Friday, March 18, 2011

Evolutionary medicine - understanding malaria drug resistance

Forgetting for a minute their use of complicated mathematical formulae, scientists are, really, like children. They ask: why? And when they have the answer, ask again: but why? And once a satisfactory explanation has been found they wonder, but why? And on and on and on…

But this stubbornness pays off. Daniel Hartl, from Harvard University, gave us an example today of how this relentless questioning actually helps come up with interesting and useful explanations about how things are the way they are.

In his talk at the PRBB Conference Hal, Hartl talked about the evolution of drug resistance in the malaria parasite. He pointed out how the different existing treatments for malaria that have existed have been effective for less and less years each, before resistance appeared.

He focused on his analysis of DHFR, a parasite enzyme which is the target of the antimalaria drug pyrimethamine. There are 4 aa changes that can be combined following 24 potential evolutionary pathways. Hartls simulations and laboratory experiments (using E.coli) showed that only three of those account for most of the outcomes. When he checked the ‘real world’ and looked at all the polymorphisms that exist for DhFR he found that, indeed, there were few that were common, and these coincided with those he found to be more successful in the lab.

Now come the questions :)

Hartl found that a particular polymorphism very common in South East Asia (which contained all four aa changes, let’s call it 1111) was not present in Africa. Why?, he asked (especially since he found some resistant strains found in Africa had their origin in East Asia). Well, he found that the fourth mutation had a high fitness cost associated (the enzyme was less efficient), so it was not very good. ..

But then (second why) why was that mutation present in Asia to begin with? Well, because in Asia those 1111 strains had high copy numbers of a gene linked to the 1111allele which coded for the enzyme substrate, and those high copies resulted in high levels of the enzyme substrate, which meant that having a less efficient enzyme was not that bad.

But then (yes, a third one!) why was that CNV not present in Africa? Well, it turns out that while in Asia people are usually only bitten once, in Africa a person can be infected by several parasites at the same time. That means that recombination takes place between the different parasites, and therefore the CNV and the 1111 allele are easily separated. Therefore, having a 1111 is bad, and it’s not compensated by high copy numbers of the CNV, because they are not linked.

Interesting, eh? If you (or your 3-year old child) can think of any other whys don’t be shy, contact Daniel Hartl who, I am sure, will be delighted to keep on investigating…

No comments: