A Sign, a Flipped Structure, and a Scientific Flameout of Epic Proportions

21 Mar 2007 // protein

update: fixed some typos, thanks to the comments

One of the most spectacular flameouts in science happened last year. In a short letter (barely over 300 words long) published in Science in the very last issue of 2006, Geoffrey Chang, a crystallographer, retracted 3 Science articles, a Nature article, a PNAS article and a JMB article. The sum of 5 years of work was destroyed, apparently, over a single sign error in a data-processing program.

Geoffrey Chang was one of the youngest faculty member at the Scripps Institute, La Jolla. Winner of a slew of prestigious awards, he had made his name solving the crystal structure of the MsbA protein, a membrane protein, arguably the most difficult type of protein to crystalize, due to the greasy nature of the trans-membrane surface of the protein.

The story reads like a pulp science novel. A rising star, Geoffrey Chang solves a number of immensely difficult problem. A former labmate (from the days when Chang worked in the Rees lab) Kaspar Locher, now a scientist at the ETH Zurich Institue in Switzerland, solves a similar crystal structure, except that his crystal structure had a helix that was flipped over 180 degrees. Locher published his own paper in Nature, in 2006, setting alarm bells ringing. Just by looking at the flip, Locher realized that his former labmate's structure contained a phasing error. An error that was "in the category of monumental blunders," said Locher in an interview with Science.

From what I've read, it seems to be a genuinely honest mistake on Chang's part. Although some commentators think that the reviewers in Science should have caught the error, I don't think the reviewers should be held accountable. Reviewers can catch relatively straightforward calculation mistakes, but the truth of the matter is that when we review articles, we take a lot of things on faith. What we can do as reviewers, is look for methodological soundness, and apply our hard-earned intuition on the results.

Still it's instructive to look at the nature of the error, as quoted in the retraction:

An in-house data reduction program introduced a change in sign for anomalous differences. This program, which was not part of a conventional data processing package, converted the anomalous pairs (I+ and I-) to (F- and F+), thereby introducing a sign change.

A single sign change in the data-processing program. And an in-house program at that. This should send chills up the spine of every computational biologist out there.

Don't get me wrong, I am not questioning the use of in-house software. After all, in-house software is the bread and butter of all working computational biologists. Still, Chang explained that the in-house program was legacy software inherited from a neighboring lab.

What this should flag is the necessity to aggressively test all the software that you write. One method is to apply a unit-testing methodology to your software. Even on programs that are written by someone else (a clever grad student in my last lab found many bugs in AMBER, a huge third-party molecular dynamics program). Eeeep!

In a later interview with The Scientist, Chang said, "I deeply apologize to those that used the old structures to come up with results that are incorrect," Chang said. "I feel pretty bad about that." This is a severe understatement. Due to the influential nature of Chang's 2001 paper, major grants have been awarded and denied in the study of the MsbA protein, based on the compatibility with the crystal structure. From the science news article,

David Clarke of the University of Toronto in Canada says his team had a hard time persuading journals to accept their biochemical studies that contradicted Chang's MsbA structure. Clarke also served on grant panels on which he says Chang's work was influential. "Those applications providing preliminary results that were not in agreement with the retracted papers were given a rough time," he says.

I've heard on the grapevine that Chang is a somewhat aggressive character, and he had dismissed the work of biochemists working in the field of MsbA. Maybe he should not have been so dismissive after all.

The moral to be drawn from the story is that crystallographers ought to pay very careful attention to what biochemists say about their proteins. What comes to mind is the ATP Synthase, the work for which won the 1997 Nobel Prize. One of the winners was John E. Walker, the crystallographer who solved this massive structure.

What shouldn't be forgetten is that one of the other winners was Paul E. Boyer, who figured out from biochemical analyses, a full 20 years earlier, much of the mechanism of how ATPase works – the existence of 6 subnits, made up of alternating domains, and how the binding site must be in the interface between the subunits. This mechanism was subsequently confirmed by Walker's crystal structure.

Crystallography, like any other scientific discipline, does not operate in a vacuum, and only in the interstices between disciplines, can the truth be found.