Tuesday, 7 April 2009

Evolutionary Medicine (4)

This is the fourth and final installment.  Go here for the 1st, here for the second and here for the third installments.

The fact that natural selection is focussed upon genetic replication, and not necessarily an individual’s health, is a counter-intuitive bar to many people’s understanding.  However, understanding this fact brings into view battlegrounds that would otherwise pass us by.  Most famous is Trivers and Haig’s idea of the maternal-offspring conflict [part of their larger theories around the parent-offspring conflicts], which hinges on the fact that mother and child aren’t obviously genetic clones.  From a mother’s point of view, benefits directed at the fetus only benefit half her genes, since this is the proportion shared by it.  But the situation is reversed from the fetus’ side.  The upshot of this is that although both parties agree that a transfer of resources is in order, they haggle about the price.  The optimum amount of resources the mother would like to donate will be less than the optimum amount of resources the fetus would want.  Thus conflict is predicted at the margins of the wonderful cooperative venture: the mother can be expected to pull back a little where the fetus pulls forward.

This may sound implausible, but it is predicted by evolutionary theory, and backed up by evidence.  The most obvious case is the tug-of-war that takes place in the placenta for fetal glucose supplies.  Human placental lactogen ties up maternal insulin so that her glucose levels rise, and thus the fetus can skive more off from the top.  The mother retaliates by increasing her output of insulin, to which the fetus responds by pumping out more HPL.  From there the two sides engage in an arms race, with the hormone levels skyrocketing on either side until the levels of both hormones reaches a thousand times their normal concentrations.  As Haig notes, elevated hormone levels, like voices, is a sign of conflict.

Usually the two forces more or less balance each other out, but if for whatever reason the mother is unable to produce enough insulin, the result is the familiar gestational diabetes.  

Lastly we have the “smoke detector principle”, which is that so long as the costs are cheap, the body will often err on the side of extreme sensitivity in detecting and dealing with potential problems, even when the result is mostly false positives.  A smoke detector would rather be wrong 100 times and right about the one true fire than more accurate but miss the fire.  So it is with many of our body’s defences.  The archetypal example is fever.  

Although it is usually regarded as merely a troublesome side-effect of infections, the evolutionary evidence says otherwise. Fever is one of the most conserved immune elements among higher animals, and is the result of an impressively complicated apparatus centred in the anterior hypothalamus.  The notion that it is a pathological side-effect of bacteraemia is absolute nonsense when viewed from an evolutionary perspective.  The hypothalamic set point exhibits a prodigiously complex design, and is acutely sensitive to numerous cytokines involved in the inflammatory process; if this were deleterious on balance, it would be exceptionally easy to prevent. Just stop the hypothalamus from responding to cytokines! Indeed, knocking out just one gene, a cinch to evolution, renders mice incapable of fever at all.  Furthermore, we have direct evidence that fever interferes with bacterial enzymes, enhances leukocyte mobility and phagocytosis, and promotes the proliferation of T cells.

A fair few trials have now been done to see whether treatment of fever might actually be harming the patient. The results are contradictory.  In some cases, aggressive treatment of fever has been shown to increase mortality, whilst other studies have shown neither this nor a benefit.  Why the ambiguous results?  Well, the smoke detector principle.  The body fires all its guns in the hope that enough of them will hit the target, but fever is often one that misses.  Fever seems most effective against bacteria, but the body dutifully raises the hypothalamic set point, just in case, to anything that causes the fairly non-specific cytokines to be released.  Therefore, fever can accompany certain conditions where there is likely no benefit, such as viral infections (e.g. influenza), or inflammation from non-infectious causes (e.g. burns).  Even within the bacterial group, there are likely certain organisms or situations where fever has a greater effect than in others.  However, the smoke detector principle ensures that fever is so non-specific as to make our general studies underpowered.  What is necessary is to conduct much more targeted research.  Instead of asking whether letting fever run its course improves outcomes (it might not, in total), we should be asking whether or not fever improves outcomes in, say, demonstrable bacteraemia, or even in Klebsiella septicaemia, for instance.  Once we are able to answer questions like these, we will have a very clear idea of when to treat fever (which is undeniably uncomfortable) and when to let it run its course.  The evolutionary viewpoint can guide us in this research by assuring us that there is a point to fever, or at least was, even if we don’t yet know what it is.

There’s so much more brilliant work where evolution and medicine cross paths.  I’ve only shined the spotlight upon a handful of theories, and then only for the briefest of moments.  The cup overfloweth though.  For instance, there simply wasn’t enough time to explain Hamilton’s theory of why we have sex at all (why don’t we just clone ourselves, save time and pass on twice as many genes?) and thus why we tend to pick HLA-discordant partners.  But at least we did help answer why, after millions of years of evolution, we still get colds.  (The main reason: they out-evolve us.)  Using evolution to step backwards a little enables us to appreciate that disease itself is a mystery worthy of explanation.  And the answers that we eventually prise from nature can only deepen our appreciation of the human condition. 

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