Some humility is in order

Sometime this month the 60th anniversary of the publication of “Sickle Cell Anemia, a Molecular Disease” will be celebrated. It’s just one of Linus Pauling’s many chemical achievements — electronegativity, quantum theory of the chemical bond, the alpha helix of protein structure and on and on and on. Unfortunately most docs know of him by his crackpot theory that vitamin C was of use in cancer. The general public knows of him as an activist against the Vietnam war. Too bad, he was one of the greatest chemists of the 20th century.

Just figuring out what was wrong with hemoglobin in Sickle Cell anemia was remarkable. The first actual determination of any 3 dimensional protein structure (myoglobin) didn’t occur until 1957. From then on, hemoglobin became to protein structure what E. Coli was to genetics and molecular biology. We know more about hemoglobin than any other protein. Countless studies of its structure and dynamics have been made.

So why be humble? Because we have essentially no treatment of Sickle Cell anemia based on all this structural work. We do have treatments — transfusion, manipulations to increase the production of a fetal variant of hemoglobin, etc. We don’t have a small molecule which stops hemoglobin from aggregating with itself (polymerizing if you will) under conditions of low oxygen, distorting the red blood cells which carry it, which makes them plug up vessels causing sickle cell crises (or even strokes, a few of which I saw as a neurologist).

Why don’t we have a drug? There are all sorts of molecular dynamics simulations of hemoglobin, and computational chemists use models to figure out how to dock molecules onto proteins. For a very cleareyed view of what the various models can and can’t do and just how good they are, go to “The Curious Wavefunction” and start reading.

If we really understood protein structure and dynamics we’d have such a drug, so some humility is definitely in order.

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Comments

  • Curious Wavefunction  On November 14, 2009 at 3:40 pm

    Thanks for the plug. I have not kept up with the Vit C literature but wasn’t there some paper in PNAS recently suggesting (yet another) link between ascorbate and cancer in terms of actual mechanisms?

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