1. Sledge, George W. JR. MD

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The crickets in my back yard have been particularly noisy these last few days, louder than they have been all summer, so loud they have kept me awake with their chirping. But I enjoy listening to them. Sometimes I hear just one, sometimes a veritable orchestra, or at least a robust string section. It is, for reasons I cannot explain, a deeply comforting sound.

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I have had warm feelings towards them since my youth. I grew up as part of a generation raised on Walt Disney's Pinocchio, where a charming Jiminy Cricket served as (somewhat ineffective) conscience for the long-nosed wooden boy. Hollywood anthropomorphism favored crickets, and why not? Unlike mosquitoes and lice, these insects never mean us any harm.

GEORGE W. SLEDGE JR.... - Click to enlarge in new windowGEORGE W. SLEDGE JR., MD. GEORGE W. SLEDGE JR., MD, is Professor of Medicine and Chief of the Division of Oncology at Stanford University. His

As a child I was fascinated with their amazing ability to tell me the temperature. Maybe you learned this as I did. Count the chirps in 15 seconds, add 40, and you have the temperature in degrees Fahrenheit. This observation was formulated as Dolbear's Law in 1897, and it still works, more or less. More or less, because there are over 900 cricket species worldwide, and they do not all chirp, and do not chirp at the same rate for a given temperature. So Dolbear's law is not exactly a law of nature.


I was taught that these living thermometers rubbed their hind legs together to create the chirps, and believed it for decades, but it just isn't so: the crickets have something called a stridulatory organ, a large vein running along the bottom of each wing. In fact, the scientific name for chirping is stridulation; I'll stick with chirping. Crickets run the top of one wing along the bottom of the other to create the sound. And, in case you are wondering, crickets have a tympanic membrane to hear the chirps-though oddly enough it is located just below the knee.


Why crickets chirp is another matter: largely this is mating behavior, the male of the species announcing himself to potential mates. Entomologists distinguish four separate chirping behaviors, including a calling song that attracts females and repels other males, a quiet courting song used when a female is near, an aggressive song triggered by the near presence of other males, and a brief copulatory song produced after a successful mating. You can't make this stuff up.


The timekeeping aspect of the chirping has nothing to do with its underlying reproductive purposes. Crickets are, like all insects, cold-blooded, and their chirpings heat up along with their bodies. The thermometer is coincidence, an artifact of physicochemical design, albeit a happy one for a six-year-old boy on a warm summer's night in a field in Wisconsin.


Living Thermometers

Nature is full of living thermometers. Measuring temperature must be something basic to all living organisms, for even lowly bacteria are capable of it: they contain temperature-sensing RNA sequences, known as RNA Thermometers, or RNATs, in their mRNAs. RNATs control virulence, heat shock, and cold shock genes in E. coli.


Their two structures are simple but clever: a zipper-like structure that gradually melts as temperature increases, and a switch mode, where two mutually exclusive structures depend on ambient temperature. RNATs are such a clever natural design that they are now being co-opted by biotechnologists.


Sometimes these internal thermometers can have seemingly bizarre purposes. Red-eared slider turtles (and many other reptiles) lack sex chromosomes. Turtle gender is determined by the temperature at which their eggs are incubated, with colder temperatures producing males and warmer temperatures females. The cut point is right around 29[degrees] C.


How this occurs has been partially elucidated in recent years. Aromatase (which, as all good medical oncologists know, converts androgens to estrogens) is under epigenetic control, so that, in the words of a recent PLOS paper, "female-producing temperature allows demethylation at the specific CpG sites of the promoter region which leads the temperature-specific expression of aromatase during gonad development." And, in case the breast cancer docs are wondering, you can change the turtle's gender by exposing its egg to letrozole. And you thought it was just a breast cancer drug.


But mammals are the ultimate living thermometers. If you are a warm-blooded animal whose edge over crocodiles and snakes involves continuous thermoregulation (and we live within a very narrow temperature range), then you need to have some means of measuring your degree with precision.


And we are quite good at it, we humans. The skin at the base of our thumbs can perceive temperature differences of 0.02-0.07[degrees] C. I find this little short of amazing: our fingers are thermometers. The explanation for this impressive ability is an evolutionary masterpiece. Temperature-sensitive transient receptor potential channels (or thermoTRPs) are a family of ion channels, activated at different temperature thresholds, each exquisitely sensitive to a particular temperature range. One of them, TRPV1, is also activated by capsaicin, which is why those red-hot chili peppers make your throat feel like it is burning up.


We rarely think of this internal thermometer, perhaps because it is hidden in the background, unlike the more showy, in-your-face senses of sight and hearing and taste and smell. It gets lumped in with "sense of touch" and promptly forgotten. And, since the invention of thermometers in the 17th century, we have rarely felt the need to rely on it, or even recognize its existence.


We are the only species on the planet to have an external thermometer-two if you count our cricket biothermometers. But the old thermometer is still there, sitting quietly in the back.


Temperature Metaphors

This temperature sense is hard-wired into our psyche, as our language (indeed, every human language) commemorates. We speak of "an icy stare" or say that a relationship is "heating up" or that someone has a "burning desire" or of a lawman being "in hot pursuit" of a criminal, only to discover that "the trail has gone cold." We live by metaphors, and temperature metaphors are exceptionally common.


It goes even deeper than language. Psychological studies have shown that the simple act of handing someone a warm cup increases interpersonal warmth, and that someone excluded from a conversation will judge a room to be cooler than one who is included. Our subconscious is deeply invested in temperature, and it is wired into our internal thermometer.


The oncologist in me always wonders whether such things affect cancers. Temperature dysregulation is, of course, common in cancers such as Hodgkin's disease, and a rare complication of treatment for Hodgkin's is prolonged hypothermia (lasting up to 10 days) following chemotherapy administration. I'm sure there is some interesting biology there, perhaps involving thermoTRPs, but at the end of the day it probably doesn't matter all that much.


Thermoregulation has not been a huge therapeutic player in the cancer field, despite half-hearted attempts at cryosurgery and hyperthermia. Are cancers essentially cold-hearted, or do they burn with the desire to harm? Or both at the same time? Metaphor only carries you so far, and attributing emotions to lethal Darwinian machines is pointless. But when I lay my hand on an inflammatory breast cancer I am always impressed, sometimes even shocked, by its malignant heat, its angry redness. Perhaps ion channels are irrelevant to their darker purpose, or perhaps like so many other things we haven't looked closely enough.


As it turns out, there is a growing literature on capsaicin as an anti-cancer agent: the active agent in chili peppers induces necrotic cell death in cancer cells, and does so in direct relation to TRPV1 expression levels. Is that cool, or what? Or a hot research area? Whichever.


So I sit on my back porch pondering all this as the evening proceeds, the temperature gradually falling, the symphony of chirps slowing bit by bit, and eventually dying out. Perhaps the crickets have found their special ones tonight. Is that a celebratory chirp I hear?


More from George Sledge on His OT Blog!

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