Thursday, January 12, 2012

Cholesterol (orange) buried within the transparent protein, including interaction with a lipid in the membrane (cyan). Credit: Grace Brannigan and Jerome Henin, University of Pennsylvania

In a good article on the confusion over cholesterol, Johan Lehrer gets at tendency to assume that when we have a lot of detailed information about something we understand it. We have wheelbarrows of data on cholesterol, but have almost no idea how its related to heart disease. Lerher writes:

“The cholesterol pathway is one of the best-understood biological feedback systems in the human body. Since 1913, when Russian pathologist Nikolai Anichkov first experimentally linked cholesterol to the buildup of plaque in arteries, scientists have mapped out the metabolism and transport of these compounds in exquisite detail. They’ve documented the interactions of nearly every molecule, the way hydroxymethylglutaryl-coenzyme A reductase catalyzes the production of mevalonate, which gets phosphorylated and condensed before undergoing a sequence of electron shifts until it becomes lanosterol and then, after another 19 chemical reactions, finally morphs into cholesterol. Furthermore, [the cholesterol drug] torcetrapib had already undergone a small clinical trial, which showed that the drug could increase HDL and decrease LDL… The success of the drug seemed like a sure thing.
And then, just two days later, on December 2, 2006, Pfizer issued a stunning announcement: The torcetrapib Phase III clinical trial was being terminated. Although the compound was supposed to prevent heart disease, it was actually triggering higher rates of chest pain and heart failure and a 60 percent increase in overall mortality. The drug appeared to be killing people.”

Good scientists know that sometimes it's necessary to step back from the data and look at the big picture. One post-doc friend, when his mentor quizzed him on what we don't know about molecular biology answered (I think correctly) - "All the little things. No wait, all the big things!" The nice thing about looking at the big things is that it forces you to look at the really big things. As T.S. Eliot put it in the opening of “Choruses from the Rock:”

Endless invention, endless experiment,
Brings knowledge of motion, but not of stillness;
Knowledge of speech, but not of silence;
Knowledge of words, and ignorance of the Word.
All our knowledge brings us nearer to our ignorance,
All our ignorance brings us nearer to death,
But nearness to death no nearer to GOD.
Where is the Life we have lost in living?
Where is the wisdom we have lost in knowledge?
Where is the knowledge we have lost in information?

Of course, sometimes there is a roundabout path to wisdom through information: Siddhartha Mukherjee, in the Emperor of All Maladies, notes that a successful understanding of certain forms of cancer was generated accidentally from the findings of researchers diligently beavering off in the wrong direction. Perhaps an understanding of cholesterol will rise out of the data in a similar way.

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