This Week's Citation Classic: Being Wrong

With my latest grant submission submitted, I can relax just a bit. I confess I am suffering separation anxiety though. There are still changes and additions I want to make, but it's gone out the door. Anyway, without further ado, this week's citation classic is:

Boyer, P. D. 1963. “Phosphohistidine.” Science 141: 1147–1153.

Adenosine triphosphate (ATP) is the prime driver of life. It provides the energy for most the energy-consuming reactions in the cell. Naturally scientists are interested in how it is made. When Paul Boyer published his one-word title Science paper, Phosphohistidine, he veritably turned the field of bioenergetics on its ear. For years, biochemists were trying to determine energy from the electron transport chain is coupled to ATP synthesis, and at last, a solution! Phosphohistidine was the high-energy intermediate of oxidative phosphorylation.

As Douglas Allchin writes, "Biochemists were primed to celebrate. One might well have imagined that the achievement here would surely garner Boyer a Nobel prize."

However, Boyer's triumph was short-lived. One of Boyer's grad students noticed that the results were sensitive to the concentration of succinate, a component of the Kreb's cycle. Further work, including the discovery of Phosphohistidine in E. coli (which have no mitochondria), put a damper on the claim.

In 1981, Boyer bluntly said, "I was wrong."

What happened? Boyer and his team missed a simple control. That is, they mistook other mitochondrial reactions for ATP synthethis. Phosphohistidine turned out to be important in the Kreb's cycle, but not for ATP synthesis.

"...Boyer did exhibit an important, perhaps under-appreciated element of scientific practice: finding the error and then recovering from it. Here, detection emerged from a combination of chance and effort to amplify the initial findings. Further interaction with the experimental system exposed an unusual aspect of the pattern they had already documented. Boyer perceived how all the results could fit another pattern, or explanatory scheme, and then collected additional data to show how the phenomenon fit one and not the other. He had to both recognize the oddity as significant and be able to imagine and appreciate an alternative explanation."

So these errors were quite informative for Boyer and pointed him in the right direction. Some 30+ years later, Boyer shared the 1997 Nobel Prize for in Chemistry with John Walker and Jens Skou "for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)".

"Although errors entail further work, they do not necessarily become worthless scientific residue. When probed, errors can guide researchers to deeper knowledge. Errors may be a source of discovery."

Allchin, D. 2002. To Err and Win a Nobel Prize: Paul Boyer, ATP Synthase and the
Emergence of Bioenergetics. Journal of the History of Biology 35: 149–172.

Cartoon from the ATP synthase page.