capsaicin. And indeed, Mike was able to do this, and he succeeded in this. This was somewhat, of course, of a Eureka moment. Uh and he showed through sequencing and uh together with Makoto Tominaga and others in my lab, that this gene encoded, in fact, an ion channel that has permeability to both mono and divalent cations.

A couple of years later, uh oh, and I should also say that um that pharmacologically what Mike was able to show is that uh in fact, this receptor is a great reporter for pungency. So if you ask how this receptor responds to extracts from chili peppers, uh uh ionic currents go through this receptor uh respond in direct proportion to the perceived pungency of the chili pepper, using capsaicin as a uh as a standard. Uh and so in essence, we now had a molecular reporter that was a uh a substitute or a mimic of the so-called Scoville units, uh which are classically used to report pungency.

Now, a couple of years later, uh Dave McKemy joined my lab and together with Werner Neuhausser, uh asked the same question for menthol. Is there a receptor for menthol, and can we use the same uh function-based cloning uh approach to identify that? And indeed, uh Dave and and and Werner were able to identify a cDNA uh encoding a uh a menthol-sensitive receptor.

Uh now, I I think one of the most beautiful outcomes of this uh of of this uh part of our work was really to find that um there's a beautiful molecular convergence and and logic here.

And that is that both of these receptors turn out to be members of the same molecular family, the so-called family of TRP ion channels. The menthol receptor, TRPM8, and the capsaicin receptor, uh TRPV1, are molecular cousins by belonging to this family. And in fact, the receptor for the so-called wasabi receptor that's activated by these other agents, pungent agents, the isothiocyanates and thiosulfinates, also belong to this family. Uh and so we see this beautiful example of of convergence of mechanism for for these natural product irritants acting on these channels, which really illustrates the importance of TRP channels in uh sensory processes at large, but in somatosensation and pain uh specifically.

Now, today I don't have time to talk about uh TRPA1, the wasabi receptor. This is a very interesting channel that plays a major role in chemonociception, that is our ability to detect environmental and endogenous uh irritants, chemical irritants.

Uh and hopefully, if I come to Sweden next year, I can tell you more about work that we and others have done in this area.

But for today, I'm going to focus on the capsaicin and menthol receptor. And the real question here, of course, is what is the natural role of these uh ion channels in in physiology? Uh and and this question was really answered when uh when Mike and Makoto and others in my lab found that the expressed channel, whether you express it in a in a fibroblast, in a frog oocyte, whatever, uh has intrinsic sensitivity or has renders the cell sensitive to heat. And as you can see here in this beautiful uh uh temperature response curve, the salient um uh characteristic of this response is that the channel shows this very steep sensitivity to an increase in temperature, shown here on the X-axis with ionic current on the Y-axis, uh and uh and it shows a uh a temperature coefficient of activation greater than 20.

For most ion channels, this would be uh no more than one to to uh three in that range. So it has a very uh uh a very uh steep um uh cooperative activation by heat. And the other thing is that there's a very defined threshold at about 43 degrees, which is uh which is actually in keeping with our psychophysical threshold for when we can discriminate between an innocuous warm stimulus and a noxious heat stimulus. So this is really the threshold for psychophysical discrimination of cooling. So this sets up the idea that these two channels uh serve as little molecular thermometers uh that report uh that allow our sensory nerve fibers to report changes in ambient temperature in the hot and cold direction.

And when you come in contact with a natural product, agonists or or allosteric modulators for this channel, namely capsaicin or menthol, what they do is they lower the activation threshold for the channel and allow the heat-activated channel to open at a lower temperature and the cold-activated temperature to open at a warmer temperature, in essence, serving as a as a chemical psychophysical mimic of a hot or cold experience respectively. And this um model lays out at least two predictions. One is that these ion channels are intrinsically temperature sensitive, that they themselves uh that their biophysical properties themselves describe their uh sensitivity to temperature.

And uh perhaps most importantly, that they actually contribute to an animal's ability to discriminate ambient temperatures uh in vivo. And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah.

When he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface. Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning. Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.

And here's a wild-type mouse in this very simple paradigm where we ask if it can discriminate between a a warm platform at 30 degrees and a colder platform at 20. And as you can see, even without any training, this mouse prefers, as we would, to sit on the nice warm comfortable side, and will not even venture onto the cold side. But if you look at an animal in which the menthol receptor has been deleted from the genome, a TRPM8 knockout mouse, you can see that that animal really loses its discriminatory ability and can no longer discriminate a warm from a cold surface and will wander freely over this surface and spend equal amount of time in both ends.

And you can continually lower the temperature of the cold plate until you get to very noxious temperatures of about 5 or 0 degrees, and only at that point can the animal uh um uh then discriminate between the warm and the cold surface.

Uh and this little chamber is actually our donation to the Nobel Museum, which we just sent off this morning.

Um so, I think that that experiment really beautifully shows that uh that these receptors, uh specifically in the case of TRPM8, is are required for an animal's ability in vivo to discriminate ambient temperatures uh in vivo.

And and the first prediction was beautifully borne out by the work of Erhu Cao in my lab, now at the University of Utah, when he purified the channel to homogeneity, reconstituted this into a totally synthetic lipid bilayer, and then used patch-clamp analysis to ask what happens when you expose this patch to a quick burst of radiant heat with an infrared laser. And what he showed together with our collaborator Fong Tsien at the University of Buffalo is that this leads to beautiful activation of the channel, uh as you can see in these in these characteristic outwardly rectifying ionic currents, uh in a temperature-dependent manner. Uh and in fact, if you look at the biophysical and thermodynamic properties of this response, in terms of the temperature threshold, the activation rate, the temperature coefficient of activation, it beautifully matches uh the parameters that we and others, including Fong and Peter McNaughton, have measured in transfected cells expressing this receptor, uh and indeed, even in sensory neurons that are that are heat sensitive.

So, I think this fulfills one of the beautiful predictions that in fact, these proteins themselves are little biophysical machines that act as molecular thermometers.

Now, what about in vivo?

I think the most elegant demonstration of this comes from an experiment that Diana, Jan, and Sven carried out when they were in my lab, where they made a knockout mouse in which the menthol receptor has been deleted from the genome.