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Published online 13 February 2008 | Nature | doi:10.1038/news.2008.569
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Protein prize up for grabs after retraction
Credit for enzyme-engineering breakthrough could change hands.
A retraction of a paper by a high-profile chemist has left a prize on the table in the protein-design field, and now, another scientist is poised to grab the limelight.
On 1 February, Homme Hellinga and two former students retracted1 a June 2004 paper that had been lauded as a breakthrough in the field of protein design2.
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In the section describing the 'innocent mistake', Ms. Hayden writes: "...he (Richard) and Hellinga had used slightly different purification methods. While both methods are standard, Hellinga’s method did not separate E. coli’s natural triose phosphate isomerase from the engineered version." Surely what this really means is that Hellinga's laboratory just didn't purify the protein properly. This is not an innocent mistake, but sloppy - really sloppy - science. No serious biochemistry lab would ever find themselves in this position - it's such an obvious pitfall to protein design. If this is a serious biochemistry lab, one is left wondering how 'innocent' the mistake really was. How well purified are other proteins studied in this lab ? Kudos to Richard's lab for doing Hellinga's controls for him (and the rest of us).
There is no doubt that Dr. Hellinga’s concept of is brilliant and will be used extensively to understand and develop a whole new class of enzymes with novel functions. It appears that the method for purification of enzymes used in his lab was not as sensitive as the one used by Dr. John Richard. In addition to Dr. Mayo’s suggestion about an internal verification of these kind of high-profile results, I would like to add that using more than one method of purification (like in this case) & characterization just to ensure that no artefacts/enzyme contaminants go undetected might have helped ‘catching’ the bacterial enzyme contaminant early on . What happened with Dr. Hellinga’s group can happen to the best labs & the best groups – it does not in any way reflect on the intellectual or experimental capabilities of Dr. Hellinga and his group. Dr. Suparna Martis
The explanation given in the retraction of this paper is entirely insufficient. In the original paper mutant enzymes were shown to have no activity but the explanation given in the retraction is that the mutants purified differently. This is not a sufficient explanation. Furthermore, in the original paper the engineered protein was shown to complement deficiencies of TIM- bacteria but the retraction states, "The in vivo experiments have not been reexamined". How can this be acceptable to the scientific community? This article is disturbing because it calls this affair an "innocent mistake" by resting on the investigations (or lack thereof) of Duke University. I'm sure Duke (and Hellinga et al.) would like this all to go away and so they have motivation to sweep this under the rug as an "innocent mistake". I'd like to hear more from the first author Mary Dwyer who only has two quotes in this article, one of which is "It didn't have to be handled this way". What does that mean? What about the follow-up article in J. Mol. Biol. or the earlier Nature article by the same authors? Are these experiments being re-examined? Also disturbing is that this article appears to validate the ideas of Hellinga and coworkers without substantiation. Why should Hellinga get any credit because someone else designed an enzyme after botching the affair himself? Overall this Nature news article appears as a "puff-piece" spoon-fed from Hellinga. I expect more from Nature journalism.
Suparna: I must disagree with you. What happened to Dr. Hellinga`s group does reflect on their experimental capabilities. They obviously did not bother to purify the protein properly - and this is a very easy thing to do properly. The best labs would have done a professional job. Richard did. Hellinga and colleagues have no excuse for poor technique, and for not doing the right controls themselves. They clearly rushed to publication without being thorough, and deserve extremely harsh criticism for misleading the field.
The protocols used by the Hellinga lab and the Richard lab are both standard methods for purifying a His tagged proteins, and rarely would there be any difference between proteins purified using the two methods. I believe in the retraction they were saying that the ‘mutant’ control protein expressed at a much different level, which may have led to different levels of contamination in the purified protein as compared to the ‘active’ protein. That being said, if I were running a lab where we were attempting to do something this novel, I would have had the protein purified by two different methods to help eliminate any contamination issue. In addition, if bacterial strains exist deficient for this activity (such as the ones used for the complementation experiments), then I would have investigated expressing the protein in these strains. While this level of experimental design is ultimately the responsibility of the Primary Investigator, I think some responsibility also has to be given to the reviewers of this paper. If the two suggestions I made above had been made in the review process, then perhaps this artifact would have been caught. The issue of the in vivo controls does need to be addressed, and I think Duke does need to investigate this to make sure everything is on the up-and-up. Mary Dwyer’s quote of “It didn't have to be handled this way� was taken out of context. My understanding is that she was referring to the fact that Dr. Hellinga reported her to Duke for academic misconduct with the potential consequence of having her Ph.D. revoked. Understandably, I believe she would have preferred that the matter had been investigated in more of an ‘innocent until proven guilty’ manner. The fact that the investigation cleared her of misconduct indicates to me that at least we aren’t dealing with a case of fabricated data. Hopefully further investigation will reveal if there is some level of misconduct involved, or if this is just a case of negligent biochemistry that the review system didn’t catch.
I don't think that the reviewers of this paper can be held accountable for this retraction, at least without knowing what went on during the review process. For one thing, maybe the reviewers DID request an alternative purification. This would undoubtedly be seen as "nit-picky", however, and I can easily see the authors arguing their way out of it (e.g. "The lack of activity that we measure in mutant novoTIMs conclusively demonstrates that the results are not due to endogenous TIM activity"). An anti-TIM western or some other way of quantifying the level of endogenous TIM may have been a more legitimate request, but again, we don't know what happened. And that's exactly my point when I say that the explanations given in the retraction are insufficient. Certainly the explanation they give for the in vitro measurements is possible, but in the absence of hard data, it's just one of many possibilities. The burden is on the authors to DEMONSTRATE what went wrong. If I were them, I would want to do this just to prove that the retraction speaks more towards incompetence or "sloppiness" rather than malicious intent. And certainly if I were an administrator at Duke University, I would want to proceed with a formal investigation to show due diligence.