Cont’d Hellinga Fall-Out (May 2008)

Ugh. Nature summarizes the continued (& spreading) negative repercussions of the retracted Dwyer et al. papers discussed here and throughout the scientific community. An excellent Nature feature article by Erika Check Hayden covers the entire saga in detail.

Earlier, our man-on-the-spot David added a nice summary of an article in the May 5, 2008 issue of Chemical & Engineering News, including a bit more insight from John Richard in Buffalo and Hellinga’s dismissive reply (thanks so much, David, for all your contributions).

Nature notes that Richard and his group “wasted seven months and tens of thousands of dollars failing to reproduce the results from Hellinga’s lab” and that Mary Dwyer’s scientific career is over before it started. The editors also observe the questionable rationale in Hellinga’s accusing her of scientific misconduct: “As Dwyer’s adviser, Hellinga was responsible for training her. If she made mistakes, they are ultimately his responsibility.”

And, Nature spreads the wealth by noting that Duke itself owes something to the scientific community, and indeed, one hopes they are not holding their breath and hoping this will blow over so Hellinga can get back to the business at hand: bringing in research dollars to the University.

Earlier discussion can be read first here (initial Science retraction and detailed comments on problems with the science involved) and then here (The Scientist blog coverage, Chemical & Engineering News synopsis, et al.).

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142 Comments »

  1. BB said

    In retrospect, Dwyer was warned by numerous folk that Hellinga wasn’t the best advisor. She was a lowly grad student at the time and so wasn’t in a position (she thought) to keep Hellinga from publishing. Hindsight is always 20/20; perhaps the cautionary lesson here is that the future Dwyers bring concerns about an advisor’s rush to publish to a chair, dean, or ombudsperson. And to be prepared to switch labs, unless one’s thesis committee can pressure the Hellinga advisors of this world (at some schools, they can).

    I agree with Nature’s conclusion vis-a-vis Dwyer: her work was Hellinga’s responsibility. Kudos to her post-doc mentor for standing by her and giving her good advice. I think she’ll come through this fine in the end.

    Probably the saddest fact is that similar things albeit less publicized often happen to lowly grad students and unpopular post-docs.

  2. I just caught up on this controversy through the Nature articles and your earlier blog thread.

    Aside from all the shady ethics, what also deeply troubles me is the statement that Dr. Richard’s work leading to the retractions was done with “no discernable benefit to his own career”.

    The lack of credit given to those who reproduce (or refute) others’ work directly leads to the perverse incentive to rush to publish work first, often with data that is shoddy at best, fraudulent at worst.

    One way to improve these perverse incentives is to give more credit to those who reproduce or refute others’ findings. Though there will never be a perfect formula, we should strive/collaborate to come up with the best system possible to gauge an individual’s overall contribution to science.

    You are all invited to collaborate on this project, tentatively named the Public Contribution Rating, at my wikispaces collaborative science site.

  3. JSinger said

    A few various points…

    1) What struck me as odd was:

    But Dwyer’s new adviser, Donald McDonnell, a professor of pharmacology and cancer biology, advised her not to meet Hellinga alone; he felt she should go with someone who could advocate on her behalf. McDonnell arranged a meeting later that week at which he, Dwyer and Hellinga were joined by two other faculty members from the biochemistry department.

    Presumably, something was left out of the story before this. Normally, meetings with the old advisor don’t involve the postdoc coming in with an OJ-like defense team behind her. The rest of the department must have known she was getting ambushed even if she didn’t. (I give them credit for not reflexively backing the PI, although my cynical guess is that they don’t like Hellinga much.)

    2) My favorite part was:

    Some point to a Duke policy that states that if an allegation of misconduct is found to be “baseless and malicious or reckless, the matter will be dealt with in accordance with existing university policies and mechanisms”.

    Sure, if there’s one thing Duke is known for, it’s sanctioning faculty and administrators who make wild accusations of misconduct against students! At least they didn’t make the whole biochemistry department sign a demeaning statement like the lax team had to.

    3) On the plus side, the two-body problem seems to be getting adequately addressed! There’s, what, three pairs of spouses entangled in this?

    4) re: In retrospect, Dwyer was warned by numerous folk that Hellinga wasn’t the best advisor. I always counterbalance these warnings to heed warnings by noting that I did the same thing she did, and it worked out very well for me. There are plenty of awful PIs out there, but there are plenty of gossipy, petty, vengeful grad students also.

    5) Can’t WordPress get a freaking preview button? I’m holding my breath and hoping that I got all those tags right!

  4. In defense of reviewers said

    Wow, Hellinga sure doesn’t help himself in that article. He basically takes no responsibility down to the bitter end and comes off looking like a huge jerk.

    “Dwyer says that she raised her concerns with Hellinga at the time. But Hellinga says he does not feel he pushed Dwyer or anyone else to publish prematurely. “These things were talked through very carefully with all the people involved,” he says.”

    In my opinion, Hellinga’s culpability really comes down to this: how much did he know about the variability (which didn’t end up in the final paper)? Whether or not he talked it through with his graduate students makes no difference – he’s the boss and should have held off on publishing until this issue was worked out.

    “Asked whether he would have done anything differently in the NovoTIM experiments, Hellinga says, “I would like to not have the problem that we encountered.” When asked whether the lab moved too quickly, he says: “Given how we understood things to be at the time, no. Obviously if we had known things had gone wrong, we wouldn’t have moved forward with the speed we did.””

    How could he say that he wouldn’t do anything differently unless he’s completely arrogant? If he was quoted correctly in this article, he should be banished from science.

  5. noblesse d'epee said

    Hellinga is a crass embarrassment to Duke’s Biochemistry Department. His outrageous mistreatment of his student Mary Dwyer and his breathtakingly unethical approach to his recent retractions have confirmed what many here at Duke long knew: Prof. Hellinga is a malign influence upon the educational program to which he purports to contribute.

    I fear that the widespread coverage of Hellinga’s sleaze will cause collateral damage to the reputation of Duke Biochemistry. The public should know that Hellinga’s behavior and science are not representative of our program. When faced with the choice between publishing questionable data and delaying publication in order to perform rigorous control experiments, the vast majority of our faculty, post-docs, and students choose the latter. There is no “culture of corruption” here. If anything is corrupted, it is Homme W. Hellinga. As is appropriate for rubbish, his exit from Duke Biochemistry should be rapid and unceremonious.

    Despite his supremely arrogant aspirations, Hellinga may never be as famous as Charles Darwin. But all is not lost. Hellinga has furnished a superb case-study for research ethics courses the world over. That shall be his legacy.

    Ph.D. Candidate, Duke Biochemistry

  6. In the Know said

    JSinger,

    Your suspicion is correct – there are many PIs at Duke that don’t care for Homme, although after reading the article I don’t think you would have to be cynical to think that Homme had rubbed a number of people the wrong way. More famous than Darwin? I didn’t even know he was that arrogant.

    I agree with you that the student population can be gossipy, but when ten of the PI’s first dozen graduate students quit grad school (as in Homme’s case) and the people WITHIN the lab are warning you not to join… I don’t think flags get any bigger, redder, and wavier. I would say this to any first year graduate students: if people outside the lab are warning you not to join while people within the lab are advocates of the PI, then think about it. But when the people within the lab are warning you not to join, run like hell.

  7. George Smiley said

    “In my opinion, Hellinga’s culpability really comes down to this: how much did he know about the variability (which didn’t end up in the final paper)?”

    You understate Hellinga’s culpbability, and that of the referees. Consider the goal: to design a novel enzyme that mimics the activity of triosephosphate isomerase (TIM). TIM is, as all competent biochemists know, an enzyme with nearly perfect efficiency. TIM is also highly abundant in most cells, including E. coli, and WILL be a contaminant of any purification scheme. To produce your putative novoTIM, you will use E. coli. It is nearly a given that multiple separations will be required to separate your novoTIM from the real thing. How good does the separation have to be? If your novoTIM has 1/1000 the activity of the native enzyme – and you’d have to be very skilled AND very lucky to achieve this – 1% contamination by native enzyme would mean that 90% of the activity would be from the native enzyme. He surely knew this. Every competent protein biochemist in the wolrd knows this.

    Yet Hellinga went to press with a single-step separation using a method known by every competent biochemist to be susceptible to significant contamination. No ion exchange. No gel filtration. No purification of novoTIM from cells genetically deleted for the endogenous enzyme. For this, Hellinga should be run out of the field on a rail. And this is not, of course, the only defect in a manuscript positively rancid with questionable details.

    As for the referees who apparently did not consider this possibility, and demand more stringent biochemistry? They should take a break from refereeing papers and consider that if they had done their due diligence, they might have saved the career of a young woman whose prospects are now very much in question.

  8. In defense of reviewers said

    George,

    I disagree. The experiments in the original paper are well-controlled as described. There are many mutant proteins they made which exhibit no activity arguing against co-purification of endogenous activity. Furthermore the designed variant complements Tim- bacteria. In fact, this is why the explanation given in the retraction is unsatisfactory. Only later do we find out that there were red flags that weren’t included in the paper. Could data have been cherry-picked to make a case for the author’s conclusions? If so, this is fraud and should be punished. And this is what I believe happened. Hellinga thought he had a whale of a result on his hands and ignored the evidence against once he started envisioning all the accolades that would come.

    Finally, we don’t know what went on during the review process. Perhaps reviewers did request the things you mention (further purifications, etc), but because the data seemed so air-tight, these requests were considered unreasonable? This is not an unlikely scenario from my experience on both sides of the peer review system. I can easily see a reviewer making requests like the ones you describe and Hellinga responding that the data in the paper clearly shows that the activity is not from endogenous TIM (e.g. lack of activity in mutants and novoTIM complements a TIM- strain).

  9. scotus said

    JSinger raises some important points.

    Duke’s misconduct policy will definitely require that all parties respect the confidentiality of the process with possible penalties for not doing so almost certainly including dismissal so its notable that Dwyer has decided to speak out about her interactions with Hellinga that led to the misconduct investigation.

    Duke’s policy will also have a provision that everything possible should be done to restore the repulation of an exonerated “respondant” (ie Dr Dwyer) so my suspicion is that she probably doesn’t feel as though this has been done to a sufficient extent and is taking the matter into her own hands.

    Finally Duke’s misconduct policy will definitely have a provision to sanction individuals who make “Bad Faith” allegations of research misconduct. If Dr Hellinga accused Dr Dwyer of misconduct knowing that the charge was false then he would be guilty of making a bad faith allegation. Of course, looking objectively at whole mess I think its pretty obvious that being accused of a bad faith misconduct allegation is the least of Hellinga’s problems….

    This whole episode could very easily turn into a science version of the Duke lacrosse case except that Hellinga will be playing both the Crystal Mangum AND Mike Nifong roles…

  10. George Smiley said

    IDoR,

    you make some excellent points. It’s clear that Hellinga’s conduct leading up to submission of the publications was a admixture of incompetence and dishonesty; in some respects the fractional contribution of each is irrelevant. He’s shown that his work, as the Nature editorial very nearly said, cannot be trusted, and that he does not deserve resources or attention, particularly at this moment when there are so many struggling scientists who are both competent and honest, if a bit less self-promoting.

    Your points about the referees are well taken. Most importantly, no one here knows what went on in the Nature and JMB review processes, or if they do, they are not saying so. So we should be careful about criticising this process. Nevertheless, extraordinary claims require (or should require) extraordinary evidence, and I still find it shocking that the paper contains no statements dealing with the issue of contamination by native TIM. It is painfully evident now, and should have been evident all along, that this would be a major issue: TIM is, after all, a perfect enzyme. The paper as published contained elegant controls, but lacked obvious and simple ones.

    Ultimately, of course, the question that we have to ask is to what extent we can give our colleagues the benefit of the doubt during the peer-review process. Unfortunately, the peer-review process does not proceed from a coherent or consistent set of assumptions about this, and referees often bury one manuscript in trivia while another sails through with fundamental and obvious flaws. I don’t think that anyone really knows how to fix this situation without putting an undue burden on the majority of good scientists.

  11. whimple said

    Since the NIH awards grants to institutions, rather than to individuals, the NIH should investigate, and if it determines that its money was fraudulently wasted, should require Duke to repay the grants (out of whatever source of money Duke chooses). The NIH in theory holds all the cards here… I just don’t understand why the NIH continually throws in its hand to seemingly cater to the institutions’ every beck and whim.

  12. scotus said

    Whimple-

    The NIH requires institutions holding grants to adhere to their rules on responsible conduct of research which are ultimately governed by Federal Statutes. The misconduct investigation of Dr Dwyer and the now in my opinion inevitable investigation of Dr Hellinga are mandated by those rules. The institution, in this case Duke, has to conduct an investigation to establish if misconduct (ie deliberate fabrication or falisification of research results) occurred. Duke has to inform the NIH Office of Research Integrity (ORI) when the investigation is initiated, if it proceeds from an initial inquiry to a full blown investigation and at the end a complete report has to be submitted. The ORI would then make a decision about the validity of the conclusions drawn by the Duke investigation and determine any sanctions to be taken against Hellinga.

    Duke could of course contemporaneously determine that Hellinga’s conduct is grounds for dismissal and pre-emptively fire him (or ask for his resignation) and give back his grants. This has actually happened in two recent high profile misconduct cases that also attracted a lot of popular science press attention (Luk Van Parijs- MIT and Elizabeth Goodwin- Wisconsin). However, the process can be interminably slow. Neither the Goodwin or Van Parijs cases appear to have been settled by the ORI yet even though the first of these is now almost 4 years old.

    The good news is that once the process is started, it can’t just go away. The bad news is that it could take years to resolve.

  13. In defense of reviewers said

    George,

    Your statement, “Unfortunately, the peer-review process does not proceed from a coherent or consistent set of assumptions about this, and referees often bury one manuscript in trivia while another sails through with fundamental and obvious flaws.” succinctly describes what scientists probably find to be the most frustrating aspect of practicing science. Of course the big challenge is who decides what is a “trivial” vs. “fundamental” flaw? The editor is typically responsible for making these tough judgment calls and they have a very difficult job on their hands that isn’t getting any easier (more manuscripts, more complex science). Often the reputations of authors and reviewers come into play and this isn’t always a good thing (but shouldn’t be ignored either).

  14. mark said

    I would bet that Hellinga used data from these papers to get NIH grants, if not his Pioneer award. Now that they are retracted, doesn’t he lose those grants?

    Excellent point. And even so, the Great Zerhouni should consider whether Hellinga represents the sort of Pioneer he sought to promote through these awards. – writedit

  15. Federale said

    Office of Research Integrity. Director is a Duke Alum. I’m sure a few phone calls inquiring why ORI has not decided to open an investigation wouldn’t hurt. Likewise, a phone call to NIH in the Office of the Director, as well as to the Office of the Secretary of Health & Human Services (HHS) might help.

    Additionally, one could go for the jugular – the money. A call placed into the Office of Management and Budget (OMB) to their health division could be in order if someone felt there was a failure to comply in here..

    Office Phone FAX
    Office of the Director 240-453-8200 301-443-5351
    Division of Investigative Oversight 240-453-8800 301-594-0043
    Division of Education and Integrity 240-453-8400 301-443-5351
    Assurance Program 240-453-8400 301-594-0042
    Research Integrity Team/Office of the General Counsel 301-443-3466 301-594-0041

    P R O F E S S I O N A L S T A F F

    Office of the Director

    Chris B. Pascal, Director, J.D. from Duke University

    Division of Investigative Oversight

    John E. Dahlberg, Director, Ph.D. in Virology from Purdue University

    Nancy M. Davidian, Deputy Director, Ph.D. in Biochemistry from the University of North Carolina, Chapel Hill

    Peter H. Abbrecht, Medical Expert, M.D. and Ph.D. in Chemical Engineering from the University of Michigan

    Kay L. Fields, Scientist-Investigator, Ph.D. in Molecular Biology from the Massachusetts Institute of Technology

    Susan Garfinkel, Scientist-Investigator, Ph.D. in Molecular Genetics from George Washington University

    John W. Krueger, Scientist-Investigator, Ph.D. in Biomedical Engineering from Iowa State University

    Linda D. Youngman, Scientist-Investigator, Ph.D. in Toxicology from Cornell University

    Division of Education and Integrity

    Sandra L. Titus, Director, Intramural Research Program, Ph.D. in Family Social Science from the University of Minnesota

    Cynthia S. Ricard, Director, Extramural Research Program, Ph.D. in Biomedical Sciences from the Albany Medical College

    Loc Nguyen-Khoa, Director, Online Education & Communication, Ph.D. candidate in Public Health at the University of Maryland

    Robin Parker, Assurance Program Manager

    Research Oversight Legal Team/Office of the General Counsel

    Christian C. Mahler, Research Integrity Team Leader, J.D. from the University of Maryland

    Jo An Rochez, Senior Attorney, J.D. from the University of Maryland

    Alice Tayman, Senior Attorney, J.D. from the University of Maryland

  16. postdoc said

    I’m not sure I understand this. Duke has cleared Mary Dwyer of fraud, but her lab notebooks could not possibly be consistent with the published data.

  17. In the Know said

    @ postdoc:

    From the article (http://www.nature.com/news/2008/080514/full/453275a.html):
    “By early 2004, Hellinga was ready to publish. On 29 March, he submitted a paper describing the NovoTIMs to Science, which accepted it on 6 May. The paper did not mention the variability Dwyer had noticed.”

    The implication is that Dwyer didn’t write the paper, and amongst the piles of variable data, Hellinga cherry-picked the data that fit the model. You’ll notice a lack of reporting of statistical error in the original paper(http://www.sciencemag.org/cgi/content/full/sci;304/5679/1967).

    Now we wait for a more in depth investigation to see if these inferences are true…

  18. noblesse d'epee said

    Update from Duke Biochem.:

    Prof. Hellinga has been telling his laboratory (and others) that Mary Dwyer is mentally unstable and that her data were artifacts of this state. This brilliant “defense” by Hellinga is not only weak, it is vile slander.

    This is consistent with a pattern that has long been recognized by graduate students in Duke Biochem: Hellinga is widely known to instigate whispering campaigns against other students who have left his lab. In each case, he has questioned students’ intelligence, sanity, and general mental well-being. Interestingly, Hellinga’s wife (and collaborator) Prof. Lorena Beese has consistently employed the same modus operandi to discredit her own graduate and rotation students — always behind their backs. Such behavior is a particularly despicable, if disingenuous, method by which a PI may “cover” for his atrocious mentoring and/or misconduct. Why do this pair of professors get away with this? Does having large grants and high profile publications really excuse all other wrongdoings in the eyes of the scientific community? Do Hellinga’s colleagues and superiors have insufficient conscience and decency to demand of him some modicum of responsibility?

    If academia tolerates this sort of behavior by so-called “educators,” I want no further part of it.

  19. Trevor said

    Noblesse d’epee:

    Please, please, please don’t paint us all as with the same brush. The vast majority of us would not, could not, do not tolerate such behavior. It is reprehensible that at least some in the Duke biochemistry department apparently do.

    I am left wondering why Hellinga is not under investigation – the system is currently failing. It has not as yet failed, but it is coming close.

  20. postdoc said

    Noblesse d’epee:

    You obviously have a personal problem with HH, therefore your claims about this matter lack credibility.

  21. postdoc said

    In the know:

    So, basically, she was a victim? Please. It is very hard to accept that a first author of two major papers that are not backed by her lab notebooks can be declared innocent of misconduct.

    A grad student in that kind situation does not have to confront her superviser in person. She could have gone to the dean of students or the dean of research and asked for help.

  22. Trevor said

    Postdoc:

    Are you actually there in the Duke biochem department? Have you ever been put in a situation similar to that of Dwyer? Have you met HH? I think you are misjudging just how difficult it would be for a student to dispute an advisor such as Hellinga (I have met him). Yes, she could (and probably should) have taken her concerns to a higher authority, and yes, she shares some culpability for not doing so. However, it is very easy for us to pass that judgement. We weren’t there and most of us, I wager, have never been personally involved in a situation such as this.

  23. noblesse d'epee said

    @ Postdoc:

    Were one to survey my graduate student colleauges in the Duke Biochem. Dept., I think that one would find that my claims are indeed credible. Since we’re talking anonymously on the internet, I fear that you will just have to take my word for it.

    It is true, as is clear from my posts, that I detest Hellinga (HH). From my vantage point, I think that any decent, concientious scientist might feel similarly. Do my opinions invalidate what I have observed and experienced? Only if one assumes that my bias causes me to fabricate such observations. I’ll leave the fabrication to HH.

  24. David said

    In response to Postdoc.,

    First, the Biochemistry Department at Duke is within the Medical School. The difference between departments in Medical Schools and Arts and Sciences Colleges is striking from my experiences in both types of departments. The power structure and focus on students is far different than in an Arts & Sciences Department where teaching and students are a major focus.

    Second, while I do not know HH at all, I know four people who have left his lab – unhappily. One is now successfully self-employed. The other three left unhappily only to find success in other labs. The claim that a disproportionate number of his grad. students left his lab and/or science seems to be true.

    Third, as for what the student should have done, why don’t we reference another case that has been mentioned – where the students did report alleged misconduct. This is the UW-Madison case of Prof. Elizabeth Goodwin. see http://www.uwalumni.com/home/worms.aspx

    The 7 students/employees banded together. In the end, all but one student left Wisconsin, careers in shambles. As bad as that seemed, it could have been worse. The administration in the UW Ag School was very supportive of the students. All of them seemed to genuinely like Goodwin and had a good relationship with her before they went to the administration. Still there were reports of a whisper campaign behind their backs.

    Contrast the UW circumstances to the Duke circumstances. Is it realistic to expect solitary Mary Dwyer to oppose HH by going up the Medical School Administrative ladder? I can be certain that her career would be in shambles AND she would be unemployed.

    Here is an idea. Anyone who attends one of those mandatory ethics training sessions should be introduced to an administrator entrusted with the well-being of students/postdocs. If such a relationship were cultivated before problems arose, perhaps problems could be caught earlier. It takes unrealistic bravery to send a career in shambles without a safety net.

    In the end, Mary Dwyer was cleared by a committee of HH’s peers. Would that have happened without the forced retractions and scrutiny of the scientific community?

  25. Trevor said

    David wrote:

    Here is an idea. Anyone who attends one of those mandatory ethics training sessions should be introduced to an administrator entrusted with the well-being of students/postdocs. If such a relationship were cultivated before problems arose, perhaps problems could be caught earlier. It takes unrealistic bravery to send a career in shambles without a safety net.

    Many institutions have ombudsmen who have the responsibility you described. Unfortunately they are often anonymous administrators who have little or no contact with their constituents, and also little or no experience in science.

    In addition to an all-purpose ombudsperson, every institution should have a Research Integrity Officer for just this reason (neutral, confidential sounding board/reporting official for scientific misconduct concerns), but their (unpaid) role is often downplayed, possibly because they too are busy trying to do their own work, get grant funding, write papers, train students, etc. Plus, different institutions give them different degrees of power/authority. – writedit

  26. In defense of reviewers said

    Postdoc writes:

    “A grad student in that kind situation does not have to confront her superviser in person. She could have gone to the dean of students or the dean of research and asked for help.”

    It’s not the student’s responsibility to do this. Students should have avenues for such situations, but if they don’t take advantage of them, it doesn’t mean they’re responsible. The advisor is ultimately responsible for deciding when and what to publish. If Dwyer had kept the variability from Hellinga then she would be at fault, however this is not the case (from what I understand). Instead Hellinga was made aware of this and still decided to publish and thus is completely responsible and should be punished appropriately.

  27. In the Know said

    @ postdoc:

    I was there, heard the progress talks, met the people involved, and knew several of the people who left the lab previously. You can maintain your suspicions, but from what you have written you don’t know the players involved. The reason I even started posting to this forum was to offer an inside view of this situation, since I had seen knee-jerk “blame the lead author” reactions from several of my colleagues. Ultimately, however, I’m hoping that my views here and your suspitions are all rendered meaningless by a published report of an in-depth investigation of the situation.

  28. another postdoc said

    @postdoc,
    There is no reason for her or anyone in her position to believe that their personal interests would be served by speaking to someone about their advisor, especially given that they have no good reason to have much trust in the people whom you mention. There is a huge asymmetry of power between a grad student and a tenured professor, and I think most grad students in such situations are acutely aware of this asymmetry. Why should one trust a bunch of people who have consistently looked the other way when the advisor behaved like a jerk ?
    A tenured professor can get away with anything short of a criminal act, and not be really penalized for it, and it is not in the interests of others in the dept or the administration to go after one of their colleagues. It is on the other hand a lot easier to let the student out to dry. Also, given that there is no public investigation by Duke into Mr. Hellinga’s actions (he has after all openly slandered his former student who has been exonerated, and not acknowledged any wrongdoing) even at this stage, she probably did the sensible thing by not going to anyone else in the administration.

  29. postdoc said

    I’m in COAS, and indeed, as another poster said, students and teaching are taken seriously. Perhaps I’m naive, but I still think that a dean or a department chairperson can be trusted to offer good advice and not to spread the word in cases of conflict with one’s adviser. Sure beats being complicit in scientific fraud.

  30. In the Know said

    In this particular situation, the department chair (at the time) did not have a reputation of confidentiality, and taking this type of situation to a Dean when your PI is the darling of the Medical Center and has a reputation for ruthless retaliation takes some serious faith.

    For others following this drama, I think the lesson is to not allow yourself to be cornered in this manner. If a PI has this type of reputation, don’t join the lab. If you are in the lab before you see these issues, then quietly leave the lab and tell someone in power if you know you can trust them. Graduate students often have the mistaken idea that changing labs will come at a high price in terms of time, and that other PIs will never take them, when in truth this often isn’t the case.

  31. In defense of reviewers said

    Postdoc writes, “Perhaps I’m naive, but I still think that a dean or a department chairperson can be trusted to offer good advice and not to spread the word in cases of conflict with one’s adviser.”

    That is a naive assessment of the situation. Who knows what any individual might do, but deans and department chairs definitely have conflicting interests in these situations. Look at Hellinga’s case. He had brought tons of money into the department and was supposedly on a steep upward trajectory. There’s no question that a chair or dean would want this to go away. Now they might do the right thing anyway, but the motivations for saving the PI vs. the grad student are definitely there. So to just assume that the administration is going to do the right thing in cases like this is simply a matter of not thinking it through.

  32. postdoc said

    In defense of reviewers:

    You’re forgetting the context. HH already had a unsavory reputation in the department. Let’s further assume that MD was respected by her colleagues and the faculty members. In such conditions an astute administrator should realize that the accusing student is telling the truth and that something has to be done to avoid a scandal.

  33. In defense of reviewers said

    Postdoc,

    I don’t really know what you’re arguing anymore. We now need to assume that the grad student is well-respected and the administrator is astute? Can’t we just agree that contacting the administration is not an obvious course of action in this situation, what you were stating earlier in the discussion?

    And speaking of context, in this case Dwyer was concerned about variability but her mentor was telling her that it was nothing out of the ordinary (from the Nature article). I could easily see her second-guessing any decision to make an issue out of it.

  34. noblesse d'epee said

    A “Former Hellinga Graduate Student” posted recently in one of the older, inactive portions of this thread (see below). What he/she says is interesting. I suspect that an investigation of HH would not suffer from a shortage of testimony.

    Former Hellinga Graduate Student said,
    May 30, 2008 @ 11:30 pm · Edit

    Federale said:”Office of Research Integrity. Director is a Duke Alum. I’m sure a few phone calls inquiring why ORI has not decided to open an investigation wouldn’t hurt. Likewise, a phone call to NIH in the Office of the Director, as well as to the Office of the Secretary of Health & Human Services (HHS) might help.”

    This sounds great, and as a former graduate student in Hellinga lab at the time the designs were made I could testify (and so could other former lab members) about many wrongdoings on Homme’s part that were not just unethical and unprofessional, but just plain wrong from a human perspective. He treated his students as some data collecting monkeys, who were supposed to train themselves to be able to collect the vast amount of groundbreaking data in the first place. And those multi million dollar grants received for which absolutely no work had been done in the lab. Ever. And why would science fiction type research proposals be funded and never worked on? Without any preliminary experimental work? I wonder how much those phone calls could change the reality. ( Forgive my cynicism, but its all about money he brought in.)

  35. writedit said

    A few thoughts on all this finally …

    First, there won’t be a “published report of an in-depth investigation of the situation.” Maybe, in a few years (as was noted earlier by scotus), ORI will publish their summary findings. Of course, ORI needs to hear from Duke about this first, but I’m sure they have. We just won’t hear about it nightly on the 6 o’clock news.

    Second, as evidenced by the fear of tenured professors and senior researchers to speak out against something that is very public & very obviously not right (see local article describing the lengths faculty are going to protect themselves), it probably is too much to think a grad student would feel comfortable going to administration officials whose salaries are paid off the indirects from her “mentor’s” grants. Hellinga is a cash cow, plain and simple.

    However, the research conduct and compliance arm should be completely (reporting lines & budget support) independent of any other branch of research development to avoid any such conflict of interest (this is how they structure things here at Baby It’s Cold Outside anyway so the engine driving the research train is not the one to put on the brakes). Unfortunately, I can’t quite figure out, going through the Duke Research links, who manages their conduct & compliance issues.

    Third, for concerns about grant funding being misused in any way, anonymous tips can be submitted to the US DHHS Office of the Inspector General Hotline (and rewards are paid based on savings to the federal government).

  36. scotus said

    It’s been well established that PHS/NIH grants are not “contracts” to conduct the research proposed. If Hellinga had support from other agencies such as the Department of Defense, Department of Veterans Affairs or private sources it is likely that some sort of a contractual obligation to attempt the funded research could be invoked. However, when it comes to NIH grants, only egregious misuse of funds for purposes unrelated to scientific research would be grounds for a complaint. Of course, were a misconduct investigation to find that Hellinga obtained funds on the basis of fraudulent research and/or used the funds for fraudulent research then the implications for him and Duke are clear as established by the Poehlman case (which was of course a lot more egregious than the alleged Hellinga misconduct).

    The other point I wanted to make is that all of the suggestions that Hellinga will be protected by Duke because of all the funding he attracts are way off the mark. In the scale of things Hellinga’s support may be high on an individual basis but it’s a tiny portion of all the PHS research support at DUMC. Duke will not jeopardize this by doing anything that could be seen to be complicit with Hellinga’s alleged misconduct.

    Some “creative tension” between mentors and their trainees is an inevitable part of the academic research “circle of life”. I have had an NIH funded lab for 15 years (I’m negotiating the 4th renewal of my R01 now). I’m not as “successful” as Hellinga by any stretch but I have learnt from experience and mistakes that if I do not maintain an open, trusting and respectful relationship with the people who work with me in the lab the fundamental equilibrium of the research process is disrupted. It sounds as though Hellinga had been sailing close to the wind for a while. Research misconduct is such an emotive issue that I really can’t see an easy exit strategy.

    My prediction is that Hellinga will end up moving to the private sector later and that it will take another 3-4 years before ORI publishes anything about the case.

  37. noblesse d'epee said

    Scotus said:

    “Duke will not jeopardize this by doing anything that could be seen to be complicit with Hellinga’s alleged misconduct.”

    Perhaps. But DUMC, early in its misconduct investigation, “lost” the laboratory notebook recording Mary Dwyer’s work on the Novo-TIMS. Fortunately, Dwyer made *NOTARIZED* copies of the relevant notebook. These copies were apparently used to mount a successful defense against Hellinga’s charges. If this unusual precaution had not been taken, the outcome of the investigation would have hinged upon Hellinga’s word vs. Mary’s. If Duke isn’t complicit in Hellinga’s misconduct, it is doing a superb job of pretending to be. Of course, we must remember that Duke is run by the ham-handed crowd who brilliantly managed the lacrosse fiasco, so we cannot assume malfeasance when gross incompetence would suffice.

    I should point out the my information about the lost notebook is well-vetted. This, among other sordid details, will continue to bubble to the surface as this disaster continues to lurch into the open.

  38. scotus said

    It would be standard procedure for copies of the research records to be made at the time when they were submitted to the panel conducting the intiial investigation. Don’t forget that according to the ORI misconduct regulations failure to produce these records by Drs Hellinga or Dwyer would constitute misconduct (see below). One thing that I don’t understand is that if Dwyer had already left Hellinga’s lab then the original lab records should have stayed there and not been in her posession at the time the investigation was initiated. If she held on to these records that might be significant and suggest she knew they might become a focus of attention in the future. Does anyone know anything about this?

    I am sure that the relevant administrators at DUMC are doing their best to handle this in a fair way that respects the confidentiality of the process. I am also sure Hellinga has retained counsel who are pressurising Duke not to do anything to harm Hellinga’s reputation until they reach a decision. I can’t believe that Duke are not now investigating Hellinga but I expect his lawyers are doing their best to make sure the process is super confidential, particularly in light of Dr Dwyers decision to talk publically about it through the science press.

    If there was an attempt to protect Hellinga by tampering with the records whoever instigated it was both reckless and stupid. In the end the reputation of the institution is what matters. There are plenty of decent investigators at Duke doing worthwhile highly regarded research. The $100s of millions of research funding they bring in each year are much more important than the money it appears as though Hellinga has scammed out of the NIH for his “research”.

    Q: Is the destruction, absence of, or the respondent’s failure to provide research records adequately documenting the research that is the subject of an allegation of research misconduct evidence of research misconduct?

    A: Yes, if the institution or HHS establishes by a preponderance of the evidence that: (1) the respondent intentionally, knowingly, or recklessly had research records and destroyed them, had the opportunity to maintain the records but did not do so, or maintained the records and failed to produce them in a timely manner; and (2) the respondent’s conduct constitutes a significant departure from accepted practices of the relevant research community. Section 93.106(b)(1).

  39. In defense of reviewers said

    Scotus, thanks for your well-written posts (and good luck on your renewal). I have one nit to pick. You state, “failure to produce these records by Drs Hellinga or Dwyer would constitute misconduct” but the quote you supply does not support such a strong assertion. First, the question says that not supplying these records could be “evidence of research misconduct”. Second, the answer states that additional things (that could be very difficult) must be proven in addition to failing to supply the records, in order for this to constitute misconduct.

    However, I think you hit the nail on the head:

    “My prediction is that Hellinga will end up moving to the private sector later and that it will take another 3-4 years before ORI publishes anything about the case.”

  40. In the Know said

    It is my understanding that Mary copied the notebooks before she left the lab in anticipation of future troubles, but I don’t know for sure. Since she was/is still working at Duke, she may have simply gone back to the lab early in the drama and photocopied them then.

    I have also heard that Duke lost the notebooks, but from another pretty reliable source I heard that the notebooks are not (and never had been) lost, and are being securely held by the Med School administration. It is hard to beleive, given the “impact factor” of the issue, that someone would be negligent enough to loose the notebooks, or stupid enough to ‘misplace’ them on purpose.

    For the more experienced commentators on here:
    Wouldn’t, at least in this case, the manuscript drafts and editing communications between Mary and Homme be the most revealing? Assuming that these communications occurred through e-mail, couldn’t the school pull communications between the two from department servers? Certainly if we were talking about a company, e-mail communications would be fair game. With a university, however, I don’t know if e-mails can be pulled without a search warrant, or if the university/department would even maintain records that are several years old.

  41. scotus said

    IDOR- You are right. Inability to produce the data would not automatically result in a finding of misconduct.

    I was trying to make the point that “losing” the data in mid investigation would not terminate the process and would therefore not be a particularly sensible or effective strategy for some unknown Duke operative to protect Hellinga for the purpose of retaining his research funding as some others here have suggested.

  42. scotus said

    ITK-
    Good points. Email is discoverable and its very likely that these emails could be obtained by the investigators. At most universities, the computer system belongs to the university and the resonable expectation of privacy can be usurped when matters that potentially contravene the universities rules and regulations are involved. If Hellinga and Dwyer did communicate by email I wouldn’t be surprised if Dwyer didn’t share these and drafts of the manuscripts with the investigators. In any case, at this stage the issue of these communications seems moot. Dwyer has been exonerated and, as I explained above, it is very unlikely that anyone at Duke will confirm Hellinga is under investigation although I cannot imagine he isn’t. If the investigation has started just about anything is fair game which could include forensic analysis of his computers to examine drafts of the papers. I am sure Duke will have some CSI fanboy IT people who would be only too happy to look into this.

    My Chair, Division Chief and VP for research will not communicate with me by email about certain “sensitive” matters like hiring, promotion, space, research resources for exactly the reason that they don’t want an electronic paper trail.

  43. Federale said

    There seem to be a number of individuals leaving comments on here who really need to hear the following:

    1 – If you feel you have information that is pertinent to this case, and you feel you have a duty to provide it (ie familiar with the players, discussions, data, witnessed acts, analysis of other potential misconduct acts, analysis of other papers that are suspect) you should say something to one of the following appropriate authorities. Contacting these groups (which constitute a number of funding agencies for the laboratory of the person involved) and the appropriate other actors who have a stake would constitute a fulfillment of a duty-bound obligation to scientific integrity.
    a, Office of Inspector General at HHS
    b. Office of Inspector General at DoD
    c. Office of the Director of DARPA
    d. Office of Research Integrity at HHS
    e. Editorial Staff at any Journal with a suspect publication

    You can contact any of these places and outright demand confidentiality. They take these matters very seriously, as any issues that are brought to them and not followed up on is a black eye for them too. It’s their job and they are professionals. Do not be afraid to contact these groups, keep good records of when you contacted them, whom you spoke to, and what you provided. Also, consider how effectively you control your own disclosure that you’ve spoken to any of these groups. Controlling your own personal release of information and knowing who you’ve said things to can go a long way in killing/preventing whispering campaigns and protect you from retaliation.

    Likewise, should it become known that you’ve contacted authorities about something, and should you be retaliated against in any way; the individuals who retaliate are in for a world of hurt. Universities, and the Federal Government come down on people with an iron fist for retaliating and the penalties in all aspects are steep, sweeping, and lasting.

    2. It is expected and accepted that Duke has a financial interest in this matter. It is expected and accepted that the administration of Duke University Health System has a managerial interest in this matter. If you feel that you have substantive issues relating to managerial or financial impacts of this case, directly contacting them is a duty-bound thing to do. Appropriate contacts include.
    a. Biochemistry Dept. Chair Kenneth Kreuzer
    b. School of Medicine Dean Nancy Andrews
    c. DUHS Chancellor Victor Dzau
    e DUHS Dean Gordon Williams

    3. For graduate student concerns over the power dynamics within a medical center teaching institution, avenues exist within the medical center as well as the university proper. Important contacts include
    a. Graduate Student Affairs Deans Tomalei Vess, Jacqueline Looney
    b. DUHS Vice Dean for Research Sally Kornbluth
    c. Dean of the Graduate School at Duke, Jo Rae Wright

    It is my distinct hope that all those who have been hurt by these events can find a way to positiively contribute to such things never happening again. In the end many will regret their severity in complicated situations like these. Few people ever regret their compassion in situations like this. Do the right thing, for the right reasons, and find it within yourself to muster up the courage to speak up when you need to without fear.

  44. whimple said

    I completely disagree. If you are a grad student and you know something, you should *SHUT UP ABOUT IT* and get on with your life. There is no upside to you to coming forward. There is a significant downside to coming forward. I can guarantee that if you get involved, you will be attacked, and nothing “Federale” ever does for you (if anything) will make up for (at a minimum) this distraction to your career.

    There’s nothing left to know. Hellinga published bogus science. His grad student is exonerated. There’s no one else to blame. Duke should fire him, end of story.

  45. Trevor said

    I completely disagree. If you are a grad student and you know something, you should *SHUT UP ABOUT IT* and get on with your life. There is no upside to you to coming forward. There is a significant downside to coming forward. I can guarantee that if you get involved, you will be attacked, and nothing “Federale” ever does for you (if anything) will make up for (at a minimum) this distraction to your career.

    Unfortunately whimple is right. I would like to think we had developed our institutions in ways where all was open and accountable, and people pointing out wrongdoing would be lauded as heroes, but we have not. Anyone know of a single case where there was a happy ending for the whistleblower? Not just in academia, but anywhere?

    Having said that, I do firmly believe that academia is more open and accountable than most of society. We should all keep in mind that sordid affairs such as this really are very rare occurrences. Not much comfort to those directly involved, but hopefully encouraging to those who have been turned off academia by this.

  46. John Richard said

    Courage can only be shown in situations where one’s actions carry an element of risk. Risks are weighed and one acts in one’s own best interests. The penalty for playing it safe is the knowledge that one has acted in a cowardly manner, and this is a penalty that some are reluctant to pay. A person comfortable with their cowardice might make the argument that there is “no upside in coming forward”, but most will understand this to be specious. The reward for “doing the right thing” is simply to have done what one thinks needs to be done.

    I do not consider this sordid occurrence to be a rare one. What is rare is the very public and vigorous effort being made to keep its full sordidness hidden. At present, I see no reason for Duke to fire Homme Hellinga.

  47. scotus said

    As a tenured professor, firing Hellinga would require a lengthy process that would not be initiated until after any misconduct investigation had concluded. Unless Hellinga admits to misconduct I don’t see this happening. What I do think will happen is that Hellinga will quietly move on, perhaps back to Europe but more likely into the private sector where venture capitalists will see some of his more fanciful protein design projects as “high-risk high-gain” investments. All we scientists have are our reputations. Irrespective of the eventual outcome, this episode has established that Hellinga is either dishonest or a terrible scientist or both. Neither scenario is compatible with Hellinga’s continued ability to operate in academia, sustain research funding and publish high profile papers, all of which are regulated by peer review conducted by individuals who would reasonably regard his future work with skepticism.
    With regards to the issue of weighing the potential harm of speaking out against one’s duty to do the right thing when faced with evidence of research misconduct thing I agree with Dr Richard that this is essentially an issue of character and conscience. Science is a strange business because as practitioners we both compete with and depend on each other. Hellinga’s efforts in the area of TIM design were built on the work of other scientists, including Dr Richard, who identified the gene, determined its function, solve the protein structure, defined the catalytic mechanism and so on. Being a scientist means honoring and building on the work of our predecessors and contemporaries. The fundamental harm to everyone of deliberately introducing false information into the scientific record is something that anyone who spends their time designing, conducting and interpreting experiments should be able to easily comprehend.

    Hear, hear. So well said. Thank you, scotus. And Dr. Richard’s eloquent commentary on courage as well. – writedit

  48. noblesse d'epee said

    Federale, Trevor, Whiple, John Richard, Scotus,

    As I have mentioned in a previous post, I am a graduate student in Duke. Biochem. While I have not worked under the supervision of Hellinga, I am familiar with several colleagues who have. Long interaction with these students has convinced me of the high probability, through multiple lines of evidence, that Hellinga has committed gross violations of commonly accepted scientific ethics, if not perpetrated outright fraud. I should note that this alleged (mis)behavior is not limited to the novo-TIM work.

    For the past several months, a letter has sat, unsigned, on my desk at home. In it, I summarize the troubling accounts of the research wrongdoings described to me by primary witnesses. I then provide the names of these individuals, urging investigators to contact them. Some of these (former) Hellinga lab members have told me that they fear to initiate contact with investigators, but will provide information if asked and/or compelled to do so.

    I am faced with some dilemmas. First, I have never worked for Hellinga, so the appropriateness of urging an investigation based on my second-hand knowledge, however accurate, may be questioned. Second, my detestation of Hellinga and his wife is well-known (I was the subject of a whispering campaign by the latter), so one may argue that my involvement is merely “sour grapes.” Despite my admitted bias against Hellinga, I have tried to keep my mind open to ways by which accounts of his alleged misconduct may be explained by non-controversial mistakes and misunderstandings. The more that I have learned, the more I feel that serious allegations against Hellinga would be supported by primary testimony, and therefore ought to be investigated. When considering whether to facilitate such testimony, I arrive at my third dilemma, namely, the “outing” of witnesses who I consider friends, and who have expressed to me their desire to quietly pursue their careers as far away as possible from Hellinga and his scandals.

    I am left with the following choices:

    1. Leave my letter unsent, hoping that investigators will interview former Hellinga lab members without my prompting (by no means an unlikely outcome, but surely much delayed).

    2. Send my letter, signed, and risk hurting the careers of my friends and myself. No company is likely to hire someone known to be a “trouble-maker,” even if for a good cause. I should note that academic jobs will not be pursued by any of us; we’ve had quite enough of academia, and consider the pursuit of money to be more practical than academia’s pursuit of ego.

    3. Send my letter, unsigned, thereby protecting myself but potentially harming my friends. Effective, but cowardly. If Homme’s lawyers start harassing the witnesses, I know that neither they nor I have the resources to retain counsel of adequate quality to prevent their lives from being picked apart in an attempt to scare them into silence. We can’t count on support from our program’s faculty, which has shown itself to be remarkably spineless in the face of Homme and his supporters in the DUMC administration.

    At the same time, I am keenly aware of my responsibility to my nominal profession, and to the millions of taxpayers who have not had the opportunities which I have been afforded, but by whose hard-earned wages my education and research have been so generously funded.

    I would send my letter, which I think is the “right” course of action, but only if I could find a mechanism by which to protect those whose interview it urges. I have no shortage of courage with regard to my own future, as I’ve concluded that life is too short to abet, through silence, wrongdoing on the scale of Hellinga’s. However, I am hesitant to act with the assumption that my friends and colleagues share this opinion.

    Given what I have told you, what course of action would you suggest?

  49. David said

    noblesse d’epee,

    It seems that these primary sources to which you refer are not comfortable sending their own individual letters (to your knowledge). I do not think it would be fair to them to name them in a letter to Duke without their permission. If these primary sources merely desire a intermediary with Duke, there are better choices than a “graduate student in Duke. Biochem.” Three clearly trustworthy and informed choices named in the Nature article are Dr. John Richard, Dr. Jack Kirsch, and Dr. Donald McDonnell. If the above post is indeed from Dr. John Richard [it is indeed - writedit], he seems an excellent choice. It is a shame that no Duke Biochemistry faculty have been mentioned in any reports, but if you know of one, he or she would also be a better choice than you.

  50. whimple said

    Obviously, my advice is to let go of your hate, and get on with your life, and not send the letter. Dr. John Richard advocates courage, but the measure of the courage of a graduate student in Hellinga’s own department is not necessarily similar to the courage of a tenured full professor at an institution in a completely different part of the country. In any event, your hearsay evidence is of no legal value.

    I wonder if there are going to be parallels in the Hellinga case to the fallout of the well-documented case of Steven Leadon down the road at UNC-CH a few years back. Beth Ruggiero, a graduate student in Leadon’s lab, spoke up and finally managed to bring an end to years of extensive scientific fraud. I wonder what she’s up to these days.

  51. noblesse d’epee said

    I agree that Prof. Richard would be a good person to contact. Unfortunately, it is true that no Duke Biochem. professor seems willing to publicly demand, as a colleague ought, accountability from HH. Why are they so afraid of offending him? In contrast to most employees, tenured professors have extraordinary autonomy. However, the price of not having a “boss” is the expectation that these professionals will, in effect, informally regulate their colleagues. This just isn’t happening when it is needed most. Secure in their jobs and their status, Homme’s colleagues have a responsibility to demand, loudly and publicly if neccessary, that he explain himself in a satisfactory manner. If he can’t, they are morally obliged to request that he consider resigning from their company. Ideally, graduate students should have no role in this controversy, but if no one else will . . . .

  52. John Richard said

    noblesse d’epee

    I see you as a spectator, and don’t think that you would be happy with the result of sending your letter. I will not become directly involved in matters about which I know very little and I think you should be talking with someone at Duke. However, if there really is no one there you trust, then I am willing to discuss with you what I think your options might be.

  53. science_first said

    noblesse d’epee writes:

    “ I should note that this alleged (mis)behavior is not limited to the novo-TIM work.”

    There is no risk for you or your friends (and many benefits for those interested in the scientific implications of this scandal) in being explicit about what other results/publications we should double check. Let science speak for itself after that.

  54. In defense of reviewers said

    I don’t have any inside information, but it isn’t much of a leap to wonder about the following work which has the identical set of authors to those of the retracted Science paper:

    Dwyer MA, Looger LL, Hellinga HW., “Computational design of a Zn2+ receptor that controls bacterial gene expression.” (2003) PNAS, 100, 11255

    Looger LL, Dwyer MA, Smith JJ, Hellinga HW., “Computational design of receptor and sensor proteins with novel functions.” (2003) Nature, 423, 185

    The Nature paper really concerns me because it is more complex and much more difficult to verify than the enzyme design paper (thanks to Dr. Richard for taking care of that one).

  55. David said

    Another problematic paper that has been whispered about is:

    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):4955-60.
    Conversion of a maltose receptor into a zinc biosensor by computational design.
    Marvin JS, Hellinga HW.

    Another group published a follow-up:

    J Mol Biol. 2005 Dec 9;354(4):829-40. Epub 2005 Oct 28.
    Structural studies of an engineered zinc biosensor reveal an unanticipated mode of zinc binding. Telmer PG, Shilton BH.

    The Telmer and Shilton paper states that the goal of Hellinga’s work was to “produce an MBP molecule in which Zn2+ binding was accompanied by a conformational change from open to closed. Thus, two of the Zn2+-binding residues were introduced onto the N-terminal domain of MBP, and the other two on the C-terminal domain; in this way, full tetrahedral coordination of Zn2+ could only be achieved when the protein was in the closed conformation.”

    However Telmer and Shilton “were surprised to find that binding of Zn2+ to the engineered MBP molecule does not result in domain closure. Rather, Zn2+ is bound in an unexpected manner by residues on the N-terminal domain alone. Furthermore, the engineered metal coordination site can bind Cu2+ and Ni2+, although in a slightly different manner than Zn2+. The plasticity of the engineered Zn2+-binding site results in unexpected metal coordination that is accompanied by only a subtle conformational change from the fully open form of the protein.”

    Telmer and Shilton’s data proves that the assumptions and molecular modeling by Hellinga are probably not correct. It is not obvious how zinc-binding results in a fluorescence response without formation of a closed complex. At least the mutant MBP binds zinc, but no else has confirmed the zinc-dependent fluorescence change. In light of the retractions, someone really ought to check on this.

  56. Trevor said

    John Richard wrote:
    Courage can only be shown in situations where one’s actions carry an element of risk. Risks are weighed and one acts in one’s own best interests. The penalty for playing it safe is the knowledge that one has acted in a cowardly manner, and this is a penalty that some are reluctant to pay. A person comfortable with their cowardice might make the argument that there is “no upside in coming forward”, but most will understand this to be specious. The reward for “doing the right thing” is simply to have done what one thinks needs to be done.

    I do not consider this sordid occurrence to be a rare one. What is rare is the very public and vigorous effort being made to keep its full sordidness hidden. At present, I see no reason for Duke to fire Homme Hellinga.

    Dr. Richard, in principle I fully agree with you. I have the greatest admiration for the efforts you have made in this matter. However, I stand by my opinion that there is little or nothing for a graduate student to gain, and everything to lose, in speaking up in a Department where the faculty are apparently not willing to say anything. Should there be even just the one faculty member in that Department willing to stand up for what is right, then my opinion would be quite the opposite.

    I also disagree with you when you say such affairs are not rare. Yes, “data massaging” is unfortunately commonplace, but fabrication of data in a high-profile publication coupled with abuse of multiple students, such as has been alleged by some in this case? I truly doubt that. Note that I said “alleged” – I am not in a position to adequately judge either the science or the tales of abuse.

    I do agree with you that there is no reason for Duke to fire Hellinga at this point in time. Whether or not that is necessary can only be determined after a full and open investigation.

  57. John Richard said

    There are no good options for a student confronted by unethical behavior by his/her research adviser. My advice to someone in this situation would be simply to try and find a better position elsewhere. Now, if this situation is repeated over and over again in the same lab, then it is likely that some sort of breaking point will eventually be reached.

    I am under the impression that some of the contributors to this blog want very badly to tell their stories to someone. I expect that these people understand they are free to walk away and say nothing, but they still want to tell their stories. They stand to lose a lot by coming forward. On the other hand, in doing nothing they may become so embittered at their own weakness, and cynical about the way science is done as to have to find another career. It may be that they simply have no good options in struggling to find their way out of a bad situation. This is very depressing to think about.

    There is sordid, more sordid and most sordid. I know of many cases of academic misconduct that I would consider to be sordid. They are not rare. If this is something else entirely, then I expect that people will eventually come forward.

  58. ruggizzle said

    A friend of mine at Duke just told me about this ongoing story, and asked if I was interested in posting something here since unfortunately I’m somewhat qualified to comment on issues of alleged scientific misconduct.

    (whimple said,
    June 8, 2008 @ 5:33 pm
    “I wonder if there are going to be parallels in the Hellinga case to the fallout of the well-documented case of Steven Leadon down the road at UNC-CH a few years back. Beth Ruggiero, a graduate student in Leadon’s lab, spoke up and finally managed to bring an end to years of extensive scientific fraud. I wonder what she’s up to these days.” )

    Well, I’m actually the aforementioned former grad student. It’s weird to see my name here, since I tried to stay out of the spotlight but did agree to one interview once the frenzy had died down. But if putting my two-cents in helps out, or just adds to a worthwhile discussion, I’d be happy to share my experience. I had intended to read all the posts and a maybe a couple of the articles before commenting, but haven’t had a chance to get through them all. But already there are several things here that seem familiar to my experience, even though many of the details are different.

    It’s been several years since I came forward regarding my (former) PI’s misconduct. It was between my 5th and 6th year of grad school, and I had to start over in a new lab with a new project (yes, that totally sucked) but was able to finish about 2 1/2 years later (that didn’t suck as much). There’s a whole long, sad, infuriating story about all the fabricated data, what was being fabricated and how it was done, and how long it had been going on. You can Google my former PI (mentioned above). Most of the articles are accurate, although some of it is crap, especially most of the quotes from one very skilled liar.

    My decision to come forward was not made lightly and it took a very long time for me to decide what to do. There’s no way to know how things will turn out if you turn someone in, but for me it got to a point where I really had no other choice. The investigation dragged out for several years (long after I had completed my role as a witness) and there were many retracted papers, and probably millions of NIH dollars wasted on the primary research as well as the follow-up studies by other labs.

    I’ve read a lot of stories about whistleblowers, especially those in science, and it seems that their outcomes vary widely. Some of them didn’t turn out well at all and those students or postdocs involved have left science altogether. I guess things for me turned out fairly well, except for those years I lost in grad school. To be honest, part of what kept me motivated to finish my Ph.D. was the “screw you” factor (as in, “screw you, I got my Ph.D. anyway you big liar!” ).

    After finally getting my Ph.D., I did 3 years as a postdoc in the lab I had moved to. Now I’ve changed directions somewhat and am training to become board certified in medical genetics, learning how to make clinical diagnoses of patients with suspected inherited diseases. If I pass the boards I’ll become certified to run a diagnostic genetics lab. It’s probably not a coincidence that one of the things I really like about this area is that clinical labs are highly regulated and subject to random audits of all their records and laboratory procedures.

    Regarding misconductees (a.k.a. lying liars who lie):
    Unfortunately, the fact is liars can be found in every profession, even in science. “Career-liars” seem to share a lot in common in how well they lie, how they try to cover things up and defer the blame to others, how long they can go on lying before being found out, and how they’ll almost never admit they did anything wrong (so don’t hold your breath!). Please note that I’m not claiming to know if anyone in this current case is lying or not.

    If you’re curious about what happens to “known” misconductees:
    You can go to the Office of Research Integrity website and read the “Case Summaries.” (http://ori.dhhs.gov/misconduct/cases/). (ORI is a division of Health and Human Services, and HHS is in charge of NIH.) It can be infuriating to read about these people, but it’s also satisfying to see them busted and usually barred from NIH funding for some period of time. And they remain on the Federal Register forever! (not that most people check the federal register, but anyway… ) The ORI case summaries are pretty matter of fact and “sans drama” but you might Google the people mentioned to find out more.

    Someone asked why ORI hadn’t initiated an investigation into the Duke matter:
    Generally an institution conducts an investigation first, and if the institution receives PHS (NIH) funding, then once they’ve reached a conclusion in the investigation they’ll refer it to ORI for review. ORI then makes an independent finding and a decision on any disbarment from future NIH funding. Throughout the process there are multiple opportunities for the accused person to appeal any finding and then it has to be reviewed independently all over again. For various legal reasons, an institution is usually not allowed to comment on an ongoing investigation and/or whether they’ve referred it to ORI. Apparently a whistleblower can also report the misconduct directly to ORI, but I don’t think that happens very much. Either way, someone (a person or an institution) has to make an allegation to ORI before they can look into it.

    Regarding the possible outcomes for whistleblowers:
    There’s an interesting report from a study at Research Triangle Institute, posted on the ORI web site, on “Consequences of Whistleblowing for the Whistleblower in Misconduct in Science Cases”. Some of their findings may seem like common sense once you finish reading them, but there’s actually data to go along with it (ori.dhhs.gov/documents/consequences.pdf ). I’d recommend it to anyone who is considering blowing the whistle and wants some objective information on how things can turn out for whistleblowers.

    Well, this comment has become MUCH longer than I’d planned, so I’ll stop commenting for now… hope you find some of the info helpful.

  59. Trevor Creamer said

    John Richard wrote:
    I am under the impression that some of the contributors to this blog want very badly to tell their stories to someone. I expect that these people understand they are free to walk away and say nothing, but they still want to tell their stories. They stand to lose a lot by coming forward. On the other hand, in doing nothing they may become so embittered at their own weakness, and cynical about the way science is done as to have to find another career. It may be that they simply have no good options in struggling to find their way out of a bad situation. This is very depressing to think about.

    Indeed, it is clear some of the contributors to this blog do have stories to tell, need to tell them, and have already become embittered. Very depressing.

    Perhaps even more depressing is the extent to which the system is broken. Dr. Richard, when this story first broke a good friend emailed me excitedly about how “this is science working!” Yes, your contributions show how science should work, but this whole affair has demonstrated quite clearly that aspects of academic science are well and truly broken. The graduate students involved are caught in a situation with no good options. Hence our conflicting opinions (Trevor = Trevor Creamer).

    But you are right of course. We should all strive to do the right thing.

  60. Trevor Creamer said

    Ruggizzle, I’m glad to see myself proven wrong re the fate of whistleblowers. Good luck with the boards and may you have a long and fruitful career in medical genetics!

  61. whimple said

    Ruggizzle, fascinating account. Thanks so much for sharing your first-hand experiences with us. I know several PhD’s that have either finished or are partway through medical genetics training. This is a field with a very promising future and I wish you all the best.

  62. justaguy said

    Yes, the Telmer and Shildon JMB paper calls into question the interpretation by Marvin and Hellinga in PNAS, but there is no indication of fraud or even sloppiness. Shildon agrees that Hellinga’s conclusions — based on the data at hand — were quite reasonable.

    Any further papers to consider?

  63. scotus said

    Rugizzle-
    Kudos for your persistence. As Dr Richard put it, you should take pride in having done the right thing. I’m also pleased to hear that your career is progressing.

    N d’E-
    Allegations of misconduct by proxy are not really appropriate. As I’ve noted elsewhere, I cannot imagine that Duke is as rotten as some of the posters here seem to think. Duke is clearly aware of the unresolved issues from the Science paper (inadequacy of the retraction, incongruous kinetic parameters for the engineered enzymes and the implausible complementation experiments). I suggest waiting to see how this all plays out. There is no statute of limitations on research misconduct.

    Quick question. Lets accept that your observations of widespread Hellinga misconduct are genuine. Surely Hellinga’s students have dissertation research committees that can at least police his activities to some extent. What’s going on here? Does he just load up these committees with colleagues that won’t challenge his behavior? Perhaps Dr Mcdonnell needs to be on every Hellinga graduate student committee from now on?

    John Richard-
    Could you provide some insight into how the Science retraction was handled? Did you consider asking them to publish your data as a “technical comment” which presumably would have been reviewed and could have then required Hellinga to provide a more complete response to some of the more disturbing aspects of the Dwyer paper. Who required Hellinga to provide any explanation for the retraction at all?

  64. In defense of reviewers said

    justaguy writes “Shildon agrees that Hellinga’s conclusions — based on the data at hand — were quite reasonable.”

    Based on the data at the time the enzyme design paper’s conclusions were quite reasonable. The question about many of Hellinga’s papers is could the “data at hand” be flawed as it was in that paper. The two papers that I pointed out earlier in the comments are obvious ones to be suspicious of.

  65. Trevor Creamer said

    A couple of people here have mentioned Hellinga publications that may or may not be suspect. I’m certainly not leaping to Hellinga’s defense here, but I will say I do not think this forum should be used to try to divine which publications might contain fabricated data. Or to hold some kind of de facto trial. We have all been frustrated by Duke’s apparent unwillingness to hold an investigation. However, as Ruggizzle has recently pointed out, any university embarking upon such an investigation is likely to keep very quiet about it. In an earlier post I had bemoaned the “fact” that Duke wasn’t doing anything. That was a lack of thought on my part. Simply put, we don’t actually know for a fact that Duke is not investigating Hellinga. Despite Dr. Richard’s data and all the subsequent speculation, we also don’t know for a fact that Hellinga did fabricate or cherry-pick data. The only thing that is clear is that he has acted abominably towards Mary Dwyer (at least according to the Nature report) and perhaps to other members of his laboratory.

    I have stated that I believe that academic science is in part broken. I do believe that. I also believe that we need to allow other parts of the system a chance to prove they are not broken.

  66. noblesse d’epee said

    Scotus said:

    “Surely Hellinga’s students have dissertation research committees that can at least police his activities to some extent. What’s going on here? Does he just load up these committees with colleagues that won’t challenge his behavior?”

    Often, these committees don’t have membership whose expertise extends to key types of experimental work undertaken in a project. For instance, a committee heavy on bioinformaticists is rarely in a position to look critically at data arising from enzymological experiments. I do know that in the case of one Hellinga graduate student, a faculty member with a specific experimental expertise strongly suggested the completion of essential controls, and saw his/her input dismissed by Hellinga. The issue was never pursued, as the expert professor was not in a political position to insist that his/her concerns be acted upon. The outcome has been regrettable.

  67. ruggizzle said

    Quoting Scotus,
    “N d’E-
    Allegations of misconduct by proxy are not really appropriate.”

    I completely agree that there’s no point in making an accusation you can’t back up with proof. This can be very frustrating for people who really believe there’s something fishy going on but don’t have proof. Still, the bottom line is that you either MUST either have tangible proof or be a direct witness (and preferably have other witnesses to back you up) to the misconduct. The best situation is to have tangible proof AND multiple witnesses. Remember, too, that just because someone is a complete asshole doesn’t mean they are lying, and just because someone seems like a great person and everyone likes him and you get along well with him it doesn’t mean he’s not a pathological liar. Again, I’m not referring to anyone in particular, just something to keep in mind.

    Even if know in your heart of hearts that someone is doing something wrong, without hard evidence there’s no point in making any formal claims of misconduct. Nothing is likely to come of it, and it may just end up reflecting badly on you because it will seem that you don’t comprehend or respect the process that requires tangible evidence.

    Liars suck! That’s just a fact of life. But it’s better to wait for someone who has direct proof, and if you personally know anyone who does have proof, please encourage them to consider coming forward in whatever manner they feel comfortable with. If they’re just not ready or too scared or whatever, I guarantee you will be unsuccessful in trying to force them into blowing the whistle. Perhaps you can try gently steering them in that direction, but ultimately it’s a very personal decision. Either way, be as supportive as you can – it is quite a traumatic experience to see this stuff going on first hand, and especially to become a whistleblower.

    P.S. Ditto on the comment that this site needs an Edit option!! I inadvertently had several smiley faces on my last post :( (that’s an intentional frowny face)

  68. noblesse d’epee said

    IDoR,, scotus, Trevor, whimple, John Richard, ruggizzle, et al.,

    Thanks for your input, and for the time that you have spent in its thoughtful composition. I’ve concluded that the direct witnesses of Hellinga’s misconduct will have to come forward on their own accord — I’ve done everything that I can to convince them to do so. But, as Prof. Richard so nicely states, “a person comfortable with their cowardice might make the argument that there is ‘no upside in coming forward.’”

    I should point out that there are a few Hellinga papers about which I am deeply suspicious, but my mention of these papers may cause the readers of this blog to speculate regarding the identity of my “primary sources.” I will leave it to former members of the Hellinga lab to speak about their scientific misgivings. You should trust, however, that my concerns as an imformed “bystander,” are not fabricated, not exaggerated.

    Will Duke make a good-faith effort to investigate Hellinga? I doubt it. I’ve directly observed plenty of evidence that DUMC is unethical to its core. Perhaps all “teaching” med. centers are. If I do post-doctoral work, it will be in an Arts and Sciences program. There are just too many conflicts of interest in medical center settings. The cost of these conflicts tends to be the well-being, both personal and academic, of the graduate students and post-docs upon whose labors these medical centers build their research reputations.

    Mary Dwyer will never really find justice, nor will the many others who Homme Hellinga (and others like him) have buried, screwed over, driven from the science they once loved.

  69. John Richard said

    Scotus -

    Science sets a time limit after the initial publication date for submission of Technical Comments – perhaps six months. In any case, technical would not have been the appropriate word for my comments. None of Hellinga’s mutations introduced any TIM activity into ribose binding protein. All of the experiments designed to demonstrate a viable design strategy, or that wildtype and novo-TIM were different proteins were wrong for reasons known only to Homme Hellinga and Mary Dwyer.

    After having convinced ourselves that the protein we expressed had no TIM activity, we decided to sequence the plasmid Hellinga sent us, only to find that it coded for a protein that had a sequence different from NovoTIM. At that point we decided to cut our losses and write Hellinga.

    I am unhappy about the way Science handled the retraction, but am too tired to write a narrative account. The initial publication of the retraction was delayed for perhaps two months while the coauthors worked to find wording that they all could agree upon. I asked to see an advance copy of the retraction, but Science never responded. I sent my letter to Science a couple of days after publication of the retraction, but only learned from Jack Kirsch that the letter had been published electronically many weeks later. Oh well.

  70. scotus said

    John-
    The revelation that Hellinga sent you plasmids that didn’t encode the actual Novo-TIM proteins described in the paper is frankly mind-boggling. Since you weren’t able to observe any activity I suppose we can rule out the obvious possibility that this was an attempt by Hellinga et al to “cover their tracks” by sending you plasmids that might encode, for example, catalytically crippled variants of wild type TIM. Do we even know that the Novo-TIM constructs described in the paper actually exist?

    To the disillusioned young people posting here-
    Have any of you read Allegra Goodman’s book “Intuition”. It’s not a great (or factually correct) account of the trajectory of a research misconduct investigation but what it does do well is to capture the sense of bitterness and resentment that “underlings” can feel when working for a “successful” investigator. A month or so ago after something disappointing happened, my wife said to me something to the effect that “we got into science because we loved the sense of purpose that working carefully on important problems provides but she wished someone had told her that research is actually an advertising and public relations job”. I thought about this some and realized that I used to feel like she does but part of my own “growing up” is that I now understand that science isn’t all about high profile publications, NIH directors awards and prizes at all. The reality is that a lot of what we do is about frustration, disappointments, difficulties and imperfection. A lot of the time it’s like climbing a big ladder only to find you put the ladder up against the wrong wall. At the same time, if you work carefully and critically, doing things the right way as Dr Richard put it becomes its own reward. If you keep your eyes open and, yes, have a little luck, you’ll get to see and find out things that nobody knew before you. You can make an everlasting contribution to the body of human knowledge. You can make some of the best friends you’ll have in your life and eventually you can pass along your skills and knowhow to the next generation of scientists. And that’s pretty cool.

  71. whimple said

    The revelation that Hellinga sent you plasmids that didn’t encode the actual Novo-TIM proteins described in the paper is frankly mind-boggling.

    Not really; this kind of thing happens innocently all the time. I have found it easily worthwhile to have the inserts of all plasmids we receive from other labs sequenced at the time of arrival, regardless of how trusted the source of the plasmid is. Trust me on this, it’s worth doing this.

  72. Trevor Creamer said

    Whimple wrote:
    Not really; this kind of thing happens innocently all the time. I have found it easily worthwhile to have the inserts of all plasmids we receive from other labs sequenced at the time of arrival, regardless of how trusted the source of the plasmid is. Trust me on this, it’s worth doing this.

    I would second that. We recently received a plasmid for a heterodimeric protein. Upon sequencing we found the two encoded subunits were from different isoforms! I’m not sure how that happened, but sequencing certainly saved us a lot of time and money.

  73. scotus said

    Yes, its easy to screw up and send people the wrong things although one might expect that a lab like Hellingas that must make a lot of constructs and has a lot of resources would have a pretty foolproof inventory system in place to avoid this from happening. All you need is a freezer, some boxes, some software and someone with basic attention to detail to curate everything.

    Its pretty clear from the sequence of events that led Dr Richard to get his hands on the Novo TIM plasmids that, for reasons that are now obvious, Hellinga appeared resistant to providing them in the first place. Given the scrutiny that he must have known was going to be applied to these reagents it still seems mind boggling to me that Hellinga didn’t take extra care to make sure that the correct constructs were provided.

    Having said that, last week we sequenced an expression construct provided by a collaborator and found that it was not only made using a different splice variant of the relevant gene but also in a different variety of the vector he thought it was in….However in this case the construct worked as advertised and a re-examination of the provider’s lab records essentially ratified our findings.

  74. In defense of reviewers said

    “she wished someone had told her that research is actually an advertising and public relations job”

    I find it amusing that so many scientists neglect to realize this is a big part of the job. I guess we start from this belief that we throw an idea out into the system and it rattles around with other ideas and the best one wins. But of course that’s hardly the case – even the best ideas need to be properly “sold” (presented in well-written papers, clear talks, etc.). While it’s offensive to see a sales job when there’s no meat to back it up, we have to realize that a big part of an effective scientist’s role is a cheerleader for the models that they’ve constructed based on their observations. Failing to do this can make all your hard work end up in the dust-bin of science.

  75. John Richard said

    All

    We were/are novices at protein expression, and did not think to sequence these plasmids. It is an inexpensive precaution, but in this case probably would not have saved us any time. When I received the plasmid for E Coli NovoTIM I imagined that it held a position of honor in the Hellinga lab as the point of departure for the design of even better catalysts. I have since learned that Hellinga was telling people that EColi Novo TIM was thermally unstable (Figure 4A of the Science paper). Hence the application of his design strategy to produce a second NovoTIM from a RBP present in a thermostable bacteria. This led to a second publication and retraction. Note that wildtype TIM is a robust enzyme.

  76. anom_01 said

    John Richard wrote:
    “After having convinced ourselves that the protein we expressed had no TIM activity, we decided to sequence the plasmid Hellinga sent us, only to find that it coded for a protein that had a sequence different from NovoTIM. At that point we decided to cut our losses and write Hellinga.”

    Now things are even less clear to me. Were the differences in sequence minor (like a couple of nucleotide changes), or very significant (i.e. changing the protein sequence in ligand binding or active site)? Was the version you received and tested the same one used in the published experiments, i.e. the published Novo TIM sequence was never tested in reality? Did you inform HH about the different sequence in the same e-mail exchange that was sent to Science and JMB?

  77. George Smiley said

    I’ll add to the sentiment that sequencing is worthwhile for nearly any plasmid that comes into your lab. Sequencing is cheap.; in many cases cheaper than even a simple restriction mapping verification. Time lost is never cheap…

  78. John Richard said

    For the record, here is the relevant except from my letter to Homme Hellinga, copied to Science and JMB.

    “We also sequenced the plasmids that you sent us. We found that the plasmid for ecNovoTIM1.2 codes for a protein with a single amino acid change from the published sequence, namely a change from the published aspartate at position 89 to an alanine. For tteNovoTIM1.2, the plasmid codes for a protein with the same change from the published aspartate to alanine at position 89, along with two other changes. I have attached our translated sequences. The molecular weight of our purified tteNovoTIM1.2 obtained from electrospray TOF MS analysis is in agreement with that calculated expected for the protein sequence obtained from our DNA sequencing data.”

    Along with the reply from Homme Hellinga, copied to Science and JMB.

    “In regards to your plasmid sequence, we sent you ecNovoTIM1.2’ and tteNovoTIM1.2’ instead of the 1.2 versions. We will send you the correct plasmids (Asp89).”

    Readers of this blog are welcome to refer to the original Science paper in trying to decide if these changes might have been important. We never received the correct plasmids, and early last fall rather foolishly made the Asp for Ala substitution to reverse-engineer ecNovoTIM1.2. It was inactive.

    Sorry about the brief appearance of an inappropriate link to Dr. Richard’s letter addressed to the editors of Science, versus his letter to Hellinga (copied to Science but not published) from which he quotes above … and from which he would be most welcome to quote additional material here. A great deal more is being learned through this exchange than simply Hellinga’s bad behavior. Thanks to David for pointing out the erroneous link. – writedit

  79. whimple said

    If I read the retracted Science paper correctly, Ala89 is the Ntim1.1 construct, listed as having ‘+++’ activity, and Asp89 is the Ntim1.2 construct, listed as having ‘++++’ activity.

    John, did you find that any of the NovoTims you expressed were able to bind either dihydroxyacetone phosphate (DHAP) or glyceraldehyde 3-phosphate (GAP) with any appreciable affinity?

  80. anom_01 said

    To Dr. Richard:

    Thanks for the clarification, however I don’t think it was foolish to make the Asp for Ala substitution; despite the contamination issue, it would have been possible that that mutation was crucial for NTim 1.2 to show *some* level of activity. Thanks to your work we can rule out that possibility.

    To whimple:
    I don’t think the version that Dr. Richard received was Ntim1.1, notice that despite the change in position 89 (relative to Ntim1.2) there are other substitutions in positions 192, 215 and 235. If I understand Dr. Richard explanation correctly, the only difference between the Ntim1.2prime he was sent and the supposely optimum version Ntim1.2 was in position 89. I could not find any reference to Ntim1.2prime in the Science article (including the Supporting Online Material).

  81. John Richard said

    Wimple and anom_01

    Once I thought there might be a problem, I wanted to expend minimal resources seeing that it was corrected. Therefore, I did not check if the expressed proteins bound either dihydroxyacetone phosphate or glyceraldehyde 3-phosphate. It was pretty clear from the purification Scheme used that the activity observed for all of the constructs was for wildtype TIM, but we chose to be cautious and prepare Novo-TIM 1.2. This turned out not to be an issue.

    I also have not been able to find any mention of ecNovoTIM1.2’ and tteNovoTIM1.2’ in the literature.

  82. David said

    If anyone would like to hear the lecture with slides of Dr. Hellinga talking about NovoTIM (among other topics), it is available online here:

    http://tinyurl.com/4lxyk6

    It seems to be from a lecture from the New York Academy of Sciences. It is good to hear/watch it in retrospect.

    Dave

  83. In defense of reviewers said

    One thing that bugged me from the C&E News piece:

    Hellinga tells C&EN that he decided not to address such questions because he believes the fact that the designed enzyme ultimately didn’t show TIM activity made many other points moot. “I didn’t see a reason to go into the design methodology because the experiment clearly didn’t work,” he says. “By inference, obviously the design was wrong.”

    Hellinga’s completely wrong here. Just because this particular experiment didn’t work doesn’t prove the design methodology is incorrect. In fact, any engineer would tell you that you can often learn more from the failures than the successes. At the very least, wouldn’t Hellinga want to know how this happened so that he could prevent it from reoccurring?

  84. In the Know said

    IDoR,

    I think his statement was misleading. Nobody was questioning the design methodology, they are questioning the experimental methodology.

    If all of this was one big honest mistake, a “We did all the right things and came up with the wrong answer” type of deal, then you’re right. Anybody would want to inspect the process and figure out where it failed. Of course here I think everybody is in agreement that this wasn’t an honest mistake and somebody had to have manipulated the controls or cherry-picked the data shown to get the results that were reported.

    In terms of the actual protein design process, if would be no surprise at all that one of the predicted proteins was inactive. Homme has a robotic cloning system in the lab to help them generate the huge number of predicted sequences. They then test them for expression & solubility and screen the pack for ones that show activity. As far as I know, the vast majority of the engineered proteins are duds. (The Nature article says that 2/25 were active in this case, which according the the Hellinga-ites that I’ve heard crying into their beer would be a exceptional batting average.) Often, the ones that show hope are then itteratively mutated to try to make them better. In a similar thought to yours, I’ve often felt that solving the structures of the produced proteins (dead or alive) would allow you to refine the program and make it better. Some people in the lab have gotten so frustrated with the process that they designed proteins by eye, and they claim they had a better batting average than DESIGNMER. In the literature, however, they are all reported to be designed using the program. (At least one paper has yet to be published because a reviewer raised concerns that DESIGNMER did not predict the protein that was reported in the manuscript.)

    Knowing this process, though, leaves me with questions about this case. If all they were studying was wtTIM contaminant, then why didn’t this show up in the screening process? In other words, why weren’t all the designs tested active? Perhaps they actually engineered a protein that tended to pull down wtTIM (albeit weekly, since Dr. Richard’s removed the contaminant easily). Alternatively, if the ‘active’ constructs could have expressed relatively poorly, leaving some extra space on the IMAC column for the wtTIM to stick to, while ‘inactive’ constructs expressed well and out-competed wtTIM for all of the available binding sites on the column… We may never know.

  85. austen said

    What else is wrong in science?

    The 100% anonymous user provided news source for what’s Broken in Science.

    http://brokenscience.com

  86. On Jun 9 “David said” wrote:
    “Telmer and Shilton’s data proves that the assumptions and molecular modeling by Hellinga are probably not correct. It is not obvious how zinc-binding results in a fluorescence response without formation of a closed complex. At least the mutant MBP binds zinc, but no else has confirmed the zinc-dependent fluorescence change. In light of the retractions, someone really ought to check on this.”

    There has been an attempt to reproduce this. It is described in a poster published on the internet from a group at Imperial College. Unfortunately it’s not clear if this was ever published elsewhere in any peer-reviewed forum:

    http://tinyurl.com/5yegrd

    The Imperial group showed a 15% increase in fluorescence using the same dye (IANBD) and cysteine location (D95C) on MBP together with the same putative zinc binding mutations. This is nowhere near the 3.3 fold or 4.4 fold intensity increases displayed for the IANBD-labeled D95C MBP upon its binding to maltose (see Hellinga’s ’01 and ’97 PNAS papers respectively). And the 17.7 fold increase the ’01 Hellinga paper reports for the closely related “A2B1″ mutant is substantially more than this. Telmer and Shilton never actually repeated the IANBD labeling experiment but they did report negligible intrinsic tryptophan fluorescence changes upon zinc binding.

    In the ’01 Hellinga paper the 17.7 fold fluorescence spectra are never shown as such. All fluorescence data in this paper are instead depicted as “fractional saturation”. There is a huge difference betweeen 15% and 17.7 fold fluorescence increases but this depiction would mask that. At the least, a 15% change would leave uncertainty regarding the actual mechanism and whether this spectrum it was actually due to the closed complex when compared to the maltose data.

  87. [...] course, the lively discussion of the Hellinga retraction is just that – a discussion of the retraction and the science involved, though I suspect we will [...]

  88. writedit said

    I was sent a petition that was circulated among all graduate students in the Department of Biochemistry at the Duke University School of Medicine and signed by nearly half of them representing about a dozen labs. Notarized copies of the signed petition have been delivered to the Interim Chair of Biochemistry and the Dean of the School of Medicine, among others (see list in petition itself – please note, student names and signatures are NOT included).

    As you will see, the petition asks “that Duke University determine whether Professor Homme W. Hellinga:

    1. Published Dr. Mary Dwyer’s data, despite her objections, with the effect of “manipulating research procedures and data so as to bias results”

    2. Pursued “baseless and malicious, or reckless” research misconduct charges against Dr. Dwyer”

    Hats off to these students and the stand they have taken here.

  89. whimple said

    Did any professors of Biochemistry at Duke sign the petition?

    That I don’t know: I did not receive any of the names/signatures involved. If someone lets me know off-line, I can post whether faculty lent their support as well. It sounds like a student-led initiative, which is quite gutsy since I suspect many must have Hellinga or his wife on their committees. On the other hand, the students are also the ones who will pay the greatest price if Duke does not act, so have significant motivation for making their collective voice heard (faculty should be quite concerned about the potential misconduct, of course, but do not have to interact with the parties under discussion in order to secure their degrees … and such turning a blind eye seems more common than we all thought per the ORI report).

  90. noblesse d'epee said

    I am told that the signers totaled 18, of which 17 are current Duke Biochem. students (mostly senior, e.g. Ph.D. candidates) and one recent alumnus. My understanding is that current students (as opposed to alumni) were sought by the petition’s authors because:

    1. There arose logistical inpracticalities in the gathering of alumni signatures
    2. Graduate students theoretically had the most to lose by signing, thus their position carried more significance that that of alumni

    It is important to mention that this was a completely student-led effort. Professors were not asked to sign the petition, nor was it circulated among them. The signers of the petition did NOT sign as proxies for their laboratories or PI’s.

    I am told that the petition was written and distributed without the knowledge of Mary Dwyer. It seems that scrupulous efforts were made by the signers to avoid Dwyer while the petition was circulating.

    There are ~55 students currently in the Duke Biochem. Dept. If one subtracts the Hellinga graduate students, Hellinga’s wife Lorena Beese’s students, and students who have either of those professors on their thesis committees, ~45 eligible students remain. So 18 represents close to 1/3 of the eligible population. I am told that few students without Ph.D. candidacy signed the petition. If one substracts students who have not taken their candidacy exams from the pool of eligible signers, the petiton represents ~1/2 of the remaining students.

    In my opinion, a majority “vote” of students was in no way required to add legitimacy to the petition. That 18 current students were willing to sign was unexpected, and was an indication of the bravery and ethical conviction of our program’s student community.

    A final note: I did not provide WriteEdit with a copy of the petition, although I am not unhappy to see it published on this blog.

    I will confirm that noblesse d’epee did not send me the petition, but I appreciate these additional details. Again, I am so very impressed with these students and their decision to act on their convictions. One would hope the faculty will independently register their concern with the administration in solidarity with the students. – writedit

  91. scotus said

    In essense, this is an allegation of research misconduct against Hellinga. Unfortunately its an allegation “by proxy” because none of the petitioners have first hand knowledge of of the “facts” of the Dwyer-Hellinga interactions that led to Hellinga’s alleged misconduct. On the other hand, the very unique public nature of this affair demands that Duke address what the petitioners note as the concerns of eminent biochemists “that the Hellinga-Dwyer retractions are insufficient to explain the manner in which Hellinga and Dwyer arrived at their erroneous conclusions”. As I have said before, if Duke are not already conducting an investigation into the “insufficiency” of Hellinga’s explanation then this petition ought to prompt them to do so. If they are already investigating the issue then I hope Duke’s response to the petition will be to make the existence of this investigation public despite what I am certain will be very strong opposition from Hellinga and his counsel.

  92. noblesse d'epee said

    Scotus,

    Thanks for your insights and commentary. At this point, given the obvious gaps in Homme’s scientific explanations coupled and the ethical issues raised in the published analyses of this scandal, I think that it is perfectly reasonable for students other than Dwyer to request a misconduct investigation. In fact, considering the faculty’s apparent inaction, doing so is arguably students’ obligation to their (former) peer, to their graduate program, and to their field. Neither Hellinga, nor Dwyer, nor Duke Biochem. benefit from leaving this issue unresolved.

  93. George Smiley said

    Noblesse, I respectfully disagree. Depending on what actually occurred here, one or more of the parties you mention may benefit quite substantially by leaving this matter unresolved. Kudos to the students at Duke for pursuing this. I sure would not want to be the acting Chair at this moment, though.

  94. scotus said

    The only individuals who would “benefit” from making the matter go away would be those who may have done something that could be exposed by an investigation.

    My understanding of the “case” so far is that Hellinga made an allegation of misconduct against Dwyer pertaining specifically to the Novo-TIM expression/purification/kinetics experiments and that this allegation was not sustained by the initial investigation. However, we don’t know the details of why the allegation was not sustained and can only infer that Dwyer was not found to have done anything that was grounds for a formal investigation.

    As I understand the process, as a condition of their acceptance of federal funding Duke would be compelled to investigate any reasonable and credible allegation of research misconduct made against any of their employees. I would think that the very public statments documenting the insufficiency of the Hellinga-Dwyer retractions would constitute grounds for another initial investigation focussing on issues that were apparently unresolved or un touched upon by the original investigation of Dwyer.

    Duke are now in a bit of a bind. On the one hand, an investigation of Hellinga seems inevitable if not already ongoing. On the other hand as I have said repeatedly, Hellinga is probably entitled (as was Dwyer) to have the intial investigation treated confidentially. Unfortunately by not commenting on the matter Duke are creating the perception that nothing is being done.

    The petition is not dated? When was it submitted? My best guess is that Duke will respond in a week or so with some more lukeward assurances that they are aware of these concerns but will not comment further on the matter to preserve the confidentiality of everyone involved.

    Has this matter been picked up on by the local press? The more widely-known it becomes, the harder it will be for Duke to sweep it under the table.

    The dating would be done on the signature pages and via the notary. I believe the petition had just recently been submitted when I posted it. Local press coverage wouldn’t be as meaningful as national media or academic publications such as The Chronicle of Higher Education. On the other hand, local coverage could lead to the story getting picked up nationally. Still, it’s a tough story to sell in an elevator speech, especially for a lay audience, unless you focus on behavior rather than science. – writedit

  95. scotus said

    Writedit-
    The RDU population is pretty savvy when it comes to matters relating to higher education and research. Besides, this story has a lot going for it..money, fame, abuse of power, intrigue, scandal and an opportunity to put the boot into Duke University which is generally not well-liked by the locals (as established by the intial phases of the Lacrosse Case). You’re right, the science could be a bit dry but at the core this is a morality tale. I bet a good journalist could write a story that would capture the interest of the readership of the local press.

  96. noblesse d'epee said

    The notarized page was dated yesterday, 2nd July. The signatures were gathered in the preceding week. I am told that the petition was delivered to the last of its recipients’ offices by mid-day today.

  97. Zero Lime Guts said

    noblesse d’epee –

    I would like to congratulate you on your tenacity and ability to hold true to that which you believe in. Clearly it is no small feat to challenge a professor in the very department you are in, with obvious potential risk to yourself in some form. It is never easy for an ‘inferior’ to speak out against a ‘superior’ for fear of reprisals. You have drafted and disseminated your petition with bravery, and I feel you should be commended for your actions. Indeed, I believe that there is not a student, staff, or faculty member in our Biochemistry Department that did not get a forward of your petition!

    Sadly, I believe it is unfair of your student colleagues to simply dismiss your efforts and label you as “Petition Boy”; I feel that very few of them have the conviction to their beliefs as you do, and I certainly hope that you pay them no heed. I have no doubt that at some time in your graduate career you will make a contribution to the scientific community that your peers will remember you for in lieu of your petition.

    I’m just not sure _why_ you did it, though. Hellinga petitioned the Dean of the Medical Center last month for an investigation onto himself, and was granted the investigation, so the collection of student signatures to accomplish the same task is/was moot. I’m not sure what is to be served by petitioning the administration to start an investigation that it has already started? Perhaps the signers of the petition just want to formally be recognized in public? I speculate; I do not see the logic here. I am curious about why you pursued this redundancy?

  98. noblesse d’epee said

    Zero Lime Guts,

    Thanks for your comments. The petition was made because a number of us saw no evidence that Duke was pursuing an investigation of Hellinga; we thought that our program might benefit from “balancing the investigative equation.” Prof. Hellinga certainly told few people that he had asked for an investigation of himself. I have heard nothing of it until your post. To the knowledge of the petition’s signers, no “redundancy” was pursued.

    If Hellinga asked to be investigated, one may imagine that the scope of such an inquiry is limited by the wording of his request. The students’ petition may still be germane because it formally poses specific questions, ones that may or may not be covered by Hellinga’s putative letter to the Dean.

    On a different subject, I thank you for opining:

    >I have no doubt that at some time in your graduate career you will make a >contribution to the scientific community that your peers will remember you for >in lieu of your petition

    The student petition was, for those of us involved, a temporary endeavor pursued amid the usual research efforts. I don’t care if a subset of my colleagues label me “petition boy,” because all of them know that I work as diligently as any other student in our program on a risky and difficult project. If I want to be involved in an ethical cause on the side, how can they fault me?

    In my case, it did not take much bravery to subscribe to the student petition against my “superior,” Prof. Hellinga. If someone denies me a position in the future because they value Hellinga’s opinion (or that of some of his colleagues), such a person is an employer for whom I would rather not work. Besides, such is my disgust with academia that I have no intention seeking a long-term career in it.

    My academia-bound colleagues who took the risk of signing our petition demonstrated considerably more bravery than I.

  99. David said

    For those interested in seeing Dr. Hellinga at his peak in popularity, here is a television commercial touting the excellence of Duke in which Dr. Hellinga is featured.

  100. George Smiley said

    Correspondence from Hellinga appears in the new issue of Nature:

    Nature 454, 397 (24 July 2008 ) | doi:10.1038/454397b

    Sir

    Your Editorial ‘Negative results’ (Nature 453, 258; 2008 ) and News Feature ‘Designer debacle’ (Nature 453, 275–278; 2008), on the retraction of two papers from my laboratory and the events surrounding those retractions, have provided opportunity for misunderstanding and misinterpretation.

    Regrettably, as with all human endeavours, mistakes can occur in scientific research. When a mistake is made, it should be admitted through retraction of the published paper. Such retractions should then lead to a process of impartial scientific enquiry and analysis, as well as introspection by the participants.

    I have acknowledged, and will continue to acknowledge, my personal responsibility to the scientific community for these errors as well as my responsibility as a research supervisor to my students.

    As my actions have been called into question, I have asked the Duke University Medical Center administration to hold a formal and impartial inquiry into these retractions and the events that have followed. My request has been granted by the university.

  101. noblesse d'epee said

    May Duke University find the courage to make a full and honest investigation of the “events surrounding” Hellinga’s retractions. As I mentioned earlier, I hope that an investigation addresses, along with whatever “inquiry” Hellinga actually requested, the specific questions posed by the Duke Biochem. students’ petition.

  102. In defense of reviewers said

    “Regrettably, as with all human endeavours, mistakes can occur in scientific research. When a mistake is made, it should be admitted through retraction of the published paper. Such retractions should then lead to a process of impartial scientific enquiry and analysis, as well as introspection by the participants.”

    It’s funny that Hellinga should write that now, because it’s not the tune he was singing earlier (according to what he was quoted saying in the earlier Nature news article).

  103. [...] They conclude that “Overall, the punishments we observed were related to the crimes: Acts of falsification and fabrication were punished more harshly than were acts of plagiarism.” I suspect a large body of interested individuals are watching to see if this eventually holds true for the recent unpleasantness in North Carolina. [...]

  104. not me you don't said

    There are several things going on in this situatioN:

    One has to wonder if they sent the correct construct to Dr. Richard. This lab was notorious for designing hundreds of constructs, and prior to the addition of a ‘core’ group of analysts there wasn’t much in the way of organization.

    I worked with this novoTIM design in the Hellinga lab and could never get any activity. I used a modified step method, instead of using the 100mM, 500mM and 1M or whatever, I used more concentrations and collected more fractions. I got less TIM activity than with the negative control…I always felt that something was fishy, but of course I was ‘incompetent’, whereas Dwyer could come in and make it work with her magic wand.

  105. George Smiley said

    It’s *not* like this is a new concept:

    Don’t waste clean thinking on a dirty enzyme.

    Duh.

  106. writedit said

    You know, I’m thinking Hellinga and Taleyarkhan (misconduct at Purdue with regard to bubble fusion experiments) could start a club of sorts. They seem like compatible chaps in terms of personality and ethics.

  107. [...] with the Hellinga case again serving as a poster child for this and other reform to provide better institutional oversight [...]

  108. writedit said

    Nature reports on another high-profile retraction involving a well known researcher and her graduate student:

    The University of Minnesota has asked the journal Blood to retract a high-profile paper on adult stem cells following a university investigation. The paper reported that mesenchymal stem cells isolated from adult bone marrow could generate a surprising number of tissues (M. Reyes et al. Blood 98, 2615–2625; 2001), but other labs had trouble replicating that work. The investigation concluded that the paper included manipulated images.

    Lead author Catherine Verfaillie, now director of the Stem Cell Institute at the Catholic University of Leuven in Belgium, was cleared of academic misconduct but blamed for insufficient oversight. That suggests the blame rests with the only other scientist under investigation, Verfaillie’s graduate student Morayma Reyes, now at the University of Washington. However, the findings regarding Reyes cannot be released because of privacy laws. Reyes says that she made “honest unintentional errors”.

    Problematic images were also identified in a patent and in articles published by the Journal of Clinical Investigation and Nature. But the university did not find sufficient evidence of misconduct in these incidents.

    The University of Washington says it may decide to investigate Reyes.

  109. writedit said

    Nothing new on the Duke misconduct investigation in response to the graduate student petition (rather than Hellinga’s personal request), but in examining Pioneer awardees recently, I noted that Hellinga’s DP1 ends in July 2009 … and that he has no other NIH funding since his NIGMS R01 has not been renewed (ended May 2008). A Pioneer with no NIH funding? He would not be alone but would be in a distinct minority.

  110. George Smiley said

    CRISP is your friend. It’s not Homme’s friend, though…

  111. noblesse d'epee said

    I was watching a Martin Luther King speech, and found a phrase rather appropriate for Homme:

    “. . . the arc of the moral universe is long, but it bends toward justice.”

    At least the students of Duke Biochemistry (and a small subset of our faculty), were, one might say, ahead of the curve on this.

  112. noblesse d'epee said

    Shockingly, Duke Biochemistry is allowing Hellinga to interview recruits to our program. This is outrageous. Is the faculty collectively this tone-deaf and/or insane?

    One recruit, while meeting with Hellinga, flatly refused to believe whatever fraud de jour he was selling, and told him so! That young lady is more brave than the entire tenured faculty of our department. I hope that she finds somewhere better to study than Duke.

    Wow, this is shocking, though I guess with no official finding yet, they have no legitimate reason not to involve a tenured professor. One hopes all the potential students will be as astute as the young lady you mention above … and that any who do consider a place in the Hellinga lab heed the advice of those in and outside the Dept. Perhaps discreetly passing along the student petition, the items in Nature et al., and links to blog discussions such as these would not be amiss. – writedit

  113. foo said

    I have it from a reputable source that the other major triumph of the Hellinga lab, the PBP that bound TNT, lactate, seretonin, etc. cannot be replicated. It makes me sad.

  114. anom_01 said

    foo said:
    “I have it from a reputable source that the other major triumph of the Hellinga lab, the PBP that bound TNT, lactate, seretonin, etc. cannot be replicated. It makes me sad.”

    cannot be replicated by the Hellinga’s group or other group????

  115. noblesse d'epee said

    It figures. Like I said a year ago, Homme’s “colleagues” at Duke ought to get off of their asses and confront him. This has gone on long enough. It is making our graduate program into the laughingstock of its field.

    I also note that the graduate student petition re. Hellinga has gone completely unanswered.

    • writedit said

      Damn, really sorry to hear this. I thought the University had begun an investigation in response t this petition versus Hellinga’s request for a “show” (sham) inquiry. These things take a long time and are conducted confidentially, but the University should be willing to confirm they have taken the petition seriously and are still on the case.

  116. scotus said

    It’s interesting that the PBP paper also involves Drs Looger and Dwyer. Is another retraction in the works?

    For those younger contributors that are advocating an academic lynching I am sure the appropriate processes are in motion but proceeding at a the usual glacial pace..

  117. noblesse d'epee said

    scotus said:

    “I am sure the appropriate processes are in motion but proceeding at a the usual glacial pace..”

    I’m not so sure. The Medical School Dean (Nancy Andrews) has ceased any serious efforts to address the issues mooted by the student petition. The Dean of the Graduate School, Jo Rae Wright, is similarly inactive. Unless the O.R.I. is conducting its own external investigation, nothing is happening.

    Homme’s spouse, Lorena Beese, was recently elected to the National Academy (for political reasons rather than for scientific merit, but that is a different controversy). I suspect that this happy event has conferred immunity upon Homme.

    This place is laughable. At least in industry, ruthlessness is expected and motives are clear (profit). In academia, most professors pretend to be “educators,” but are really small business owners whose currency is ego, not money. They should drop the pretense of possessing the moral high ground and intellectual purity by which they differentiate themselves from other scientists.

  118. scotus said

    It’s ironic that, since she’s a protein crystallographer, one would assume that Dr Beese’s lab is very well versed at the expression and purification of His6-tagged proteins….

    If there is an ongoing internal or external investigation it will be carried out under conditions of extreme confidentiality so I’m not sure you can be certain that nothing is happening.

  119. David said

    I now have heard that a company was interested in obtaining the designed TNT sensor, but the Hellinga lab could not successfully replicate the preparation of the sensor to provide to the company. This may not be the genesis of the Foo rumor, but if any data cannot be repeated, Dr. Hellinga would do best to uncover it on his own.

    If the major advances leading to Dr. Hellinga’s Pioneer Award have been retracted or called into question, what else is there?

    Perhaps Dr. Hellinga will give a candid update at the Fifth Annual NIH Director’s Pioneer Award Symposium, September 24–25, 2009, at NIH. It is open to the public and no registration is required. The symposium will be Webcast. The Q&A period might be especially interesting. Dr. Hellinga speaks Friday, September 25, 2009 10:45 – 11:15.

    http://nihroadmap.nih.gov/pioneer/Symposium2009/index.aspx

    • scotus said

      Did anyone watch this presentation and if so could someone post a summary (or failing that a brief list of the most cringe-worthy moments)?

  120. scotus said

    This is apparently what he has been doing with the Pioneer Award….

    http://nihroadmap.nih.gov/pioneer/Profiles04/Hellinga.aspx

    The Idea
    Dr. Homme Hellinga’s goal is to develop and test new computational methods for protein design and engineering. Because this field is new and many challenges still impede progress, the Pioneer Award has enabled him to focus on long-term experimental methods development. This endeavor, he says, has opened up important new opportunities.

    Hellinga starts with the three-dimensional structure of a protein and uses computational methods to identify genetic changes that will alter the protein’s function in a predictable way.

    That is easier said than done: Computer algorithms must sift through a huge number of potential choices, taking into account the shapes of atoms, the chemical bonds connecting atoms, electrical charges, interactions with water, and more. Not surprisingly, Hellinga says, most of the calculations are inaccurate. He estimates that about 1 to 10 percent of the predicted protein sequences are functional “on a good day.”

    The Results
    The Pioneer Award has been ideal for Hellinga’s project, full as it is of unknowns and unpredictable outcomes. He has had to build many proteins, then test them in the lab to identify the ones he wants. The Pioneer Award enabled Hellinga to spend a lot of time developing robotic methods, an effort that proved to be much harder than expected.

    After setting up parameters for automation and other aspects of his protein design and engineering work, Hellinga has just built a synthetic protein-engineering pipeline that will enable him to construct and test hundreds of proteins in just a few weeks. He expects to begin collecting data very soon.

    • noblesse d'epee said

      “1 to 10 percent of the predicted protein sequences are functional ‘on a good day.’”

      If 1-10% of Homme’s designed constructs are active, you’d think he would be awash in legitimately functional enzymes and would publish these triumphs accordingly.

      I suspect that “a good day” for Homme is one in which he finds aberrant data to support his pre-determined results. An even better day is one wherein his students and employees don’t bring him all of those annoying data which question the functionality of his designs.

      I’d opine that no more than 1-10% of Homme’s published work is reproducible, but I’m a skeptic.

  121. scotus said

    http://dukemedmag.duke.edu/assets/articles/80/Detective_Proteins.pdf

    Maybe they should re-title this one “Defective Proteins”…

  122. Paillard Gwenn said

    I think it’s primordial that the student can trust the labo’s researchers and particulary his doctoral adviser.
    The graduate student who prepare a thesis is still learning,he have to be guided and not alone.
    The scientist doesn’t have to do only research,he has to teach and share his knowledge.

  123. David said

    It is a poorly-kept secret that an interesting paper will soon appear in PNAS online that will change the complexion of this discussion. There are some great scientists out there doing the right controls. I look forward to reading this paper.

    • whimple said

      Why don’t you make this secret a little more poorly kept by spilling some details here? :)

      • noblesse d'epee said

        The content is rumored to include “reanalyses” of data in Homme’s 2003 Nature paper. This would be consistent with “foo’s” recent comments regarding the reproducability of Homme’s PBP work.

        A stormy meeting between the Duke Biochem. department’s student body and the interim chair (a petition addressee) occured last week. One of my colleauges called the faculty “spineless,” while another opined that the handling of the Homme scandal by Duke was “a case of the three D’s: delay, deflect, and deny.” There were widespread claims of a corrosion of trust between the biochem. trainees and the faculty/administration. No one can say that the students have failed to take a vigorous and consistent stand in this controversy.

      • noblesse d'epee said

        Ack! My spelling in the preceding post was poor; not enough coffee.

      • Troubled said

        Well, I hate to be the late-coming idiot in the conversation, but this is actually important to my current work. I had assumed that the data on the PBP were solid. I know that you may not be party to exactly what is in the paper, but when you say “reanalysis”, are you saying that these redesigned PBP do not work at all? Not work by the proposed mechanism (as in the Zn binding)? Not work at the published affinity? I would be very eager to discuss this with someone in the know.

        Joss211@yahoo.com

  124. noblesse d'epee said

    “. . . the arc of the moral universe is long, but it bends toward justice.” -MLK

  125. [...] highly touted methods and their outcomes brings to mind another scientist whose star has fallen, Homme Hellinga, whom, according to recent comments here about an upcoming PNAS paper, we will soon see garnering [...]

  126. Mentorless said

    Now on the WWW is, “Fifth Annual NIH Director’s Pioneer Award Symposium
    held 24 & 25 Sept ’09.

    Friday, 25 Sept included,
    “Presentations by 2004 Pioneer Awardees—The First ‘Graduating Class’.”
    HW Hellinga was among the presenters. Apparently, the symposium
    was webcast. I missed it — unfortunately. Anyone see it and would like
    to comment?

    Follow the page’s Awardees’ links to Pioneer profiles. These list accomp-
    lishments. Whereas the other ’04 awardees’ profiles list many papers in high
    profile journals, Hellinga’s lists just one paper: describing his lab’s automated
    protein fabrication system (in “Protein Science,” not a high profile journal).

  127. noblesse d'epee said

    @ Mentorless

    I think that your linked page may have expired. The archived web-cast of the NIH Pioneer Symposium will be posted at:

    http://videocast.nih.gov/PastEvents.asp

    It appears that the archive is only current through 9/23, so there may be a few days’ lag. There were no questions following the talks, including Homme’s discourse on “Protein Fabrication Automation.” He basically told us that “rare codons are bad,” that message secondary structure can/should be minimized, and that his robots and oligonucleotide synthesizers allow him to pilot protein expression in a high-throughput manner. He even explained how he has done this for projects in (his wife) Lorena Beese’s lab.

    So, with the untold millions that Homme has “obtained” from the government, he has built a gene/protein optimization facility analogous to those used by many companies (except that his is private, whilst theirs are run on a fee-for-service basis). What a novel, pioneering idea. He’s even managed to engage in some nepotism along the way. We should publicize this triumph of innovation, so that taxpayers can be assured that the NIH budget is being spent with their best interests in mind.

    • Mentorless said

      noblesse d’epee,

      The link is wrong but the URL I provided is correct. Indeed, the page is new
      and definitely not expired. After clicking/selecting the URL and being taken to
      the NIH “oops” page, remove the close-parenthesis (last character) from the URL
      in the Navigation Toolbar and Reload or press Enter. Why this blog includes
      close-parentheses when converting URLs to links is beyond me.

      Thanks for the info on the symposium and its webcast archive.

      • writedit said

        I can’t account for how WordPress handles your HTML coding, but I did clean up both links in the posts above.

        Also, the PubMed citations of work attributed to Hellinga’s Pioneer award include 10 articles, including the Protein Science piece. The question is, what’s next for Hellinga following his “graduation” as a pioneer … he has no other NIH funding in the bank (per RePORTER).

      • noblesse d'epee said

        One of the 10 listed papers attributed to Homme’s Pioneer Award (JMB 2007) has been retracted. Oops.

  128. noblesse d'epee said

    The “reanalysis” of Homme’s 2003 Nature paper has hit the press. Nature News itself is now covering this development (as of 6 hours ago):

    http://www.nature.com/news/2009/091012/full/news.2009.998.html

    The researchers who work in the protein design field should be thankful that Prof. Hocker and her laboratory took the time to do the proper controls for Hellinga’s original experiments. Kudos to her for taking the time to do a “reanalysis,” of Homme’s 2003 triumph, a brave endeavor that few researchers would risk their time/resources to tackle.

    The best sentence: “All together, our combined analysis of the binding properties of the designs indicates that no specific binding of the target ligands to the respective designs occurs.”

  129. [...] 13, 2009 at 12:42 am · Filed under Biomedical Research Ethics, Research News Whispers that more of Homme Hellinga’s landmark work could not be replicated began last summer as part [...]

  130. Too fast said

    I just came to know about the Hellinga’s scandal…I was an investigator at Duke when this individual come to the Biochemistry department…Back them It was widely known that he was hired because of his wife…the chairman at that time wanted his wife…and Hellinga was part of the deal….. he was considering as an average scientist ….the fact that he became a James B Duke professor in such a short period of time was a surprise for many, specially those that knew his “talents” first hand…awful biochemist and molecular biologist…but a great charlatan with an English accent….once again Duke wants to keep his wife, Dr. Beese, and Dr. hellinga is part of the deal…that’s the reason Duke doesn’t say a word on the case….a shame….

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