Biocurious is a weblog about biology, quantified.

Homme Hellinga's Designer Enzymes

by Andre on 21 May 2008

Given the recent coverage of the retraction of two high profile enzyme design papers, I invited a friend of mine, Ross Anderson, who works in the field to comment on the situation. Here’s what he had to say. -Andre

There’s no fakes like Homme – the headlines and puns write themselves. The award-winning Duke biochemist Professor Homme Hellinga, the darling of protein design and by all accounts a bombastic, ruthless self-promoter has hit some hard times recently.

The current controversy centers around two papers published in Science and the Journal of Molecular Biology in which the program DEZYMER is used to redesign ribose binding protein (RBP), a non-catalytic periplasmic receptor, to incorporate triose phosphate isomerase (TIM) activity common to the TIM-barrel family of proteins. This impressive achievement was augmented by the in vivo recovery of a TIM-knockout strain of E. coli grown on lactate by the redesigned RBP – conditions which require TIM activity. In other words, he and his co-workers converted a non-enzymatic protein into one that not only had an activity he intentionally designed but that could also substitute for the natural enzyme in bacteria. Impressive stuff. Or so we all thought.

After a collaboration was set up between Hellinga and Dr. John Richard at SUNY Buffalo, Richard’s group were unable to reproduce the activity reported in these papers. They discovered that his purification had inadvertently dragged through some wild-type TIM enzyme and that this was responsible for his results. A retraction soon followed from Hellinga and he soon laid the blame on his graduate student who performed the original work, Mary Dwyer. Duke University subsequently found Dwyer innocent of experimental fraud but has yet to formally investigate Hellinga himself. Not a particular surprise, the cynical among us would think, considering the money he has brought to his department.

Worse still, Richard and others claim that even the retraction is dubious and fails to account for TIM activity changes in TIM-defficient E. coli when the designed proteins are mutated to destroy their activity. The implication is that the results are in essence a fantasy, although Dwyer claims that the variability of the assay and protein expression are to blame. Hellinga has so far declined to comment on the recent questions regarding the retraction.

Taken as an honest mistake, this situation is a protein designer’s worst nightmare: publication in a major journal followed by retraction due to protein contaminated with the very wild-type enzyme whose activity was being reproduced. Though as a fellow protein designer, the experimental design seems surprising to me. Why, if a TIM-defficient E. coli strain is already in use for in vivo work, do you use a TIM-expressing strain for your protein expression? Surely contamination is on your mind. Dwyer’s claim of variable protein expression lends a possible explanation but the co-purification of active wild type TIM enzyme is almost inexcusable, especially if your work is to be used as a high profile demonstration of this kind.

So there were mistakes. Dwyer claims that she informed Hellinga about her doubts of experimental validity. That Duke’s investigation exonerated her goes some way to confirm what most of us already know: the ultimate responsibility always lies with the PI. This is not to say that the PI should personally bear the burden of a student who falsified data. What they should do, however, is to frankly own up to the mistakes made and to issue a full and honest retraction.

In the end nobody wins from this situation: Hellinga is currently on a damage control tour and there are rumblings that more of his work should be closely reexamined; Dwyer’s career is forever tainted from the association with the retracted papers and the rumors that inevitably follow; Richard’s lab spent considerable time and money attempting to reproduce bad work and as the Nature editorial states:

Richard’s subsequent efforts to correct the scientific record thus came at considerable cost, with no discernable benefit to his own career.

How much published work is invalid? How many times have scientists attempted to reproduce published data only to find it irreproducible? I sincerely hope that the answers to these questions is a resounding “not very often”. Every scientist has a commitment to honestly present their work and based on this we trust, for the most part, what we read in peer-reviewed journals. Break that trust and you will face the consequences.

A last comment from Hellinga in his own words:

Do you think I’ll be more famous than Darwin one day?

Probably not, Homme.



References

Dwyer, M. A. , Looger, L. L. & Hellinga, H. W. Science 304, 1967–1971.
Allert, M. , Dwyer, M. A. & Hellinga, H. W. J. Mol. Biol. 366, 945–953.
Dwyer, M. A. , Looger, L. L. & Hellinga, H. W. Science 319, 569. (retraction)



  1. Andre    3496 days ago    #

    “the headlines and puns write themselves.”

    Speaking of which, I almost title this post “What’s up Hommes?”


  2. Andro Hsu    3495 days ago    #

    Was the sequence of the designed NovoTIM verified, say, by mass spectrometry? Seems as simple as sequencing your DNA to make sure you got the mutation right…


  3. Josh    3495 days ago    #

    I don’t think there are a lot of malicious fabrications out there, but there are plenty of sloppy papers. Personally on more than one occasion when I’ve really dug down into a paper, I’ve found inconsistencies, mislabeled figures or things that just don’t make sense.

    One thing people have to consider is that when a publication cites 60+ papers, how many of those were carefully read and scrutinized by the author, and how many were selected to mollify reviewers, cherry-picked for supporting evidence, or cited because another paper cited them? It would seem like neglect and errors would propagate pretty easily in the literature.

    Again I don’t think that these are malicious attempts to mislead the community, but just sloppiness that is not caught by reviewers or labs internal reviews.


  4. Duke Graduate Student    3495 days ago    #

    I must respectfully disagree with Josh. Hellinga gained much (NIH Pioneer Award, James B. Duke Professorship) from his “sloppy science,” and published it over the objections of his student (Mary Dwyer). When the charade unraveled, he accused Mary of fraud (for which she was cleared). In the six months that this debacle has been public knowledge, Homme has not even tried to explain how his retracted Science and JMB papers were filled with seemingly-impossible results. I urge you to read these papers carefully. The fact that the Km’s of Homme’s “novo-TIM” point-mutants rise in proportion to “active site” mutations makes no sense, as the wild-type novo-TIM has proven to be completely inactive. The chance of differential, patterned contamination of these mutants with wild-type TIM is diminishingly small. I would not be at all surprised if Homme re-arranged or combined real data from Mary’s experiments to fit the desired outcome. Duke investigators had access to Mary’s raw data. Their perusal of it convinced them to clear her of any ethical wrongdoing. The burden now rests upon Homme to explain the many logical and experimental holes in his work. The fact that he has not done so, and has much to gain (or rather, retain) from either shifting blame or avoiding frank scientific discussion, suggests a degree of maliciousness breathtaking in its audacity.

    As others have pointed out elsewhere in the blogosphere, Homme has long been a malign influence upon Duke’s Biochemistry graduate program. It is too bad that Homme’s passive-aggressive faculty colleagues aren’t brave enough to find out if he’s really as full of shit as the stench from this episode suggests.


  5. PonderingFool    3494 days ago    #

    At least the paper has been retracted. I have read a Nature paper that refutes part of the same lab’s Science article. It is barely acknowledged in the 2nd paper and in a manner that does not make sense. Other labs tried and tried to replicate the experiment in the first and never could.


  6. David    3494 days ago    #

    Andro Hsu,

    The DNA and amino acid sequence of the NovoTIMs are not in question. Indeed there purity is likely to be 95% or higher in the final preparations. The problem is that the NovoTIMs were purified from bacterial expression systems that have endogenous TIM activities. The NovoTIMs were then purified in a step elution method. In every case all the activity seen for every NovoTIM construct was derived from contaminating endogenous TIM contamination. Expression in a TIM-less expression strain and/or more rigorous purification (gradient elution or additional columns) would have caught the problem.


  7. Andre    3494 days ago    #

    Thanks for the great comments everyone. For those interested, there is also some good discussion following one of Writedit’s posts on the topic.


  8. mark    3492 days ago    #

    I think Hellinga’s Pioneer grant should be taken away, he should be put on administrative leave and he should have all his papers in the last 10 year critically reviewed by the editors of the journals where they are published. If he hadn’t blamed it all on his student who clearly had reservations on the data, then it would all go away. His ego is going to finish his career.


  9. kris    3489 days ago    #

    As the Duke Grad Student has pointed out, the grad student in question (Ms. Dwyer) has been exonerated, so I think the author of this blog post is being a bit unfair on her. It is quite likely in this case that she has not falsified anything, else the investigation is likely to have found to the contrary (they would have nothing to lose by confirming her adviser’s blaming her). It would be nice to see his work properly investigated, since the credibility of the rest of his work is in question.


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