In his July 23 column, Gary Herstein presented a thoughtful discussion and analysis of scientific controversies (What Does A Real Scientific Controversy Look Like?), with an example from physics. Perhaps readers of Scientific Blogging will be interested in another scientific controversy that emerged in biophysics over a 20 year period. 

To understand the controversy, you need to know that subcellular organelles called mitochondria and chloroplasts synthesize ATP, the fundamental energy currency of all life. If you give isolated mitochondria some ADP and phosphate, along with oxygen and a substrate like succinic acid, they make ATP. Same with chloroplasts, which use light as an energy source to drive ATP synthesis.

In 1965, I began to work on chloroplasts as part of my post-doctoral research at UC Berkeley, and discovered that no one really understood the mechanism by which ATP synthesis occurred. The prevailing idea was that the process involved a set of biochemical reactions similar to what occurs during glycolysis, in which ATP is produced by enzymes using the energy made available when glucose is broken down into smaller molecules. This was the accepted explanation in the laboratories of half a dozen major research groups, and appeared in biochemistry text books. But there was one niggling detail. No one could find a phosphorylated intermediate that must be there if the explanation was correct. Everyone thought it was just a matter of time, and that a Nobel would be awarded to the person who discovered it. 

Then I began to hear about an obscure English microbiologist named Peter Mitchell, who had published a new idea in Nature which he called chemiosmosis. I will use jargon to give a sense of how outlandish Mitchell’s idea sounded:  According to chemiosmosis, electron transport enzymes pump protons across mitochondrial or chloroplast membranes to produce a protonmotive force of 0.2 volts. ATP is synthesized by a reversible anisotropic ATPase that uses the proton gradient as an energy source. 

This was crazy! No one believed such a complicated idea, even though it did account for the fact that no phosphorylated intermediate had been found. 

For a couple of years, Mitchell’s proposal sank into the scientific purgatory reserved for untested ideas, perhaps never to be seen again. But then in 1963, Andre Jagendorf at Brookhaven National Laboratory happened to be measuring the pH of a chloroplast suspension and discovered that when he turned on the light, the pH increased! Jagendorf noted that this was consistent with one of the predictions of chemiosmosis, because it meant that choloroplasts were using light energy to pump protons into their interiors. Jagendorf went on to test another prediction, that a pH gradient alone was sufficient for chloroplasts to synthesize ATP. In 1966, he reported an “acid bath” experiment in which he acidified a chloroplast suspension to pH 5 in the dark, then used a buffer to increase the pH to 8 in the presence of ADP and phosphate. It worked, and ATP was synthesized.

Finally researchers began to take chemiosmosis seriously, but the chemical adherents fought a determined rear guard action, proposing all kinds of alternative explanations that became increasingly elaborate. This went on for ten years, but little by little their defenses crumbled and it became clear that chemiosmosis was correct. Peter Mitchell was awarded the Nobel Prize in 1978.

Now we can compare this controversy to the six rules put forward by Gary Herstein

Rule #1: The media IS just a circus.

There was virtually no media coverage of the controversy regarding chemiosmosis, even though the idea had a level of significance that was worthy of a Nobel Prize.

Rule #2: Follow the money

There was no money involved. In fact, Mitchell funded a lot of his own research out of pocket. 

Rule #3: Follow the publications

The publications were virtually entirely within the scientific literature. Only a few experts could follow the main points of the controversy.

Rule #4: Whimpering about conspiracies

There were no conspiracies.

Rule #5: Consensus is a clue.

There was an original consensus (paradigm if you will) and it was very interesting to watch a new consensus emerge as publications slowly accumulated that supported chemiosmosis.

Rule #6: Is the alternative even science?

There were two major alternative hypotheses, both based on solid research results, but with different interpretations and predictions.

My impression is that the controversy over chemiosmosis does approximately map onto the six Herstein rules, with a couple of exceptions. This is, in fact, another example of a “real” controversy.