Saturday, 4 April 2009

Evolutionary Medicine (1)

I had to present a speech today on a topic close to my heart: evolutionary medicine.  I thought I'd post it up here, in installments, for anyone who's interested.  I'm afraid I'm too lazy to type in all the references for my data here, but I'll provide them for anyone who asks.  The piece starts with a quote from Nesse and Williams' "Why We Get Sick" (which is a must-read for any medical student, I think).  

“Why, in a body of such exquisite design, are there a thousand flaws and frailties that make us vulnerable to disease? If evolution by natural selection can shape sophisticated mechanisms such as the eye, heart, and brain, why hasn’t it shaped ways to prevent nearsightedness, heart attacks, and Alzheimer’s disease?  If our immune system can recognize and attack a million foreign proteins, why do we still get pneumonia?  If a coil of DNA can reliably encode plans for an adult organism with ten trillion specialized cells, each in its proper place, why can’t we grow a replacement for a damaged finger?  If we can live to a hundred years, why not two hundred?”

Evolution is biology’s Big Idea.  It is the lens through which facts are interpreted, as well as the vantage point by which new data are judged.  While physicists go on searching for their great unifying Theory of Everything, biologists have essentially had theirs since Darwin’s theory of natural selection was married with population genetics in the 1930s.

Medicine, of course, falls within the biological sciences, but sometimes you’d almost never guess.  This very interesting graphic, done in 2007, illustrates the citation flow between disciplines within science.  As you can see, there is much crosstalk between the disciplines of medicine and molecular and cell biology, and a considerable exchange of citations between medicine and neuroscience, but the communication link between evolution and medicine is in fact so tenuous that it isn’t even depicted.

Does this matter? Well, evolutionary theory offers the ability to view and answer questions from an ultimate, rather than a proximate vantage point.  Both sets of questions are equally valid, but they are different.  Proximate explanations are the sorts of things that fill journal articles on pathophysiology, and include mechanistic descriptions of what happens.  Ultimate explanations, on the other hand, try to answer the question of why this particular proximate explanation, and not a thousand others, occurs.  Think, for instance, of the famous case of the sickle cell allele.  The proximate explanation, provided for us by molecular and cell biologists, is of course that this disease results from a single nucleotide mutation in the beta globin gene.  As a result of this, a glutamate is replaced by a valine in the transcribed protein, and the haemoglobin molecule risks insoluble polymerisation at low oxygen tensions. 

But to stop there would sell us short.   The ultimate explanation for sickle cell anaemia operates on quite another level.  Why is this damaging recessive allele maintained in the population?  The main part of the answer is well-known: heterozygous individuals on the whole produce enough normal haemoglobin to avoid symptoms, but they are significantly more resistant to malaria.  Thus the recessive gene, far from being eliminated, is maintained in what geneticists call a balanced polymorphism, where the benefits to the heterozygotes counteract the dangers to the homozygotes so as to maintain the gene within the gene pool.  This fact neatly explains the impressive correlation between the historical distribution of malaria and the ancestral distribution of the sickle cell trait.

Randolph Nesse, arguably the leading proponent of evolutionary medicine, illustrated the difference in approaches best, “We are not asking why some people get sick, which is what most medical research asks, but why all humans are vulnerable to disease.”  Again, natural selection is an enormously powerful force, capable of producing an eye that is sensitive to a single photon, a brain capable of love, hate and innumerous calculations and machinations, and body homeostatic processes that make the mind boggle.  So why do we then still get colds?  And why do we have an appendix, wisdom teeth, allergies, or shortsightedness? The usual answer – that natural selection is simply too weak to do better – is almost always wrong.

Nesse proposed a useful list of 6 reasons for our vulnerability, and it’s this schema that I’ve adapted for this talk.    

The first two categories centre on the idea that natural selection, whilst an enormously powerful force, isn’t necessarily a quick one by our standards.  More specifically, the rate of evolutionary change in a population is inversely proportional to the generation time.  Our generation time is about 20 to 25 years, which only leaves a handful of generations between here and, the dawn of civilisation – not even close to the number needed to effect significant evolutionary change.  The first civilisation is widely believed to be the Sumerian one in Mesopotamia (modern day Iraq), and that started in about 5500 BC.  That’s only about 7500 years ago – roughly 300 generations.  That may still sound like a lot, but that’s only 300 paternal or maternal ancestors you’ve got between yourself and prehistory.  Imagine holding your father’s right hand with your left hand, and continuing this pattern with his father, and his father’s father, etc.  If you each stood a meter apart, the entire ancestral chain wouldn’t even get from here to casualty [edit: OK, you have to remember I was giving a speech at the hospital!].  By contrast, E. coli has had the same number of generations in the last 100 minutes.

Since the dawn of civilisation our existence has undergone some quite dramatic changes with regards to disease burden, labour types, food types, and countless other trappings.  The problem is that 99% of our existence as a species predates this.  The result: there are many parts of our bodies that aren’t well-adapted to the modern world, and this explains the first category of disease: “mismatch with the modern environment.”

It is consensus opinion that the rates of allergies and autoimmune diseases have increased markedly in recent times.  The rate of increase far has been so rapid that an environmental cause must be at the bottom of it all; evolution is slow for us, remember? Numerous candidates have been proposed, and most centre on the “Hygiene Hypothesis”, which claims that it is paradoxically our rather sanitised modern lifestyles that predispose us to these conditions.  Increasingly, however, research is pointing in the direction of the helminths, since cross-sectional studies have shown a consistently negative relationship between helminth infection and allergic diseases.  These results have been confirmed by most, though not all, interventional studies.  Most of the facts begin to line up when you consider that helminths, if they are common today, were much more so in our evolutionary past.  Thus our immune systems evolved with the expectation of a significant helminth load, and the corollary of this is that helminths must have themselves evolved immunomodulatory mechanisms to ensure their own survival.  Take away the helminths, however, and the balance is disturbed.  Of course, it has long been known that the IgE system is intimately involved with both aspects, but specifics are beginning to come to light too.  For instance, in 2007 it was shown that helminths secrete a protein (ES-62) that down-regulates the Type II T cell response.  There is also abundant cross-reactivity between antigens on schistosomes and house dust mites. 

Interestingly, the immunomodulatory effects of helminths (or rather the lack thereof in today’s 1st world) have also been linked to several autoimmune diseases.  For instance, one study in 2005 reported that inflammatory bowel disease patients treated with the sterilized eggs of Trichuris suis improved markedly within months (43% improvement for U.C., 72% improvement for Crohns’).  The net has been extended to multiple sclerosis, with a small but well-designed study showing that patients who were recently infected by intestinal helminths had a much, much slower rate of disease progression.  The (American) National Multiple Sclerosis Society is presently conducting a phase 2 trial to extend this research.  At present, it must be admitted that the evidence is sketchy, but evolutionary insights should never replace hard data anyway.  Rather, their role is to offer predictions as to where to look, and what to test for.  Theories like the Hygiene Hypothesis can only be helpful, even if they are eventually disproved.

[Click here to continue to the second part.]

1 comment:

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