Popular physiology IV: Temperature
Anyone who’s taken the most basic chemistry course will recall that chemical reactions require particular temperatures to take place; sometimes these temperatures are extreme (i.e. making ammonia from nitrogen and hydrogen, which requires temperatures in the range of 550 degrees celsius). Many reactions occur in ‘room’ temperature, which — depending on where your room is — might range from 0 to 50 degrees celsius. Ordinarily, the chemical reactions running the body perform their best in and around 37.5 degrees celsius (or around 98 degrees Fahrenheit; the confusion in units is the subject of a famous short story by Ernest Hemingway).
Why 37.5 is anybody’s guess. As a recent study shows, this temperature could be just the right amount of hot to keep off fungi from growing on us (fungi require cold and moist places), but not too hot to fry us. As Richard Dawkins would have said, the marginal cost of increasing the body temperature any further would outweigh the benefits of repelling any more fungi. This is evident in places where temperatures are lower (such as between toes), where fungi grow quite easliy.
Where 37.5? Certainly not on your fingers or toes (they are much colder) or even back or chest. The skin loses water all the time and temeperatures of the skin, the ‘shell’ temperature, fluctuates all the time. In our insides, however, the temperature is tightly regulated and does not vary much. This ‘core’ temperature is what matters, and can be measured (approximately) by placing the thermometer in the only two accesses to your ‘inside’, i.e. mouth or rectum.
The maintenance of body temperature is no trivial task. The heat is generated by each cell, by the breakdown of adenosine triphosphate (ATP) — little coins of energy produced by mitochondria. The breakdown takes place in each cell, mostly in its membrane, where a particular protein pumps sodium out and potassium into the cell (recall that extracellular fluid is sodium rich and intracellular fluid is potassium rich; that’s because of this pump). The process requires ATP, and the excess heat of breakdown (enthalpy) is used to maintain body temperature.
How is temperature regulated? As it turns out- that part of the brain which is common to most vertebrates (the ‘reptilian’ brain), there is one little speck of neurones which ultimately decides behavior. This is the hypothalamus, which is the key regulator of temperature (plus the regulator for hunger, sex, sleep, and almost everything else required to survive). The hypothalamus has two temparature sensors
- the collective input from nerves in the skin provide info on the temperature outside
- a ‘thermometer’ for checking the internal temparature, i.e blood
When temperature needs to be raised, hypothalamus instructs neurons to burn fat, oscillate the muscles vigorously (‘shiver’), reduce blood flow to the skin (to preserve heat inside the core) until you get to the requisite temperature; if that doesn’t suffice, the hypothalamus will signal the cerebral cortex to think and take cover (i.e. get a blanket). When it’s time to cool down, though, the exact opposite changes occur.
Several hormones (such as thyroid hormones) promote the production of sodium pumps, and thus hypothalamus exerts its endocrine control over temeperature (ultimately, all hormones depend on hypothalamus to function). Hypothyroids, those deficient in thyroid hormones, are extremely intolerant of cold because of this reason.
In addition, the hypothalamus must sense an infection residing anywhere inside the animals and take action; cytokines, immunologist’s best friends, do the job quite well. A molecule called Interleukin-6 (IL-6), as well as a lipid horomone, prostaglandin E2 (PGE2), is released from site of infection and reach the brain via blood. Here
- they stimulate blood vessels of brain to produce more of themselves, i.e. more IL6 and PGE2
- the PGE2, thus produced and amplified, will bind to neurons in hypothalamus, and set off a downstream cascade of events
… which will eventually lead to a state of …
Fever
Evolution of multicellular organisms has alway been about one-upping the unicellular ones. Once a bacterium (or virus) gets entry in your body, it will multiply fast (typical bacterial generation time, i.e. from one to two, is about half an hour). Thus, to keep up, metabolism has to shift gears; neutrophils and macrophages must be rushed to the site of an infection, lymphocyte circulation through lymph nodes has to be sped up, fat needs to be broken and burnt for powering this flurry of activity. Thus, a multicellular animal must maintain two distinct temperature states: one for peace and one for war. There must also be a mechanism to switch between the two effortlessly.
In majority of the animal kingdom, this switch was simple: just move to a warmer place. Go to the beach, have a sunbath. Swarms of crocodiles lining up on rivershores, still as still-life, basking in the sun — what they’re looking for is a boost in immunity.
What tells the animal to find a hot-spot? This is certainly not local, but a centrally coordinated activity: the brain must be involved if the animal has to move. In ectotherms (cold blooded, i.e. every animal before birds and mammals) the hypothalamus instructs the cerebral cortex to perform a most simple task: find heat. The animal must then be driven towards heat and stay there until the infection is resolved. This phenomenon has been called behavioral fever, and is the only way ectotherms can get adequate warmth to fight bacteria.
However this approach is not without fail; lying exposed on open, sunlit beaches is not good evolutionary strategy (you might get eaten). Perhaps this is the reason endotherms came up, i.e. who have a degree of control over their body temparatures, and don’t have to move around just to maintain temparature. In such animals (birds and mammals), the hypothalamus had to expand its instruction set. For countering infections, instead of ‘move to a warm place’, the hypothalamus had to
- break down fat to generate energy
- shut off blood supply to the skin, so that heat stays within the core
This is all ‘internal’ to the organism and the cerebral cortex need not be involved; the hypothalamus sends these instruction to the spinal cord, which is relayed to ‘sympathetic’ nerves (oh these colorful names) who finally bring about the change. You get warm and fight off the infection (but also lose some fat in the process).
Now, as every kid knows, paracetamol is the go-to medicine for fever. And headaches. And sprains (well, not so much for sprains). But anybody who’s taken paracetamol knows that apart from relieving the pain, it also feels good. The sudden gush of sweat, the color coming back to the skin, the fulfilling heave of relief — what does paracetamol do, really?
The intriguing thing about paracetamol, it’s not just an antipyretic. It acts on hypothalamus directly, inhibiting PGE2 formation, and thus modifies behavior. Not just temperature, but all aspects of hypothalamic function: sleep, libido, appetite (although such side effects are rarely noticed, because paracetamol achieves is goal, i.e. bring down fever, in much lower doses than required to produce these).
The effect of such ‘antipyretic drugs’ is much more dramatic on ectotherms; in one experiment, a closely related medicine (salicylate) was fed to lizards, and then infected with bacteria. The lizards lost their drive to find a warm place, and thus could never raise their body temparatures (and then, unfortunately, die of the infection). But the ‘antipyretic’ was doing its job even in a lizard, although in a roundabout way, i.e. by preventing its movement towards a warmer place.
So is fever a good thing? Mostly yes. Repeated experiments on animals have proven the value of fever in fighting infections. But humans like shortcuts (this is not a flaw, it’s how we are, there is no changing it), and we have antibiotics for infections. Working antibiotics are running out fast, though, and once we are all out of antibiotics, we may have to resort to our God given immune system.
And fever.
