Hellinga Controversy Expands

Update: The [Duke] Chronicle reports: “The University has reached a resolution in its two-year investigation of biochemistry professor Homme Hellinga has been reached. But Duke officials contacted last week declined to discuss the outcome.” (thanks to inside tip)

Update: Links to the Höcker PNAS abstract and paper are now functional, and The Scientist has posted the full text of comments submitted by Hellinga and Looger (links to their statements posted below among the comments).

Whispers that more of Homme Hellinga’s landmark work could not be replicated began last summer as part of our lengthy discussion of the retraction of Hellinga’s 2004 Science paper (here and earlier here) and then his 2007 JMB paper … and his accusation of misconduct laid against his grad student Mary Dwyer. More recently, observers close to the situation had advised us to watch PNAS for an interesting report on the matter.

Whereas Science was mum on the whole debacle when their article was retracted, Nature has taken a proactive analytic approach to the possibility that Hellinga’s 2003 Nature article (and a 2004 PNAS paper) may need to be retracted based on a report entitledComputational design of ligand binding is not a solved problem in PNAS by Schreier et al. … announced even in advance of e-publication by Nature News.

According to Nature News,

Now Birte Höcker, a former postdoctoral fellow of Hellinga’s, and her team at the Max Planck Institute for Developmental Biology in Tübingen, Germany, have assembled and analysed five of the designed proteins that seemed to work best5. She found that all five were very unstable, and one was too unstable to analyse further.

The group then examined the structure of one of the proteins using crystallography and found that its binding pocket was similar to that predicted by Dezymer — but that it did not bind its intended ligand, which was serotonin. And using three methods to detect the changes in stability, heat and shape that normally occur when proteins bind their ligands, the team found no evidence that the designed proteins were binding their intended ligands.

“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,” Höcker’s team reports.

Hellinga’s lab is studying her re-analysis.

Höcker speculates that she obtained different results from Hellinga because she used different methods to test binding. Her methods included direct measurements of binding, such as isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. Hellinga used an indirect method: he designed the proteins so that they included a fluorophore that emitted a signal when the proteins changed shape, which his team interpreted as an indicator that the proteins had bound their ligands. But Höcker says the assay might have given a false-positive signal if the ligand or the solvent in which it was dissolved interacted with the fluorophore.

Hellinga says if his studies of low concentrations of proteins find that they do not bind their ligands, then he will accept Höcker’s explanation: “If these studies also show that our original interpretations are in error, we deeply regret that our reports of these designed receptors do not live up to closer scrutiny,” he wrote.

More deep regret. Other scientists interviewed considered various angles as to why the results might be so different – but all agreed the controversy needs to be resolved and soon. While one former Hellinga postdoc and Nature article coauthor stands by at least one of the proteins reported, the lead author – a former grad student and co-author on the retracted Science article – is not surprised that his findings have been called into question.

“I am not terribly surprised by [Höcker’s] results,” Looger wrote to Nature, adding that he had begun to think “that the designed proteins did not work very well, due to several lines of data” collected in Hellinga’s and other labs.

… In retrospect, Looger says in his opinion that “more attention [should] have been drawn to the aggregation and instability of the proteins, and how that might give rise to artefacts.”

Indeed, Hockner became concerned about questions raised and their impact on her own work:

Höcker says that she had a “good relationship” with Hellinga, and had discussed crystallizing the designed proteins with Hellinga while she was still at Duke. “Since I never heard of the outcome [of the crystallization trials], and the program Dezymer, which I myself was using, was under question, it became more and more important for me to know what it was good at and what not,” she says.

Höcker says her results also have broader importance for the protein-design field. “I think that we need to focus again on binding in order to improve receptor design,” she says, “as well as enzyme design”.

Nature alludes to findings from researchers at the University of Western Ontario (Telmer & Shilton), as does Perplexed Periplasmic in a comment in the prior Hellinga discussion on this blog.

Nature: Another group has analysed the structure of a different set of engineered proteins described by Hellinga in a 2001 PNAS paper6, and found that the proteins behaved differently than Hellinga predicted they would7. The designed proteins did bind their intended ligand, a zinc ion, but did not adopt the ‘closed’ state normally associated with binding.

Perplexed Periplasmic: There has been an attempt to reproduce this [Telmer & Shilton, cited by Nature above]. 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.

And what of the misconduct investigation at Duke?

Hellinga wrote to Nature in July 2008 indicating that Duke had, at his request, opened an enquiry into his own actions in connection with the events surrounding last year’s retractions8. [there was also a grad student petition requesting an investigation] Duke declined to answer questions about the status of the enquiry. [insiders suggest nothing is happening, though one would not expect publicized activity in such an investigation]

Other scientists said that the new developments should spur Duke to complete its analysis of both the previous retractions and the current developments. “I think it should be brought to a conclusion fairly quickly because the scientific community is perplexed by the contradictory results both from this and Richard’s analysis,” says Kirsch.

The Scientist offers their take on the whole matter as well.

404 Comments »

  1. It sounds like one possible conclusion that could be drawn from all of this, if one were so inclined, is that all of the work that Hellinga has built his fame upon is completely full of shit. Of course, that is only one possible conclusion among many possible conclusions.

    • Z said

      It’s one interpretation, and one that tallies with all available facts.

    • Finch said

      Another interpretation is that enough of Homme’s work has been called into question to render him a laughing stock. There is the work that we know is crap and the work that has not been exposed as crap…YET!

  2. whimple said

    Alternatively, one could conclude that it is Hellinga that is full of shit.

  3. D said

    At a minimum this controversy seems to be having an effect on his NIH grant getting ability. NIH RePorter reports him having 1 active grant (his Pioneer award) that is in its sixth year. Suggesting a no cost extension.

    His previous 13 year R01 ended in 2006. Not sure what he has in the hopper.

    I wonder if any companies have invested big bucks in Homme’s ideas? They might be watching BICO closely.

  4. Odyssey said

    Alternatively, one could conclude that it is Hellinga that is full of shit.

    Having interacted with the guy more than once I’m quite convinced that he is full of shit. Whether his work is is yet to be proven, but it isn’t looking good…

  5. bikemonkey said

    One thing that I (think I) realize from this post is that there seems to be some mixing up of the credulous-sloppy-rush-to-publish scientist behavior with should-have-known-to-the-point-it-is-intentional-faking behavior. yes? no?

    • writedit said

      I think this is what time – and perhaps an institutional investigation – will tell. The pattern of behavior is what is troubling, whether it involves falsification/fabrication or cutting corners. Neither serves the community well, particularly those careers and research programs that rely on the responsible conduct of research and results published by this lab.

      • bikemonkey said

        falsification points to one set of solutions, cutting corners/sloppiness to another (failure of peer review to demand high standards of evidence).

        It makes a difference which we are dealing with.

    • Odyssey said

      I think you can throw a good pinch of ego into that mix.

      • bikemonkey said

        ego is irrelevant. if the guy’s an ass or not it says little about the impact on the science. if it *drives* his behavior..well who cares? interesting sociology project but still….nothing to say about how we deal with cases like this, how we improve the conduct of science, etc.

      • Odyssey said

        What if ego drives someone to publish something he *knows* is right, even when the data doesn’t support it? If you want to improve conduct in science how can you not consider such things?

      • bikemonkey said

        People with and without ego reputations are perfectly capable of the same acts.

      • There’s a world of difference between an ego (even an inflated one) and delusions of grandeur. The former is present in may scientists, great and small; the latter is a symptom of various psychological disorders. See the DSM-IV for examples and explanations of differential diagnoses.

      • Z said

        To Bikemonkey:

        Ego is NOT irrelevant! Ego is what created this mess. Don’t misunderstand, Homme is an intelligent dude, just not real smart. You could glean both these just truths by talking to him. Do not mistake intelligence for smarts, and certainly don’t mistake either for wisdom. It was Homme’s ego that was his downfall. but in the world of high-profile bioscience, Homme is small potatoes.

  6. David said

    What are the ethics of not reporting irreproducibility of published results? If you know that at least a subset of the data in a paper are not reproducible, I think you have an obligation to publish an erratum or partial retraction.

    “Jeff Smith, who collaborated on the 2003 Nature paper3 while a postdoctoral fellow in Hellinga’s lab, says that he had performed follow-up studies on three of the proteins after the paper was published. All were intended to bind TNT. Two of them consistently did not work, and a third — which Höcker did not analyse — did, says Smith, now chief science officer of a biotechnology company in Durham. This, he says, convinced him that the third protein did work: “I would stand by it,” he says.”

    This is troubling. How many scientists could have wasted time with two constructs Jeff Smith would stand by as not working?

    Then there is Dr. Looger who says:

    “there were a number of instances in which a given designed protein did not seem to bind its target ligand; these were not reported in the paper,” he adds. “Non-publication of negative results is extraordinarily common in science; this did not seem inappropriate.”

    No, Dr. Looger, I do not agree. It is entirely inappropriate to publish something that you can’t repeat. If the controls don’t work, you throw out the experiment, but if the controls work, but the data doesn’t match, it is valid data unless and until you explain it and fix it.

    I am unimpressed by these Hellinga colleagues.

  7. Federale said

    I’d like to offer a few thoughts, but first, some level of rumors should be dispelled.

    1. Rumor in The Scientist article that Hellinga and Beese had an institute which was then taken away from them. As written, this is factually false. There was a proposed institute in the Duke Strategic Plan (which can be seen through provost.duke.edu) that talked about such an institute. Anyone who knows about university planning knows that these grand visions often never become reality. The institute was never created beyond internal discussions and empty promises. The economic environment has drastically changed university initiatives across the United States. The institute was nixed because of that, as were a score of other things in that plan – including building a huge new section to the Duke Campus, which is of much greater significance than the tiny institute for Hellinga and his wife.

    2. Rumor about the company Protabit; the company between Steve Mayo and Homme Hellinga It was announced in July 2009 as having a contract with Monsanto. The Protabit website is sparse on information, except that they are hiring.

    3. A Hellinga patent that was granted in February of 2009. Strongly encourage a discussion of this patent filing.

    Overall, here is the meat of this post…

    SEPARATE THE ISSUES: There are a number of nested issues in this dialogue that really should be kept separate for the sake of clarity. Within each of them are both ethical and scientific concerns that draw upon different pieces of either known information, or rumored information. It is incredibly difficult to keep them straight, but can be helpful in teasing out the nuances that really are worthy of discussion and add insight to the broader scientific community.

    They include

    – Scientific Misconduct Investigation
    – Student Petition Investigation / Misconduct Against Student(s)
    – Appropriate actions to take if misconduct is determined to have occurred
    – Appropriate actions to take if misconduct is determined not to have occurred
    – Investigation Process Issues

    SCIENTIFIC MISCONDUCT INVESTIGATION: Misconduct as stipulated in both the Duke Faculty Handbook, and through the NIH (which gets investigated through the Office of Research Integrity) have specific definitions as it applies to scientific misconduct. In many cases, it is not enough to show that something didn’t work. Rather, it goes further to evaluate the intention of the parties being investigated.

    Someone mentioned where the ethics comes in. It is right here. Intentions are deontological (Kant… sorry, not trying to get too esoteric). The fact remains that clarity is needed in understanding if there was intent to withold information. Evidence that pushes the interpretation in that direction is strong for declaring that misconduct occurred. In this case, that would be scientific misconduct and would meet the definitions of both NIH and Duke.

    STUDENT PETITION INVESTIGATION: This is the misconduct against student(s) portion. It is my own opinion that a PhD advisor or post-doctoral advisor has an obligation and responsibility in the professional development and training of a scientist, as well as the scientific development of the work.

    In this saga, the advisor blamed an individual who at the time was a student. This makes it an advisor/student issue. In no uncertain terms, Mary Dwyer was cleared of wrongdoing. Let that be known and understood far and wide.

    Likewise, there has been the student petition that is understood to have been accepted by the Duke University School of Medicine and directed over to the group conducting the investigation. It is understood that the group will consider the petition as part of the work it is doing.

    Of note, a back-of-a-napkin analysis of that petition should be explained. No students or other persons part of the Hellinga or Beese laboratory were approached or signed that petition for obvious reasons. Subtract that number from the roughly 60 or so students in the Department of Biochemistry at the time. Then, remove all students who either have Hellinga or Beese on their thesis committees from the total. This is the useful number to start with. Then, look at the number of signatories on the petition and calculate a percentage of students signing. The number is staggering.

    ACTIONS IF MISCONDUCT OCCURRED: There are likely different actions that could be taken for either of the misconduct types. In the case of the scientific misconduct; there are a range of options available to both Duke, and the NIH. Which option is the one to go with really should depend on the evidence and what the misconduct investigation determines.

    In the case of misconduct against student(s). This has itself a number of institutional repercussions worth considering. The easiest and most discussed is removal of ‘graduate faculty status’ at Duke. This amounts to the formal permission to mentor graduate students as their PhD advisor. The process for removing one is primarily the function of the Department, via the Dept. Chair. At Duke it is an interim chair. This function can also be performed by the escalating Deans at the Duke School of Medicine. It further could be performed by the Academic Council at the university level.

    There is also the concern over retribution against student(s) in any part of the investigations. A healthy discussion over whistleblower status is well worth it at this point. The faculty themselves should get a primer on this so that they do not purposefully or inadvertently commit such an act. There are often severe consequences for retribution style behavior. The most common one I’ve heard of is instant dismissal.

    ACTIONS IF MISCONDUCT DID NOT OCCURR: Duke has an obligation to repair the reputations if individuals where no misconduct occurred. This has nnot been addressed at all in the case of Mary Dwyer. Serious discussion and action in this area is necessary. The recommendations for this action, one would hope, would be included in the misconduct investigation report/outcome.

    What also needs to be considered is the collateral damage for other individuals who have suffered. This includes past and present members of embattled laboratories. It is understood that even some individuals who have applied for funding elsewhere in the United States and internationally have been panned and rejected based, at least in part, on their previous affiliations with the laboratories in question. This is simply unacceptable and amounts to draconian academic blood libel.

    INVESTIGATION PROCESS ISSUES: it is understood that ORI is involved, at some level, in this. Per their requirements, my understanding is that there is a timeline for investigations. Going beyond that timeline would require an in writing explanation / justification to ORI. This clearly must have been performed already. it would be interesting to see a copy of that.

    There is also the matter of confidentiality in the investigation process. This can be used as a barrier to keep others from knowing what is going on. This lends itself to creating and increasing frustration on the part of the parties waiting to hear an outcome.

    Another procedural issue is how to appeal a decision and whether or not the investigation process is being performed properly. Hiding behind confidentiality encourages a distrust in the proper process being followed. It is necessary for the final report and announcement to include a clear and substantive description of the process followed. This has potential legal consequences. It could have criminal consequences, and it could have legal consequences for Duke in terms of the relationship between the institution and the Federal Government.

    ORI has the option to take over the investigation should they consider the one performed by Duke to be inadequate and not follow NIH rules and regulations. This is the credible threat ORI can use to steer the institution into doing the right thing (and save taxpayer dollars by not taking something over unless it is warranted). This also serves as a pocket-appeal process.

    Secondarily, within Duke there is a concerted effort to exclude various ascending levels of university administrators in the investigation. This can serve to allow for an appeal upward of the process currently underway. This can be a good thing, since appealing higher can help processes internally to ensure they are properly reviewed and addressed.

    Thirdly, this can jump into a public courtroom. Let’s hope that doesn’t happen.

    • D said

      Interesting that I can’t access the Protabit website (http://www.protabit.com/). It seems to be dead now.

    • been there said

      “There is also the matter of confidentiality in the investigation process. This can be used as a barrier to keep others from knowing what is going on. This lends itself to creating and increasing frustration on the part of the parties waiting to hear an outcome.

      Another procedural issue is how to appeal a decision and whether or not the investigation process is being performed properly. Hiding behind confidentiality encourages a distrust in the proper process being followed. ”

      Confidentiality is required by federal law.

      • Federale said

        Absolutely. it is required under Federal law. My apologies for not stating that directly. The intent of that part was to explain contributing factors to increasing frustration. I would never call for improper disclosure of confidential information.

  8. Comrade PP — as an interested observer, with several friends who work in protein design and/or @ DUMC Biochem, I think that you may have missed a key possibility: that Hellinga is completely full of shit.

  9. Rob said

    What is the patent you are referring to? The latest Hellinga patent activity I can find is one filed in Oct 2006. I checked WIPO and USPTO…

    • Federale said

      The one that was granted in Feb 2009

      http://www.faqs.org/patents/app/20090048430

    • David said

      The patent _application_ in question was filed Feb 19, 2009, but has not been granted. It subsumes two previous applications. You can read it at uspto.gov or here:

      http://www.faqs.org/patents/app/20090048430

      While I didn’t see any relation to this controversy initially, I now realize that the pending patent’s co-inventors include James J. Smith. I think James J. Smith may be the same as Jeff Smith (J. Jefferson Smith of Precision Biosciences) who was quoted in the Nature News article. That continuing relationship via intellectual property brings in the appearance of conflict of interest.

      Side note: There is quite a backlog of patent applications. It may be hurting the economy (http://www.jsonline.com/business/53319162.html)

      • Federale said

        There is also a David W. Conrad on the patent. Is that D Truck or the David on here? Might explain the Homme sympathy we’ve intermittently seen around here…

  10. I’ve got to agree with Bike Monkey, I could give a shit if the guy is an asshole with an ego the size of the NIH campus as long as the guy does due diligence and is a practitioner of good science. BM is on the money with is it a case of faking the hell out of data or slipping shitty data past the reviewers because the guy has a good rep. I see some of the latter with the big-name scientists showing data with not very good or even worse no controls. A junior PI would never be able to get some of the shit they get through. You have got to should all PI’s to the same standard when publishing data. At least I have the benefit of having a PI who teaches us to be our own devil’s advocate and be critical of our own data.

  11. noblesse d'epee said

    Genomic Repairman,

    As another poster in this forum once wrote, Homme has displayed an “admixture of incompetence and dishonesty” in his pursuit of “science.” While it is too soon to determine whether the conclusions that Homme derived from his PBP data are fraudulent, I note that absolutely no scientific explanation exists for the results Hellinga reported regarding his triose phosphate isomerase design. Nor does the retraction even remotely address the gaping inconsistencies between what Homme reported and any sort of honest explanation for those data. A pattern begins to emerge.

    I agree with your opinon that science should (usually) be viewed independently of the personal attributes of its practitioners. But Homme is worse than the archetypical bombastic, high-flying senior professor; his dominant personality trait seems to be chronic professional dishonesty. It manifests itself in dishonesty with his science, his students/employees, his funding agencies, his business partners (short sell, anyone?), and ultimately, himself. He has done great harm to numerous careers, and has knowingly introduced rubbish into the basic-science foundations upon which future advances rest.

    Asshole or not, it is time for Homme to find a new profession, and for Duke and/or the NIH to help inspire this career change.

  12. writedit said

    So … does anyone know what happened to the Höcker PNAS paper announced by Nature News?

    • David said

      “Because PNAS publishes daily online, you may read about an article in the news media on Monday or Tuesday, but the article may not publish online until later in the week.”

      So, look for it this week.

  13. David said

    The Scientist also has an article on the Hocker paper:

    http://www.the-scientist.com/news/print/56053/

    I heard that the author of the article contacted a good number of current and former Duke biochemists. Evidently they were told not to comment by Duke. It seems to have worked for the most part.

    • Federale said

      I believe the students were told they could comment on it, but in an effort to protect them from a media circus they were encouraged to relay information they were sure of, and not report and spread rumors.

      A faculty member in the dept, who is known far and wide internally for being a strong student advocate, sent a message to this effect. However, the message sent to staff and faculty from the interim chair was not worded in the same manner.

  14. I think that you may have missed a key possibility: that Hellinga is completely full of shit.

    Where do you get the stupid fucking idea that I may have “missed” anyfuckingthing? Did you see that I wrote “that is only one possible conclusion among many possible conclusions”? Do you have a fucking problem with reading comprehension?

    • writedit said

      I believe Whimple (and later Odyssey), rather than you, unambiguously labeled Hellinga as full of shit, though perhaps not completely. I recognize that such a conclusion could certainly (and with high probability) be among the many you left unarticulated … but I don’t see a problem with Spiny Norman’s reading comprehension since I doubt he – nor anyone else – could possibly plum the depths of CPP’s mind to confirm what may or may not have been missed (please note that he says “may have missed” – not that you did miss – this “key possibility”).

      • Isn’t mis-citation a bitch? Snicker. (*ducks*)

    • CPP,

      writeedit has a wonderful site with very thoughtful discussions about this dude who has a high probability of being full of shit. You could consider dropping the shtick a notch, but I know better.

      Fire away, Helvetica lover! Nobody tells CPP what to do!

      • noblesse d'epee said

        I agree with the Captain. Writedit’s forum has been, in my experience, a useful place to discuss the details of issues such as the Hellinga scandal. There is no need to drown out this interesting conversation with squabbling over differing interpretations (or mis-interpretations) of a widely agreed-upon hypothesis.

        For the record (and as a student in Homme’s department), I am certain that both he and the vast majority of his science ARE shit, not merely full of it.

  15. Can hear Jameson being drunk heartily and sitting through the eerie calm before the storm that is the CPP response.

  16. Rob said

    The accepted version of the Hocker paper is quickly circulating through the scientific community. The embargo seems to have lifted, so I expect that it should be posted to PNAS accepts soon, although today is not the day……

    • Federale said

      The PNAS paper is a good read and is aptly titled..
      Computational design of ligand binding is not a solved problem.

      I think little seems to have been said about the Hellinga response to the paper. His response is quoted in the Nature News piece. I suggest some scrutiny and a simple smell test to determine whether it is excrement…

      Separately, noblesse d’epee might have just shown some odd symptoms of Stockholm Syndrome… “as a student in Homme’s department”… (*grin*)

      • noblesse d'epee said

        Ah, Federale, my understanding of Stockholm Syndrome is that the sufferer forms an attachment to his/her captor. Few people in this world repel me more than Homme.

        A pre-print of “Computational design of ligand binding is not a solved problem” appeared on my desk recently. ;-D

        Homme’s response does not surprise me. I am, for the exact reasons David describes above, quite disappointed by Looger’s position that negative data were not considered because it is “customary” not to publish such data. Like David says, if the controls don’t work, or you have data which completely contradict other data in your paper, then you are obliged (at minimum) to note the discrepancy, or (better) to do additional experiments to determine WHY the data do not agree. What should NOT be done, is to publish only the data which fit your model, whilst discarding other (equally valid data) which do not. This is research misconduct, and should be punished accordingly.

        Rob is correct; the paper will be in PNAS Online either today or tomorrow.

  17. scotus said

    To paraphrase Oscar Wilde:

    “To retract one paper may be regarded as a misfortune; to retract more than one looks like carelessness.”

    Of course, in this case carelessness would be the most generous interpretation of what has happened.

    Frankly I’m surprised that Hellinga and co are willing to talk about the matter on or off the record. The Looger response is frankly mindboggling.

    Continuting the Oscar Wilde theme, this whole situation is now a huge farce and exactly the sort of thing that harms the public trust in science and scientists.

    Maybe Erika Check-Hayden should enlist the help of Nancy Grace for her next article?

  18. “Once is happenstance. Twice is coincidence. Three times is enemy action.”
    -Auric Goldfinger

  19. Spiny, that was great.

    • scotus said

      I’m wondering if the Pihrana Brotehrs (aka Looger and Hellinga) are afraid of Spiny Norman?

      • Dinsdale! Dinsdale!

      • scotus said

        Lets hope Harry “Snapper” Organs has been transferred to the ORI and is now on the case…

  20. D Truck said

    Loren Looger sure looks like an ass in all of this.

    As quoted before,
    “there were a number of instances in which a given designed protein did not seem to bind its target ligand; these were not reported in the paper,” he adds. “Non-publication of negative results is extraordinarily common in science; this did not seem inappropriate.”

    Dr. Looger, I would appreciate knowing of any negative results you may have obtained relevant to your more current publications.

    This guy basically got a sweet HHMI job because of his part in the hoax perpetrated on the scientific community and this is his best defense? I recommend a PR agent Looger.

  21. Rob said

    The paper is available through PNAS now:

    http://www.pnas.org/content/early/2009/10/14/0907950106.abstract

    • luna Halloween said

      Rob,

      Does one need a personal subscription to read the paper ?.

      Thanks

      • David said

        Yes, it will take some time to read the paper without a personal subscription or access to an institutional subscription.

        “Without a subscription to PNAS Online, you still have access to Tables of Contents, abstracts, full-text searching, and all content older than 6 months at no cost and without having to register. ”

        In the meantime you might ask someone with a subscription to send you a reprint. There is also nothing wrong with requesting a reprint from the author.

  22. neurolover said

    “Loren Looger trained to be a mathematician, but switched to chemistry after deciding that a mathematician’s life might be too solitary. The shift took courage, because everything about his background suggested that Looger was a math prodigy of considerable promise.”

    Why would you let someone write this in their public profile? It’s got to be an annoying editor, no?

    • scotus said

      Looger is a classic example of someone who is too probably smart for his own good. Apparently Hellinga falls into the same category.

      The problem with these kinds of people is that they are fundamentally unsuited to scientific research because they are primed for mental dishonesty by the overriding belief that they are destined to succeed. In my own modest career the fact that sometimes a lot of very hard work comes to nothing has been hard to accept but in time I came to the realization that there is satisfaction in doing things properly and that the outcome of experiments is, like a lot of things in life, out of my control. Only when you accept this can you really start to make any valid progress.

      Look at this interview with Paul Nurse on Youtube:

      His discussion about “mental honesty” makes my point in a much more eloquant way.

      • Z said

        What he (she) said.

    • D Truck said

      There’s a lot of interesting quotes in that write-up:

      “When asked how he first heard about Janelia, he says: “My wife assures me that she told me about Janelia Farm first, although a colleague of mine also claims credit.”

      Gosh, but they were just lucky to get you

      “Janelia appeals to him because he does not like teaching and hates bureaucracy and the pure profit motive of industry.”

      but then…

      “Not one to sit idle, Looger is also founder of a biotech company”

      hmmmm….

      “”I see Janelia Farm as a crack team of scientists—almost like a SWAT team—that comes together to solve difficult problems. Everyone is really playing together. Not like in academia, where they say they play together, but in reality it does not always work that way.””

      Or something like that…

  23. http://www.pnas.org/content/early/2009/10/14/0907950106.full.pdf+html

    “Edited by David Baker.”

    LOL.

    • D said

      For those of us not in the field what is the significance of…

      “Edited by David Baker?”

      • Baker is arguably Hellinga’s strongest competitor, who has now published two papers that appear to demonstrate computational design of new enzymes — a claim originally made by Hellinga but retracted. The Baker papers are, by all appearances, solid reports of very strong work.

      • Z said

        To be fair, I think Baker is also open with his source, so there is some transparency there.

  24. David said

    Having now read the Hocker paper, the Nature News article, and The Scientist article, it is clear that a large part of the Nature and PNAS papers is not reproducible in Hellinga’s own lab (Looger & Smith quotes) or in other labs (Hocker paper). It would behoove the Nature and PNAS editorial staff to issue a deadline for an official Hellinga response. If the deadline is reached without satisfactory comment, the papers should be editorially retracted. I would suggest Dec. 30, 2009 as a generous deadline.

    • Federale said

      The Hellinga quotes in the Nature News article are in response to the paper. You already have his response…

  25. Federale said

    From the paper….

    From The Introduction….
    “We decided to structurally characterize these receptors further and thus learn about the strength and shortcomings of current computational design methods”

    “Taken together, our findings indicate that the investigated protein designs do not bind their new ligands in the expected way. Thus, the computational design of ligand binding is not a solved problem and needs to be revisited.”

    From the end of the Results and Discussion Section….
    “Implications for the Field of Computational Biology. Although the overall conformation of the designed binding-site residues in Stn.A2 indeed resembles the model, binding to the new ligand, serotonin, is not conferred. This should be kept in mind when judging model quality based on structures without a bound ligand. Our analysis shows the importance of experimental and structural validation to improve computational design methodologies.
    We conclude that computational ligand-binding design remains an unsolved problem that needs reconsideration in its details. Do the algorithms capture all aspects important for the prediction of small molecule binding? Could the energetic cost associated with domain reorientation in PBPs (20) pose additional
    difficulties for the design in this particular scaffold? Boas and Harbury (21) successfully used the molecular-mechanics potential energy function to recapitulate and improve upon wild-type RBP, which points toward the fact that the general principles in receptor design hold true. Nevertheless, predicted interactions need to be verified using techniques that directly probe ligand binding.”

  26. D Truck said

    Shouldn’t the title of this paper be, “Computational design of ligand binding is not solved by Hellinga’s lab”? Others have had success in this area so to implicate the entire field because of one lab’s shoddy work seems misplaced.

  27. D Truck said

    Can anyone clarify Looger’s statement:

    For instance, while collecting the data for the 2003 Nature paper, a positive readout on the fluorescence assay would “not infrequently drop off over the course of days or weeks”, Looger says.

    What does this mean exactly? I’m certain they didn’t leave their binding assays in the fluorometer for weeks at a time, and even if they did, they would probably be photobleached. So what’s Looger trying to say here?

  28. Rob said

    I think that serious clarification is required from the Hellinga lab. What other previously published results have not been validated? I’m very concerned that the Hellinga refutations are only going to expand. From the Nature News article:

    “Jeff Smith, who collaborated on the 2003 Nature paper while a postdoctoral fellow in Hellinga’s lab, says that he performed follow-up studies on three of the proteins after the paper was published. Two of them consistently did not work, but a third — which Höcker did not analyse — did, says Smith, now chief science officer of a biotechnology company in Durham. This, he says, convinced him that the third protein did work: “I would stand by it,” he says.”

    So, when the Hellinga lab discovered that two of their previously published biosensors did not work, their response was to simply do nothing. This is dishonest at best. When you invalidate something you previously published, it is absolutely your responsibility to communicate this.

    What other designs has the Hellinga lab now learned are non-functioning? It looks like the only way we’ll find out is when more labs try to validate Hellinga’s work. What an absolute waste of research dollars.

    • D Truck said

      Well when someone is willing to publish only the positive results and ignore the negative ones, shouldn’t you be skeptical of ALL of their published works? Looger’s credibility is zero based on his own statements. He doesn’t even think it’s wrong because “everyone does it”. Is this hubris or idiocy?

      • Z said

        That’s hubris in the “mission accomplished” sense. None of these guys are idiots in the normal sense. I suspect that Looger was just young (and therefore) naive. Homme, well – something else.

  29. David said

    In the Scientist article it states:

    “[Looger] did point out, however, that TNT-binding proteins cloned into bacteria were still able to perform their function in a signal transduction cascade that depended on ligand binding. “To me, this remains the biggest unanswered question of the affair,” he said. ”

    So I looked at the data and methods. The PBP proteins in this cellular assay are not labeled because intact bacterial cells are used. The dezymed PBPs are either identical or analogous to the proteins Hocker tested (i.e. unmodified by fluorophore). I don’t see any solvent/vehicle controls for these experiments. I find it hard to believe that could be the reason, but I agree with Looger that someone should try to repeat these cellular assays. It should take a day to repeat these experiments once the constructs are in hand. Hocker should probably make her own constructs. From what Prof. Richard said, Hellinga has been known to send the wrong constructs. If this doesn’t repeat either, there goes the whole fluorophore/solvent argument.

    • Aficionados will recall that the claimed functional complementation of E. coli triosephosphate isomerase (TIM) by Hellinga’s “dezymed” TIM (which in purified form had no TIM activity) has never been either satisfactorily explained or reproduced in another laboratory, either.

      • Rob said

        @Spiny-
        The single phrase that frustrates me the most out of this whole experience is “The in vivo experiments have not been reexamined.”

        I guess they could explain away their distortion of the data in many instances, but the in vivo complementation is just plain fraud.

      • whimple said

        Fraud is also my interpretation of the in vivo complementation data. As a reviewer, this is the one crucial experiment that proves the success or failure of the entire technique, precisely because a successful result can’t be easily explained away as an artifact.

      • @ whimple, I think it’s useful to be even a bit more precise here.

        As you say, a successful result can’t be easily explained away as an artifact. But an unsuccessful result would in fact be the expected result, given the craptacular kcat/km of *all* reported designed enzymes to date. The claim of in vivo complementation was for this reason an extraordinary claim in the first place, but the experiment itself is straightforward.

        For this reason I’m baffled as to why no one has yet reported the results — positive or negative — of an attempt to repeat it.

      • D Truck said

        Not a lot of motivation to publish results like the ones you describe. I’m shocked that the Looger paper, which I long suspected of being bullshit, was ever tested at all. Look at how long it took to test the enzyme stuff and the Looger paper is much more complicated. Sure, someone could get the plasmids and try the assay. Based on everything we know they’re likely to get a negative result. But there are a lot of reasons why you might get a negative result, right? Hellinga has done everything he can to try and save face at every turn (e.g. blame graduate student) rather than get to the root of the problem (because it’s too ugly to face). But the fact that this first debunking paper was published in PNAS may motivate others to publish negative results.

  30. D Truck said

    I just can’t tear myself away from this slow-motion train wreck. Look at this comment from Steve Mayo:

    “He cautions that Höcker did not analyze the same exact proteins as Hellinga reported, since her proteins did not contain a fluorophore, which might have affected the proteins’ binding properties.”

    If the fluorophores are required for ligand binding then the whole thing is bogus, right Steve? Surely the design wasn’t for fluorphore conjugated protein? And if the ligands are binding the fluorophores, I don’t see how that wouldn’t save any face.

    Also:
    “Hellinga says that Höcker used higher concentrations of proteins in her tests than his group did in its original paper, and that this could have affected her results. ”

    Or perhaps it was the magic pixie dust sprinkled by Looger&Hellinga that Hocker is lacking?

    It will be interesting to see how this gets resolved. Will Hellinga have the balls to retract or will he just sit on it? My bet is that he finds some way to try and weasel out of it saying that one or two of the things actually work so their “major conclusions are validated”. Given his record, the nature editors may not buy it.

    And what of Looger? With both of his career-propelling publications in the toilet and his stated policy of not publishing results that disagree with his hypothesis, will he keep the Janelia Farms appointment or will he get booted from the “SWAT team”?

    • “I just can’t tear myself away from this slow-motion train wreck.”

      Yup. Just can’t stop rubbernecking. Of course, many of us who’ve dealt with Homme (or similar charlatans) on a one-to-one basis have a certain (where “certain” = “large”) amount of schadenfreude associated with this series of events. It helps, too, to know some of those injured at Duke and some of the others in the relevant fields, and to have some idea of how hard-won real progress in this field really is. Hellinga has done real harm. Life is short and finite, and Hellinga has stolen irreplaceable time and imposed opportunity costs on many others who were more deserving. These costs will never be recouped, and I suppose that my fascination with this case stems from the real hope that there may in the end be some justice, and that he’ll be stopped.

      • noblesse d'epee said

        Spiny,

        Yours is a succinct and eloquent description of why Hellinga must go. This is a matter of justice, touching upon the most fundamental and salient issues facing our field.

      • Z said

        Yes. Eloquent and succinct. Mr Hellinga must go. I am reminded of an incident years ago when the NMR center in LSRC got its 800. As they removed part of a wall to bring in the magnet (why he was there I don’t recall), Homme said “if they dump the power I’ll resign my professorship …”. Well – he was an assistant at the time, as was Lorena. Could have saved a whole heap of trouble.

      • noblesse d'epee said

        So true, Z. Homme and Lorena are now so completely entenched that their malfeasance is insufficient to bring about their removal. Duke’s medical center administration is largely to blame for this state of affairs. Before Homme’s work was called into question, Lorena got away with all manner of evil because Duke wished to avoid offending Homme. Now Homme is given a pass in order to avoid pissing off Lorena. Almost no one (except a few professors and some utterly powerless students) has stood up to these two sociopaths. This debacle has hardened my opinion that academic tenure should be abolished.

  31. noblesse d'epee said

    I have a consideration to add regarding Lorean Looger, and his perceived role in all of this.

    I, like other posters here, was angered by Looger’s comment that “non-publication of negative results is extraordinarily common in science; this did not seem inappropriate.”

    Taken as written, Looger’s statement is a poor choice of words, a questionable position for a scientist to take. That being said, I have recently been made aware that this quotation was taken out of its original context, which was a detailed written statement that Looger made to The Scientist and to Nature. In his letter, which has been read to me by a mutual acquaintance, Looger is appropriately critical of Homme’s (and his own) work on the PBP sensors, and provides a candid description of the atmosphere in which the original data were generated and (mis)interpreted. According to my contact, Looger’s interaction with the journalists from The Scientist and from Nature News was tense. Consequently, one can imagine that Looger may have been portrayed unfavorably. Yes, Looger chose his words poorly as quoted, but the larger message of his letter greatly mitigates some isolated, stupid statements.

    I don’t know Looger, I’m not his friend, and I concede that he may be very much in the scientific wrong. However, I’ve been privy to information which suggests that we should be careful about judging him based upon out-of-context quotations printed by potentially hostile journalists.

    Maybe Looger should post here (or elsewhere) in order to clarify his position.

    • If this is the case, I believe Erika Check Hayden (Nature writer) and The Scientist writer should be e-mailed and perhaps urged to comment. Nowhere in their stories did it appear clear that Looger’s words were from a long prepared statement that is not and interview nor should it be quoted as if it came from a back and forth situation. This is troubling.

    • D Truck said

      It’s hard to imagine a context where this would be appropriate: “Non-publication of negative results is extraordinarily common in science; this did not seem inappropriate.” That’s just making excuses for cherry picking data in a really sick way, however much Looger may excoriate Hellinga in his full statement.

      • I detest the statement, but the next sentence could have been “this was the mindset in the Hellinga lab that I now know is a different category of negative results and wholly inappropriate.” I think that the quote was presented in a misleading way coming from a statement and not an interview. If he were interviewed, his response would have been presented along with the pertinent question. I don’t trust the writers on this one, and of course Looger has shown massively poor judgement in his career.

      • D Truck said

        I can’t see writing it that way. Furthermore, we don’t know what happened – maybe the quote was from an interview and Looger’s doing damage control. I don’t see what the journalists have to gain by misrepresenting Looger – the story’s spicy enough as it is.

      • I can only go on what Noblesse wrote above:
        “That being said, I have recently been made aware that this quotation was taken out of its original context, which was a detailed written statement that Looger made to The Scientist and to Nature.”

        I have no expectations of any journalist- it is a very tough job to get nuance and Looger’s statement out of context is wonderfully provocative. We have been told above that it may not reflect the full context, that of a written statement. We have no need to make decisions based on some decision making process of the journalist. Please see any number of science writing debacles that poorly simplify complex debates. Gina Kolata in the NY Times on grant funding in cancer research comes to mind.

      • D Truck said

        Nobless also writes:

        “Yes, Looger chose his words poorly as quoted, but the larger message of his letter greatly mitigates some isolated, stupid statements.”

        I take that to mean that Looger sticks it to Hellinga enough to make Noblesse look past Looger’s statements (perhaps Noblesse can clarify?). Looger’s quotes are straightforward and readily interpreted (well, most of them – some of the technical ones I still don’t understand). Attempts to put his statements in a benign context require a degree of gymnastics that make a more complex interpretation unlikely (but without all the evidence I can’t know with certainty of course). It’s also worth remembering that Looger and Hellinga have a lot to lose in all of this and their statements should be scrutinized accordingly.

        In any event, it appears that Looger has a more complicated story to tell than Dwyer.

    • D Truck said

      “In his letter, which has been read to me by a mutual acquaintance, Looger is appropriately critical of Homme’s (and his own) work on the PBP sensors, and provides a candid description of the atmosphere in which the original data were generated and (mis)interpreted.”

      Noblesse,

      Does it make any sense at all that Looger would have provided this information to both of the journalists, but that nothing was said of it in either article? It doesn’t add up.

      • NicaraguanContras said

        Why you guys are giving Looger the benefit of doubt is incomprehensible to me. I laid my hands on Looger’s original manuscript back in 2004/5 (long story short: my the-then girlfriend’s lab-mate had gotten a copy to go over and suggest corrections/critique manuscript, and the paper remained on the desktop folder….). The draft looks nothing like the final paper. Obviously between the draft & what Nature printed, Looger & Hellinga painted their magic……

    • goldenboy said

      Looger IS guilty, at least PARTLY… for sure! Looger’s first author paper is tortuous in reasoning and experimental design. All eyewash to hide negative data. Both Hellinga & Looger consider themselves God’s gift to science. Both of them are very flamboyant .. to the extent of being annoying.

      • Federale said

        Not sure you can claim ‘guilt’ here in the manner that is being thrown around. A difference from draft to final can hardly be pointed to as wholly one or wholly the other. The simple truth is that we all will likely never know how that turned into what it did.

  32. noblesse d'epee said

    Make no mistake, I still strongly disagree with some of the positions taken by Looger. The “non-publication” quote is bad regardless of context, but its awfulness is significantly lessened when taken with Looger’s other commentary. Other than having a second-(or third)-hand account of friction between Looger and the journalists, I’m not sure exactly what transpired between them. I don’t have a written copy of Looger’s statement. Not being able to reference this letter, and besides not having permission to do so, I am unwilling to comment further. I think that Looger (or someone closer to him than I) should describe his statement.

    My understanding of Looger’s position in the Hellinga lab is that his work was largely (if not exclusively) in silico. He was dependent upon “wet” biochemists to provide in vitro and in vivo feedback for his development of DEZYMER. I understand that Hellinga cleverly compartmentalized these “wet” data by:

    1. Reserving the ultimate acceptance/rejection of data, and their packaging, for himself, in a manner which might be charitably characterized as opaque.

    2. Creating an adversarial laboratory atmosphere which did not encourage the full exchange of data, even among “team-mates” who worked on aspects of the same project.

    3. Discouraged the performance of various control experiments, most notably direct measurements of the type ultimately done by Hocker et al.

    One might imagine a scenario wherein all parties were separately convinced by Homme that they were approaching a great finding, but were each unaware of the deficiency of controls outside of their narrow subsets of the experiments. The Hellinga graduate students were often, for this reason, “true believers” of the validity of their work. This belief was encouraged by Hellinga, who was the only one among them who had effective access to all of the data. As their adviser, why should his graduate trainees not have believed him, especially when he promised (and delivered) the glory of high-profile publications and their attendant fame?

    • Thanks Noblesse, for all of your comments. I know that you can’t say more. In my mind if Looger is essentially a computational biologist his statements suggest either his naivete about bench science or characterize his mindset about the work at the time- and that these statements could represent his contemporaneous views with the events and not necessarily his current ones. Such inartful statements at minimum require or demand explanation or further context, which the authors did not or could not provide.

      • noblesse d'epee said

        Pinko,

        When you say that Looger’s statements “characterize his mindset about the work at the time,” and “represent his contemporaneous views with the events,” I think that you are on the correct track (or at least on the same incorrect one upon which I find myself).

  33. D Truck said

    Thanks noblesse. You describe an interesting scenario that I agree is probably close to what happened. Clearly Looger is a computer guy (although a self-promoting quote from his HHMI bio is interesting in this regard: “For months at a time I live the life of a computer programmer,” he says. “Then I emerge to test my ideas in the lab.”). Apparently Dwyer did most, if not all, of the bench science so she obviously had some idea about the problems and this agrees with what we know so far. Perhaps Dwyer brought her concerns about variability, etc to Hellinga and he made the final decision that it was acceptable.

    However, what did Looger know? In your account of what went on he would know nothing about the problems because he would have been “compartmentalized”. However, based on his own statements that’s not the case – Looger knew that there were some inconsistencies but didn’t make much of it. Whether or not Looger is culpable in this case is a grey area that probably depends on details that we (or at least I) don’t know. I’m actually surprised that he looks as bad as he does at this point. Given how much heat there is on Hellinga, Looger really had to work at it to bring this much attention to himself.

    I tried to leave a comment on the nature site this evening asking Ms. Hayden to clarify Looger’s quotes given your assertion (I referenced this site). Unfortunately I think the web site ate my post before it took. Maybe I’ll try it again but I also need to get some work done🙂

  34. scotus said

    I’m surprised Looger would say anything at all. His whole behavior is a textbook example of just digging himself even deeper into the pile of shit he is already embedded in. Although he has clearly shown poor judgment if he really did try to offer an honest opinion to the journalists and was then quoted out of context for purposes of sensationalization or just making him look like an ass then he deserves an opportunity to clarify his position.

    One of the larger issues that this episode illustrates is the complexity of biological and biomedical research and the inherent difficulties in resolving disagreements and inconsistencies. I can provide examples including ones from my own research in which published results have been replicated by some groups but challenged by others. The only person who can end this is Hellinga himself.

    On an unrelatd note, has anyone noticed the similarity between Hellinga and Harold Hutchins from “Captain Underpants”? I wonder if they are related?

    http://www.scholastic.ca/captainunderpants/books/popup_char1.htm

    • noblesse d'epee said

      The only person who can end this is Hellinga himself.

      Other entities can end this far more definitively than Hellinga will ever deign to do; Duke by revoking his tenure and terminating his employment, the NIH/GAO by “nationalizing” Duke’s investigation of him and subsequently stripping him of the ability to gain (and thus waste) government funds, and various grand juries by indicting him for actions that in my opinion, rise to the level of criminal acts.

      • Federale said

        See my post far up this page about potential actions…

        Also, GAO would have nothing to do with this. More or less, they investigate the government itself and not the cases that the government involves themselves with.

        As it pertains to Dr. Looger, I offer the following thought that is in agreement with the sentiments of others here.

        If you are a student in a laboratory with an environment that is like the Hellinga laboratory you have any number of problems. First, you’ll likely start exhibiting post traumatic stress symptoms. It is my sense that people from that laboratory have behaviors that manifest themselves similarly to people who have been abused. If you’re a student, and you are developing as a scientist, and you have data that you have a shouting match with your advisor about where you disagree with the advisor and the interpretation… what choices do you have? Blow your top and risk getting tossed out of the lab and not getting your PhD? Recall, at the time, this advisor is considered a ‘hot shot.’ Who will win that battle? Not the student…

        This, my guess, is what happened with any number of students in the Hellinga laboratory. Heck, what if one or more of them stood up and disagreed. Maybe they got rushed out of graduate school in their first 2 or 3 years. Maybe they got pushed out of the laboratory and changed labs. Looger and others stuck it out. The price they paid may have included being named on papers that they disagreed with.

        This compromises the individual students in a significant way that may be tough to repair. It also significantly compromises the integrity of the science. Personally, I always liked Loren, but I disagree with the statements he’s making. I’d rather he say that he did it, but that he was coerced and under duress. That’s an acceptable explanation.

        If you don’t treat your students like data-making-monkeys, and try to help develop them, work with them, respect them, and create an environment of open science; if you did that this problem might have had a shot of never happening. Moral: treat students better.

  35. Anon_Duke_Biochem said

    As someone who has interacted with Loren, I can tell you he is a pompous ass himself! He harps on and on about how smart he is: He left the the Berkeley math program because it was not intellectually challenging enough! He is very good at pimping himself! I cannot believe that he and Dwyer did not interact to discuss, its not as if their paths did not intersect even for a second! Loren cannot, in good conscience, extricate himself from all the blame, even if the blame is one of omission (& not of commission). He pimped himself out to the Janelia Farms people on the basis of his “star” publication. If that turns out to be a dud, why should he stay on! He took away opportunity from others who are actually smarter than him but not as big of a bombastic charlatan. Maybe the overachieving has gone to his head…. surprise surprise.. his overachievement is piggybacking on a fraud!

    • Federale said

      Gotta love these one-off hate fests. One of the greatest things about the English language is that it can be analyzed and every once in a while the language someone uses can give away who they are…

      • D Truck said

        Hmm… I’ll take a stab. Drum roll please…

        That Austin guy with the whacked out blog from the first retraction?

        This thing has such a cast of characters that it’s gotta be destined for the big screen.

        But I agree that hit and runs like this just bring down the level of our “intellectual” discussion.

      • NeddleMan said

        Dude, Seriously, WTF! Why are you overlooking Looger? Get anyone who was there at the JF interviews and ask them how Looger behaved as a grand maestro know-it-all! Ask anyone who interacted with him at Berkeley or Duke. Seriously! He raised quite a few eyebrows when JF hired him, I can tell you that.

        Looger is as good a scientist as your booger!

      • D Truck said

        JF does seem good for him as he can hop onto a bunch of papers, presumably for his keen insight. The contributions from his own lab seem fairly minimal, although to be fair it doesn’t look likes he’s been there long enough to make a good evaluation. However, look for bigger stuff soon:

        http://www.hhmi.biz/bulletin/aug2008/features/engineer5.html

        “According to Looger, whose training is in math, synthetic chemistry, and computer science, making sensors and fluorescent proteins isn’t exactly easy, but “it’s pretty obvious what needs to be done.” In a year or so, after he’s taken care of his colleagues’ pressing needs, Looger plans to turn his prowess in manipulating molecules to the wiring of neurons. “We’ll start to swing the pendulum back toward crazier things, like getting inside neurons and whole-scale rewiring,” he says. “

  36. It may be of interest to those obsessed with the Hellinga story that the somewhat unusual title of Birte’s paper is a direct affront to Hellinga himself. Among other nutty quotes that have been accurately attributed to the big H (for example, the infamous, “Do you think I’ll be more famous than Darwin?”), is one that he uttered in group meeting (and possibly elsewhere) in the presence of Hocker, et al: “Computational receptor design is a solved problem.” So now you know the origin of the paper’s title. My personal favorite conversation with Homme was when we sat in his office and discussed what it would be like “when Stockholm calls.” Perhaps he was actually referring to Stockholm syndrome, commonly associated with people who work in his lab for any significant period of time.

    One interesting aspect of the Hocker paper is that it was edited by Senor D. Baker himself. I feel for the guy: he labored for years under the impression that he was lagging behind the Hellinga lab, when in fact, he was the clear frontrunner in the field the entire time! But shouldn’t he have exercised a wee bit more discretion and steered clear of the steaming pile that is the remains of Homme’s career? As if the field of computational protein design needed another layer of ick.

    I also found it interesting that Hocker was quoted in the Check-Hayden piece as saying that she had a “good relationship” with Hellinga. Those who know the situation intimately know otherwise. Additionally, there are a number of other Hellinga despisers, including J. Kirsch and J. Richards, who have repeatedly been interviewed for these articles. These are people who have yelled and screamed (literally) about Homme’s lewd and lascivious behaviour over the years. Again, only those in the know would be aware that Check-Hayden’s best sources are some of Hellinga’s most vicious critics. Let me be clear: I am NOT defending Hellinga in any way. It’s just that this whole affair is one vicious, incestuous, attempted ass-covering debacle.

    I regret my association with Homme’s lab, but, quite frankly, needed to feed my family and so I held the gig far longer than I should have. The principal concern now should be for the remaining graduate students in Hellinga’s lab, who are the true innocent victims of this ponzi scheme (sorry post-docs…you should know better). If the esteemed faculty of Duke Biochemistry fails to assist them in finishing their degrees somehow, then may they all burn in hell.

    • noblesse d'epee said

      That’s an interesting tidbit about the title of Hocker’s paper. It did seem slightly odd, but now we have a potential explanation. ;-D

      Kirsch and Richards, being honest and carefult scientists, had every reason to be screaming mad. Any honest scientist whose anger doesn’t rise to near-viciousness over this affair is a very poor or very ignorant practitioner of science.

    • D said

      Too bad the ABC Movie of the Week isn’t still around. This would be a great plot for a melodrama..

    • “I also found it interesting that Hocker was quoted in the Check-Hayden piece as saying that she had a “good relationship” with Hellinga.”

      Perhaps she merely meant that she doesn’t talk to Hellinga, and Hellinga doesn’t talk to her. It would be hard to improve on that.

      • Federale said

        Except that Hocker sent him the paper before publishing it out of respect…

  37. Absolut Vodka said

    Everyone wants HH booted out of Duke Biochem for his hamhanded hocus-pocus approach to science, but he and Beese are a package deal. A student from HH’s lab who left graduate school thanks to his abominable treatment is actually considering rallying support of the countless others who have suffered HH’s “wrath”. They plan to ensure that new recruits are scared off from Duke Biochem, new private funding is not awarded to the Department and possibly let the NIH members know the cesspool Duke Biochem is!

    BTW, there are rumors that Beese’s farnesyl transferase reaction path paper (Nature, I think) is a dud. What do the insiders say?

    • D said

      Maybe they could get positions at Janelia Farm? Although JF does have a pretty strict code about Scientific Misconduct. Note the words “integrity, responsibility, and accountability”

      Scientific Misconduct

      As an organization dedicated to biomedical research in the public interest, the Howard Hughes Medical Institute (the “Institute”) expects that its scientists will conduct research and engage in related academic activities according to the highest scientific and ethical standards. The Institute’s commitment to these standards embraces the belief that integrity, responsibility, and accountability are part of the fabric of science. Scientific research is, ultimately, a cooperative endeavor based on the central principle of truth.

      http://www.hhmi.org/about/research/policies.html#conduct

      • Federale said

        You really dislike Loren, don’t you? Over and over trying to cast it over onto him.

      • D said

        Actually, looking back over my posts (and I am not a David or D Truck) I believe that this is the first post that I ever mentioned Loren by name.

        So, Federale, I am not sure where this over and over is coming from?

        That said, LLs comments to Nature about how he thinks science is done are extraordinarily lame and naive. I’d love to hear him justify them in front of his eminent JF colleagues. I can hear Rubin’s head slap from here.

        Just to be a little more open, I do not know nor have I ever met LL. But, I do like the irony of JFs expectations compared to how LL has acted so far. I have seen little responsibility or accountability so far. But, perhaps JF is no different than any other academic institution. CYA is their first reaction.

      • GordonBoy said

        Federale,

        Do you have any vested interest in shielding Loren Looger? If not why do you insinuate that he should be absolved of his role in the paper? He is no saint! He has managed to ride the coat-tails of Hellinga and get a coveted position. If Dwyer has been investigated, so why not Looger? Of course, Hellinga is a scumbag for treating his grad students like “data collecting monkeys” but the stduents themselves do not deserve high praise to acquiescing to be SPINELESS data collecting monkeys…. Bring them all to justice. End this charade in the name of science.

      • Federale said

        GordonBoy,

        I have no vested interest in shielding Loren. I’m trying to point out that there are people who have a vested interest in going after him as a diversion away from themselves.

        I’m also more concerned with seeing what he’s written in context. Same goes for Hellinga, who submitted a written response just like Looger did. Both of those written responses deserve to be seen in the open in order to determine whether the journalists may have (likely inadvertently) taken something out of context.

        As has been stated elsewhere, the context of when something was done matters. For Dwyer and Looger (and others in the laboratory) they were STUDENTS at the time. The hierarchical relationship of a student to an advisor presents a set of issues worthy of discussion. Many of the finer points on that have been raised here. Read what I’ve written in that context. It is in that way I encourage that for the sins people believe Loren, Mary, or others have committed; everyone consider that there is a healthy dose of coercion and misleading mentorship involved.

      • D Truck said

        Federale, How do you know Looger and Hellinga provided written responses. I’m skeptical of the account provided by Noblesse as there was supposedly a lot of juicy stuff in the Looger statement and I can’t see both journalists passing that up. I believe Noblesse was told what he/she was told (in as much as you should believe anything here), but this could just be damage control.

      • noblesse d'epee said

        @ D Truck

        You can be as skeptical as you prefer. I really don’t know Looger, and I have no reason to help him with damage control. Like I said, he may very well be in the scientific wrong.

        I strongly suggest that you e-mail Looger and ask him if he’d be willing to share a copy of his statement in response to the Hocker paper. If he has any sense, he’ll at least respond to your good-faith request.

      • writedit said

        If any visitors to this blog from Janelia Farm would like to share something confidentially to be posted, please feel free to send an e-mail.

    • A proposal about a reaction mechanism based on a crystal structure not actually being the case would be nothing out of the ordinary. I have never heard anything bad about Prof. Beese, although I only know some of her work tangentially from an acquaintance who did their PhD. with her. I heard nothing but glowing comments about Beese.

      • Federale said

        Were the glowing comments not appropriate for audiences under the age of 17? If so, then I would agree that the comments and sense of Prof. Beese by any number of people are ‘glowing.’

      • I only know someone that worked for her. They did well, and they seemed to me to be a careful, hard working and unassuming scientist. That said, of course I would like to know more about what the hell is going on. Expose the seedy underbelly!

        I feel for the students here. I really do. I have been in and heard first hand of stories that fit with what some might assume is hyperbolically described as Stockholm Syndrome (it is not). Abusive and manipulative PIs that maintain empires are present in high-powered departments and they always seem to get students, with each student thinking that it will be different for them.

      • noblesse d'epee said

        Beese is, for different reasons, every bit as unethical as her husband.

        Beese has used her control of Duke’s access to SERCAT as a way to retaliate against those who have spoken out against Homme, or who have left his laboratory because they wanted to do “real” science. She recently retaliated against a student who was prominently involved in circulating and signing the student petition regarding Homme; this retaiation was spectacular enough to capture wide attention. The student in question has considered legal action.

        Homme Hellinga and Lorena Beese are a package deal — one which ought to be rejected by Duke. In fairness, Lorena’s science seems solid, but one should consider the human cost, and the fact that she is being allowed to blatantly retaliate against those who are seeking justice for Homme and honesty in science.

      • Rob said

        Don’t forget the fact that she tried to fire two graduate students this fall, right after one got [what she thought was] her protein of interest pure enough for crystallization trials and the other got his crystals to diffract to less than 3 angstroms.

        The reasons he gave these two students? She though post-docs could solve the structures more quickly.

      • GordonBoy said

        Punko said ” I heard nothing but glowing comments about Beese.”

        LMAO! LMfreakingAO! Was your friend high when (s)he said that?

    • noblesse d'epee said

      Your forgot to add that Beese denied SERCAT time to students at Duke Biochem. who either A.) left Homme’s lab but still wanted to do crystallography, or B.) signed/circulated the student petition calling for the investigation of Hellinga. Beese tried to sabotage students’ research in order to avange her husband. How dare she call herself an “educator,” a professsor, or anything of the sort? She does science for petty power and self-aggrandizement. Both Homme and Lorena should be pressured to leave Duke. They’ve done enough harm.

      • TheRoseCaptain said

        This is ridiculous. I really wish people would stop misogynistically pulling Dr. Beese into this.

      • D said

        I wish TheRoseCaptain would stop implying that Dr. Beese is being attacked because she is a women. I see do not see any misogyny in any of the posts. Perhaps you could point it out? And no, using the correct pronoun is not misogyny.

      • noblesse d'epee said

        It’s probably one of Lorena’s harpies trying to defend her. Those in Duke Biochem. know the truth, as does the PI who sat with the student and with Lorena Besse whilst she denied access to Duke’s SERCAT time.

      • D said

        Now, the term Harpie is mildly misogynistic. Let’s not go there please. It will just confuse the issues.

      • noblesse d'epee said

        You’re right, D. I should have used “evil cherub” instead, as that phrase is appropriately gender-neutral and conjures my intended mental image of this . . . defender of the indefensible.

      • TheRoseCaptain said

        Well, this “harpie” or “evil cherub” only wants to present another view into discussion that is heavily biased by one person. Perhaps this harpie should be allowed to share it without being called names. Perhaps this harpie has spent a long time working on seeing other people, including Dr. Beese, as human beings, and not as simple embodiments of black-or-white/right-or-wrong/good-or-evil.

        Perhaps this harpie has seen a fair share of gender equality at this and other top-ten institutions, lest people forget the amazing words of Harvard’s own Larry Summers that were said only a few years ago.

        Perhaps this harpie is just afraid that a decade from now, a series of jack-ass grad students will call her horrible names just because she is a strong, smart, accomplished women who doesn’t take people’s shit.

      • noblesse d'epee said

        I just don’t see what any of this has to do with the discussion. Hellinga is a fraud, who is married to and heavily collaborates with a controversial individual (Beese). Beese happens to be female. I should point out that Mary Dwyer is a female scientist. What does gender have to do with the issues at hand? Nothing!

  38. Perplexed P said

    Gee, there’s a lot of venom here. Let’s not ignore the fact that one or more reviewers and editors let this turkey slide on through. Take a look at the supplemental info for the 2003 Nature paper. Can you find any error bars? How about negative controls? Is all the data even there? Are there any fluorescence changes of more than 5-10% for any of the designed proteins? How many are decreases in signal? Do you believe those? How many Kd’s don’t match the graphs? Would you have raised a flag about all this? And lastly, who created and modified that Word file?

    • D Truck said

      I don’t see much problem with the review of the paper based on the final product. I looked at the supplemental material and there is a discussion of error analysis. Some of the fits to the data aren’t exact but not enough to be of significant concern. And then there’s the in vivo data that seals the deal. Any concerns that you might have had as a reviewer would have to be allayed by _functioning_ receptors. If you wouldn’t allow this paper as a reviewer, then what would you allow? The real problem is that all of the necessary information (variability, etc) wasn’t presented to the reviewers because everyone in science hides their negative data (paraphrasing Looger).

      It’s a similar story to the enzyme paper. It was well-controlled and then there’s the functional complementation. What more could you ask for? How about knowing some of the problems that they had with activity.

      There’s nothing wrong with the review process based on these two papers, in my opinion. Reviewers don’t know if the authors are cherry-picking data.

      • Perplexed P is saying that the experiments seemed to be performed shoddily. Just because the complementation worked shouldn’t give the “right result trumps shitty work” outcome. Perplexed P is saying that he/she would have reviewed the paper such that the current published flaws would not have been in a paper that he/she reviewed. This does not mean that in this alternate timeline he/she would not have eventually accepted the work, although most likely not on an as is basis.

        This would not be the first case of a garbage experiment finding its way into the sexy literature.

      • D Truck said

        And I’m saying that the results presented in the paper don’t support the conclusion that the experiments were performed shoddily. You can make whatever arguments that you’d like, but the paper’s published, so show me the evidence. If it’s there I’ll believe you but don’t just make baseless accusations.

        As an aside, statements like “Are there any fluorescence changes of more than 5-10% for any of the designed proteins?” are just as big a harm to the review process than laziness. Is there some rule that a binding constant can’t be measured with a small fluorescence change? Dealing with stupid reviewer comments like these has to be one of the worst parts of science.

      • It is terrible floating through space nothing but an infinitely omniscient energy being constantly afflicted by the tiniest of unevolved gnats.

        Pinko Punko stepping in here (thank you for your insight, Captain):

        Stepping back a bit, to the extent that hindsight is 20/20, if one wanted to find the hallmarks of cherry picking, regardless of whether cherry picking were occurring, they appear to be present in the 2003 paper supplemental material. “Representative designs” and the absence of statistics for curve fitting or error bars or what have you. I don’t defend either side. I do posit that if one somehow ends up modeling noise, it might be easier to do if the changes measured are only a few percent of the total signal.

      • D Truck said

        I’d posit that the signal to noise ratio would be a more relevant parameter to consider than percent signal change. But it should all come out in the wash of experiment reproducibility. There is a discussion of this in the supplementary materials of the paper.

        Evolve gnats! Evolve!

    • Federale said

      I posted this up above.. but I’m curious if the David W. Conrad that is listed on the filed patent in Feb 2009 is one of our Davids or D truck.

      I’d also strongly urge that somehow the full statements of both Homme Hellinga and Loren Looger that were provided to the journalists be seen by more people. I believe any number of concerns can find some measure of resolution with both of those in hand.

      • Absolut Vodka said

        Federale, how can we get our hands on these documents.

      • David said

        Though my real name is David, I have no connection to Hellinga or his patent applications. I have spoken to Federale and Noblesse. Not sure about anyone else.

      • noblesse d'epee said

        I can vouch (so far as anyone can in cyberspace) for the fact that the “David” in this blog is *not* David W. Conrad.

  39. ChronicInsomnia said

    Just heard: HH is moving to Monsanto. VP of Research & Development. End of a brilliant academic spell. Not sure about LB though.

    • Talk bout failing upward. If true, I’m shorting Monsanto.

    • D said

      That would be surprising given that Monsanto already bought rights to HH’s Dezymer program via his startup Protabit. (http://www.genomeweb.com/informatics/monsanto-picks-protabit-agbio-protein-design-software-project) Since that is in the process of crashing and burning why would they hire him now?

      • D said

        Protabit is hiring

        Protabit is seeking to fill positions in the following areas.

        Scientist/Senior Scientist — Scientists who have worked in the field of Computational Protein Design. PhD required.

        HH has certainly worked in the field. I wonder if his own company will hire him?

      • noblesse d'epee said

        Short sell, short sell! And it isn’t even insider trading! I hope that Homme leaves, although it is mind-boggling that Monsanto really thinks Duke’s highest-profile charlatan will further its research goals. In industry, inventions actually have to work, as the bottom line is at stake.

        On the other hand, it will be delightful if Homme leaves. Our Biochemistry Department needs a fresh start.

    • Interesting that the Nature News article quotes Mayo offering what amounts to a defense of Hellinga, but does not disclose his shared financial interests (Protabit/Monsanto) with Hellinga. That’s a rather glaring and direct conflict of interest.

    • goldenboy said

      Where the hell did you get this from? Hellinga is very much still at Duke and is not going to leave anytime soon. Monsanto will not touch him with a 10 foot pole. Lorena got elected to NAS (expect a flurry of papers in PNAS from Hellinga…..)

      • Rob said

        Goldenboy–
        PNAS is ending communicated submissions next year, so Beese can no longer help Hellinga churn out the shit he’s been publishing. He’ll have to go through the direct submission process….

        Although, I wonder if he will now designate Beese as his prearranged editor, now that she is in the academies.

      • Federale said

        That is easy to end. It violates the PNAS conflict of interest policy. One need only to send a letter to remind them that this is unacceptable.

      • TheRoseCaptain said

        Dr. Beese and Dr. Hellinga have made it a priority in their academic careers to be as independent of each other as possible. The two don’t allow students to be on the other’s committees. Dr. Beese is very careful when it comes to publishing her own papers: do you really think she would haphazardly get his papers out for him?

        Give her a little more respect and credit than that.

        And I will repeat, I wish people would stop misogynistically dragging her into an issue she doesn’t belong in.

      • D said

        Again TheRoseCaptain, where exactly is she being attacked because she is a woman? I don’t see it. Maybe the attacks are unfair but I don’t see any anti-female bias. Enlighten us.

      • noblesse d'epee said

        The jump to claims of misogyny is unjustified. There is simply no evidence for this. I would fight just as diligently against a corrupt male scientist. Note the (deserved) drubbing given to Hellinga.

  40. scotus said

    Any idea how Hellinga’s departure to Monsanto will impact on the slow moving misconduct investigation(s) at Duke?
    Is there any possibility that Hellinga decided to bail out in anticipation of an unfavorable outcome of these investigations?

  41. scotus said

    From my June 4 posting in the original thread:

    “My prediction is that Hellinga will end up moving to the private sector..”

  42. Jimmy DooLittle said

    This also just in…..

    Hellinga has been linked to the balloon boy hoax!

    It appears that the balloon was designed to carry bits of the Dezymer cluster to Monsanto headquarters in St. Louis….and they were attempting a test run with a small child aboard!

    Noblesse du Pee….there should be no containing your outrage now!

  43. TrainedInPharmacology said

    I don’t understand why changes in the fluorescence of a fluorescently labelled engineered (aka “Dezymer-ed”) protein in the presence of a substrate were ever accepted as evidence of binding when it was never validated. It seems to me that this technique would have to be validated prior to use for every designed protein-substrate complex.

    Crystallizing the protein-substrate complex is the best evidence of such a phenomenon (and would arguably have been within Hellinga’s reach).

    A simpler way (not as convincing, but less time consuming) would have been to do binding assays with a radiolabelled agonist and competition assays with an antagonist, if available. This doesn’t “nail it” like crystallography does, but would have provided an indication that further, labor-intensive structural studies would be worth the time and effort… and un/expected Kd’s would have provided evidence of actual “binding” (or not). This is what is done when screening for targets of novel small molecules.

    From what I understand, proteins/receptors are highly dynamic and will try to fold around various substrates…so of course you would expect changes in fluorescence upon introducing a substrate to a fluorescently labelled protein.

    What evidence did they have to conclude that a confirmational change, as indicated by changes in fluorescence, was one associated with binding?

    • D Truck said

      It seems that your main argument is that “more evidence is better”. That’s indisputable. What was the evidence that the ligands bound to these designed receptors? The ligands induced a saturable fluorescence change in the receptor that was not observed with related, but different ligands. That’s pretty solid evidence. Furthermore, when these receptors were included in a bacterial signaling cascade they became specifically activated by the desired ligand. At least that’s what was reported, and together it makes for a compelling story. It’s possible that a reviewer did request additional evidence, like a co-crystal structure, but that the authors argued against it and won the battle. However, my feeling is that it’s a solid paper and that the problems resulted from things that the reviewers couldn’t have known.

      “From what I understand, proteins/receptors are highly dynamic and will try to fold around various substrates”

      Are you saying that any protein/receptor will bind to any ligand because proteins/receptors are “highly dynamic”? If so, you’re incorrect.

    • D Truck said

      I will follow up by saying that no binding assay is perfect. For example, introducing an exogenous fluorophore alters the system and this should be controlled for. This control (competing a dye-RBP:ligand complex with unlabeled RBP) was lacking in the paper and I would have requested it, but I still don’t fault the reviewers.

  44. scotus said

    Right- the problem with measuring changes in fluorescence, or fluorescent reporters resulting from changes in environment or motion is not inherently quantitative. One just measures the phenomenon and then infers that changes between an arbitary minimum and maximum report changes in binding. If this isn’t the case then these measurements are invalid. One could imagine a situation where preparations of a recombinant protein that were largely inactive as a result for example of being misfolded could exhibit fluorescence reported binding as a result of contamination from say wild type proteins that were present at lower levels. A direct measurement of binding stochiometry would of course reveal this immediately.

    • D Truck said

      “the problem with measuring changes in fluorescence, or fluorescent reporters resulting from changes in environment or motion is not inherently quantitative.”

      on the contrary, it’s one of the most quantitative binding assays available.

      “One just measures the phenomenon and then infers that changes between an arbitary minimum and maximum report changes in binding.”

      If one is measuring a fluorescence change in the receptor, and the quantum yield of the receptor is changing when a ligand is added, how do you propose it is changing, if not through binding?

      “A direct measurement of binding stochiometry would of course reveal this immediately.”

      Such as….?

      • scotus said

        So in order to make these assays quantitative you would presumably have to be able to predict how the “quantum yield” of the receptor would change when the ligand bound. Sounds like a problem Hellinga could turn his attention to. The point I was trying to make is that without some independent quantitation of the binding all you have are ligand dependent changes in fluorescence that tell you nothing about how many molecules of the receptor are functionally active.

        Ideally one would independently determine the number of moles of your receptor in your starting preparation (acurate mass measurements, chemical analysis, absorbance measurements using a calculated extinction coefficient and so on) and then use a similarly quantitative approach to determine how many moles of the ligand were bound to the receptor at equilibrium in the presence of a saturating concentration of ligand. The use of a radioactive tracer of known specific radioactivity and then physical separation of the receptor ligand complex from the free ligand would be the “classical” approach here.

        I’m sure we can both agree that it would have been a good idea to make these measurements using more than one approach.

      • D Truck said

        “So in order to make these assays quantitative you would presumably have to be able to predict how the “quantum yield” of the receptor would change when the ligand bound.”

        Why would you have to predict it when you can measure it? Do you actually do this stuff or are you just pontificating?

        “The point I was trying to make is that without some independent quantitation of the binding all you have are ligand dependent changes in fluorescence that tell you nothing about how many molecules of the receptor are functionally active.”

        Typically, binding experiments are done such that the [R] < Kd such that the concentration of functional receptors only influences your signal to noise ratio.

        "Ideally one would independently determine the number of moles of your receptor in your starting preparation (acurate mass measurements, chemical analysis, absorbance measurements using a calculated extinction coefficient and so on) and then use a similarly quantitative approach to determine how many moles of the ligand were bound to the receptor at equilibrium in the presence of a saturating concentration of ligand."

        Did you actually read the supplemental materials? They performed ligand depletion (aka stoichiometric binding) for some of their supposed high affinity receptors.

        "I’m sure we can both agree that it would have been a good idea to make these measurements using more than one approach."

        Who would argue that doing more experiments and collecting more evidence isn't "a good idea"? But papers eventually have to be published. Put me down as a reviewer for your next paper and I'll find shit for you to do for the next 20 years.

      • D Truck’s technical arguments here and upthread are very sound, as are his/her perspectives on peer review.

      • scotus said

        Do you agree that in order to determine how the “quantum yield” of the receptor changes in response to ligand binding one would have to quantitate ligand binding using a technique other than measuring changes in fluorescence?

        How does “ligand” depletion (displacement) address this issue if these measurements were also made by monitoring changes in fluorescence?

        Yes, at some point it becomes unreasonable to ask authors tod o more and more but at the same time one woudl expect that the central finding of an important paper would have to be validated using complementary approaches.

      • D Truck said

        “Do you agree that in order to determine how the “quantum yield” of the receptor changes in response to ligand binding one would have to quantitate ligand binding using a technique other than measuring changes in fluorescence?”

        No. Look up quantum yield. It’s even on wikipedia.

        “Yes, at some point it becomes unreasonable to ask authors tod o more and more but at the same time one woudl expect that the central finding of an important paper would have to be validated using complementary approaches.”

        And in the paper under discussion (Looger et al.) complementary approaches were used: in vitro binding and functional assays.

  45. TrainedInPharmacology said

    Yes-Scotus’s explanation may also explain some of the variability and any difficulties with reproducibility.

  46. JimmyBoy said

    I am sure Phil Evans and Fred Richards are having sleepless nights seeing their “star” student sink so low for the quest of fame! Both Phil and Freddy were amazing professors who really knew what mentorship meant, what scholastic pursuit of science meant (and none of them claimed to be better than Darwin or spent sleepless nights in the first week of December expecting a call from Stockholm. How can such labs, such Professors sire such a student? All the lives of intelligent grad students he has quashed will come to haunt him. The SOB should be exiled from any form of science. Monsanto would not like the fall-out from hiring him! Someone who blames his grad student and wants her PhD rescinded to save his own sorry ass is definitely not a team player. May Hellinga’s scientific soul rot in Hell….

    • D Truck said

      Fred Richards died last year. RIP.

  47. JimmyBoy said

    By the way, which country is Hellinga a native of? is he from Eastern Europe? or Belgium? or is he British?

    • noblesse d'epee said

      Might any NMR spectroscopists care to comment upon the NMR titration data in Hocker’s paper? Friends in the protein NMR field tell me that even if most of Hocker’s preparations contained aggregates (as Homme postulates), one would still likely observe peak-shifts upon ligand addition corresponding to the population of properly-folded protein binding to its ligand. Obviously, nothing of the sort was observed. Moreover, the 2-D spectra look pretty well-dispersed, suggesting that the protein, if unstable, is still in relatively good condition during titration.

      As for the calorimetry: One of my colleagues worked in close proximity to the Hellinga’s ITC apparatus back in the days when it was stored in a common area on a different floor than Hellinga’s lab. This colleague observed numerous ITC experiments being performed on a near-continuous basis — for years. This colleague recently noted that none of Homme’s papers contain actual ITC curves. It seems odd, does it not?

      • noblesse d'epee said

        Oh, and Homme is from either the Netherlands or Belgium, but completed most of his education in Great Britain, before disgracing the US with his fraudulent science.

      • Jack said

        RE: Hocker’s NMR experiments, the text in the paper seem to sufficiently explain the results. What specifically did you want addressed?

      • noblesse d'epee said

        @ Jack

        I’m not an expert at NMR. I just wanted to solicit further confirmation that the NMR data seem solid, and specifically, that the data are inconsistent with ligand binding to the DEZYMED PBP’s, *even* at high protein concentrations wherein some aggregation might occur.

  48. TrainedInPharmacology said

    D Truck-
    I agree that fluorescence is an incredibly sensitive and quantitative technique. However, this is an indirect assay, and so if the quantum yields aren’t mapped to actual conformational states, how can you be so sure that the conformational changes observed represent binding? What if the saturable fluorescence change represents a non-binding equilibrium state?

    I propose a conformational change induced in the protein as a result of dynamic interactions with the ligand resulting in an equilibrium state that is non-binding.

    • D Truck said

      “I propose a conformational change induced in the protein as a result of dynamic interactions with the ligand resulting in an equilibrium state that is non-binding.”

      So you’re proposing interactions… that aren’t interactions? I don’t think that would hold up to “further scrutiny” as Homme likes to say.

  49. Verfaillie said

    What is it with these Belgians and data fraud? Remember Catherine Verfaillie from Minnesota . There are at least two more Belgians who run extremely shady lab practices in Houston & Chicago.

    • Gaby said

      The Verfaillie case reminds me. Morayma Reyes, who falsified data, is now an Ass Prof. http://www.pathology.washington.edu/faculty/profile?id=843
      She too was a “Star” grad student.

      Moral of the story: Cheat & win. Want to be recognized as a potential tenure track candidate right from grad school days? Manipulate data!!!!!

      • D said

        I don’t know that Reyes has really won much at this point. According to NIH reporter she has 1 R03 grant three years into her job at UW. Her career and reputation are clearly tarnished. Unless ORI investigates her and finds fraud (and I haven’t seen that they have) I don’t know that there is much that UW can do except wait until her fives years are up.

  50. goldenboy said

    Where the hell did you get this from? Hellinga is very much still at Duke and is not going to leave anytime soon. Monsanto will not touch him with a 10 foot pole. Lorena got elected to NAS (expect a flurry of papers in PNAS from Hellinga…..)

    • noblesse d'epee said

      “Homme may not be going anywhere soon” . . . unless, of course, Duke terminates him for, among other things, research misconduct and the serial abuse of his graduate students. His spouse, the lovely Lorena Beese, will soon face her own difficulties stemming from her well-documented practice of blocking students’ access to crystallography resources (e.g. synchrotron time) in retaliation for those students’ publicly requesting that Hellinga be investigated for research misconduct. Use of a federal resource to retaliate against whistle-blowers tends to have severe legal consequences. Homme and Lorena have, to put it indelicately, screwed the pooch here.

  51. NicaraguanContras said

    Why you guys are giving Looger the benefit of doubt is incomprehensible to me. I laid my hands on Looger’s original manuscript back in 2004/5 (long story short: my the-then girlfriend’s lab-mate had gotten a copy to go over and suggest corrections/critique manuscript, and the paper remained on the desktop folder….). The draft looks nothing like the final paper. Obviously between the draft & what Nature printed, Looger & Hellinga painted their magic……

    • D said

      Looger may be an narcissistic ass and a poorly trained scientist, the later of which is supported by the retraction of 2 or more papers, but the evidence that he is a fraud is innuendo and hearsay at this point. Anonymous comments posted on blogs have to be taken with a modicum of skepticism

      The fact that an early draft of a manuscript looks little like the final published paper says nothing about Looger. It does suggest that you have not published many papers.

  52. NicaraguanContras said

    ” The fact that an early draft of a manuscript looks little like the final published paper says nothing about Looger”.

    Ha🙂 But my friend data tables & figures dont change, they dont get MODIFIED overnight, fluorescent readouts & error bars DONT change, language & interpretation DONT change….

    • Kary Mullis said

      If your (ex?)girlfriend still has this file or can even find a print-out, PLEASE anonymously send it to medwritedit@aol.com and Writedit will publish it, doing the scientific community a HUGE favor.
      Please please please?

      As a Nobel laureate myself, I scoff at the idea that Homme would even consider joining our august ranks.

      Good luck selling seeds!

      • D said

        Kary,
        How are you doing? Still doing the HIV and Global Warming denialism circuit?

        Every meet up with that fluorescent alien raccoon again?

    • D said

      Without seeing the draft myself it is hard to say. If the data has totally changed without further experimentation then that is suspicious. You say it happened overnight but I don’t know how old the draft was compared to the published paper. This is part of the whole

      “the evidence that he is a fraud is innuendo and hearsay at this point.”

      I won’t assume someone is guilty of fraud based on an anonymous critique of a draft paper found on a computer of the labmate of an ex-girlfriend from 2004. For all I know you resent Looger because he seduced your ex-girlfriend into dumping you.

      Also, if the language and interpretation changes that can be the peer review process of science.

  53. Nintendo DS said

    Why is it that an overwhelming number of scientist couples (who are int eh same institution/department) are prone to running fiefdoms? Scientist/administrator couples are even scarier! Maybe grad students/post-docs should avoid working for such PIs.

    • “Scientist/administrator couples are even scarier! ”

      Word.

      • noblesse d'epee said

        I second Nintendo’s statement, a position I take due to recent personal experience with this problem. Homme Hellinga and Lorena Beese need to go, separately, from Duke.

    • D Truck said

      “Why is it that an overwhelming number of scientist couples (who are int eh same institution/department) are prone to running fiefdoms? ”

      Consolidation of power. Power corrupts.

  54. Perplexed said

    full comments from HH and LL were posted here:
    http://www.the-scientist.com/community/posts/list/704.page

    • Federale said

      Looks as though the Looger response is truncated. In #4 he refers to #5 which is not there…

  55. Kary Mullis said

    The manuscript submitted to PNAS by Schreier et al. reports studies on mutant periplasmic binding proteins (PBPs) that were constructed in my laboratory. In our original findings we reported that computationally designed mutations introduced into the binding sites of these proteins altered their ligand-binding specificity radically. These findings were based on changes in fluorescence intensities of single, environmentally sensitive fluorophores attached to mutant cysteine positions.
    Discrepancies between the Schreier et al. observations and our work could have several origins. First, Schreier et al. need to make their observations at high protein concentrations (micromolarmillimolar), whereas the fluorescence assays use low concentrations (nanomolar). Second, their observations were made in the absence of conjugated fluorophore. We know that the intrinsic equilibrium between the open and closed state of PBPs can have a significant effect on apparent binding affinities, through thermodynamic linkage relationships. We have reported that this equilibrium can be manipulated experimentally by making mutations and attaching non-natural bulky groups, thereby significantly affecting binding affinities. In maltose-binding protein (MBP) this intrinsic equilibrium is very unfavorable to forming the closed state (measurements made by other groups). We now also know that this equilibrium is “tuned” by specific domains in many PBPs – we are finishing a manuscript describing these observations. Therefore, attachment of a fluorophore potentially can have significant effects on binding in the designed proteins.
    We are investigating these issues for the designs in the Schreier paper, using techniques that can determine the free energies of protein stability and ligand binding using very low concentrations of protein. These techniques detect ligand binding by taking advantage of the thermodynamic linkage between protein stability and binding. This work is currently on-going, and will require some time to be completed, not least because some of the fluorophores are not available commercially and need to be resynthesized.
    A second possibility (postulated by Schreier et al.) is that a subtle artifact in the fluorescence
    observations gives the appearance that the changes in intensity are due to binding, but are in fact caused by another phenomenon. If we fail to observe binding in the studies outlined above, then we will draw the same conclusions. If that is the case, we will try and identify the physical phenomenon that gives rise to false positives in ligand-mediated changes of fluorescence intensities, so that it can be avoided in future work.
    Schreier et al. make the important point that it is necessary to establish a set of independent
    methods that allow observations to be corroborated. We have in fact carried out such a study on a different design: the design of an ibuprofen-binding site into MBP. We have completed the experimental observations for this work, and are finishing a manuscript describing it. It turns out to be a complex case study, because of some of the unanticipated properties of MBP and ibuprofen, which we had not appreciated when we started this work. Briefly, we observe interactions between ibuprofen and the mutant proteins by a) fluorescence of a conjugated fluorophore, b) isothermal titration calorimetry, c) magnetization transfer from the mutant MBPs to ibuprofen in NMR experiments, d) ligand-mediated changes in protein stability using the methods mentioned above. The apparent affinities are modest (200-400 micromolar). The ligand-mediated changes in protein stability are more complex than usual, because ibuprofen apparently acts as a mild protein denaturant at high concentrations. An X-ray structure reveals that the designed ecMBPs do not adopt the closed form, and that binding therefore appears to occur to a half-site. Our interpretation is that i) observation of ibuprofen binding in the designs is corroborated by very different techniques, ii) the binding mode is not as predicted, because the large intrinsic unfavorable equilibrium between open and closed states in MBP (see above) presents a significant barrier. These
    techniques will be used in future design studies.
    Schreier et al. also report that the side-chain positions in the designs are essentially as predicted in the original designs. This observation helps pinpoint the way forward in future design work: the problem is not that side-chains are packed incorrectly, but that we need to focus on the modeling of the energetics of protein-ligand interactions.
    We greatly appreciate the extensive effort undertaken by Schreier et al. to characterize further these designed proteins. More studies are under way to understand the discrepancies between the sets of observations. If these studies also show that our original interpretations are in error, we deeply regret that our reports of these designed receptors do not live up to closer scrutiny. In that case, we offer our sincere apologies to researchers whose work was negatively impacted by these reports. We remain optimistic that the computational design of ligand-binding sites will become a reliable technique in the future.

    Signed,
    H.W. Hellinga
    Department of Biochemistry
    Duke University Medical Center
    Durham, North Carolina
    October 9, 2009

    • noblesse d'epee said

      Homme’s statement is rife with rather implausible explanations for his non-functional designed “biosensors.” I find it interesting that he never reports the structure of his fluorophores that “are not available commercially.” It is extremely unlikely that the presence of fluorophore causes otherwise non-functional DEZYMED proteins to bind to their target ligands with micromolar to nanomolar affinities and exquisite specificity, as reported in Hellinga’s 2003 Nature paper. Even if the fluorophores mediate ligand binding, one would not expect to observe specificity (especially stereospecificity) as reported by Hellinga. While we wait for Hellinga’s mysterious fluorophores to be “re-synthesized,” he’ll hold his ill-deserved faculty position for another year.

      Homme’s argument with regard to protein concentration is likewise an unlikely explanation for the discrepancy between his and Hocker’s data. The NMR titrations, in particular, would reveal peak shifts upon ligand addition, even if a large population of the protein is aggregated due to its putative instability. Note that the wild-type PBP’s are extraordinarily stable and exceedingly soluble.

      Homme’s hand-waving discourse on “tuning” PBP equilibria and “thermodynamic linking relationships” is utter bullshit, and is typical of the florid bloviating that Homme employs to cover for his dishonesty and incompetence. The explanation has little to no scientific merit. We’ll see if his “manuscript” on these subjects ever clears the peer-review process.

      As for the ibuprofen binding protein — again, we’ll see what the reviewers say. Even if this design works, with its modest binding affinity, it in no way explains his other reported results, nor does it “forgive” them.

      Looming over all of this, of course, is the patent impossibility of Homme’s triose phosphate isomerase design. There is no explanation except for research misconduct, and Homme has never even tried to offer a remotely plausible explanation for his retracted results. This is simply fraud.

      Nature and PNAS should retract Homme’s PBP papers immediately, given his well-documented record of dishonest and incompetent science, and given the strength of Hocker’s findings. Hellinga has long since forfeited any claim upon a “benefit of the doubt.” This charade must end, and its perpetrator must be forever banished from science. How many students, post-doc’s, and PI’s have wasted precious time and money trying to replicate, or to build upon, Homme’s published work? The collateral damage from this cluster-fuck is simply staggering. Why continue to mislead people by leaving Homme’s defective science in the peer-reviewed literature?

      With regard to Homme’s PBP papers, I paraphrase Robert of Geneva, Homme’s intellectual progenitor, when I say “kill [retract] them all, and let God sort it out.”

    • D Truck said

      Yeah, what a load of BS. I don’t buy any of it.

  56. Kary Mullis said

    Tune in, turn on, drop out, retract the papers.

    Looren Looger responds to questions from The Scientist:

    1. Did Hocker send you a copy of this manuscript prior to publication? Were you surprised by the results, or did you already have a suspicion that these proteins didn’t work quite as intended? Do you dispute anything in the results or the interpretation?

    Yes, she did, on July 21st, after it was submitted. I am not terribly surprised by the results; I had become suspicious that the designed proteins did not work very well, due to several lines of data. While at Duke, many in the lab noticed that the heavily-mutated proteins seemed to suffer from poor thermodynamic stability: a fluorescence titration result, although robust over several repeats at a given time, would not infrequently drop off over the course of days or weeks, suggesting that something about the protein-dye conjugate was changing, likely due to aggregation, unfolding, or precipitation. Second, in my post-doc lab, we made the mutations to genetically-encoded FRET glucose and ribose reporters that should have conveyed lactate binding (we wished to have a genetically encoded lactate sensor). The resulting proteins showed fluorescence spectra consistent with a poorly-folded sensor. It is conceivable that the fusion with the two fluorescent proteins placed such a thermodynamic stability demand on the redesigned proteins that it dramatically altered their folding state; but I began to suspect that the redesigned proteins were sitting “on the edge” of being unfolded, most likely as molten globules. I do not dispute anything in Dr. Hoecker’s work; in fact, I strongly encouraged her to pursue this line of research.

    2. Have you previously heard of researchers having problem with the fluorescence assay? Do you know of any groups outside of Duke that have succeeded with it? Did Hocker ever try it when she was still at Duke?

    Other labs have used the small molecule dye fluorescence as a reporter for binding, but to my knowledge, this has been confined to work with wild-type proteins. Several individuals in the Hellinga lab, not on the 2 publications, were able to reproduce the fluorescence titrations from the 2 papers. I hear that labs outside of Duke were able to similarly repeat the fluorescence titrations, but encountered problems with aggregation and variability over time. The growing consensus is that for stable, well-folded (e.g. wildtype) proteins, the fluorescence reporter assay can work fine. But the current work, as well as (Marvin & Hellinga PNAS 2001; Telmer & Shilton J. Molec. Biol. 2005), shows that heavily-redesigned proteins can have their open-to-closed equilibria sufficiently altered that: 1. Fluorescence response does not equate with binding, and 2. Binding does not equate with formation of the expected bound state. While at Duke, Dr. Hoecker worked with dye-labeled wild-type proteins, where the signaling mechanism seemed to work well.

    3. It should work, of course. So, do you have any idea why there is a discrepancy between that method and the structural studies?

    I think that the robust biophysical characterization given to the proteins in the PNAS paper is correct. I think that the small molecule dye-based allosteric signaling mechanism is prone to artifacts, particularly for destabilized proteins in which the open-to-closed conformational equilibrium may be greatly perturbed. The small molecule dyes in question are exquisitely sensitive to small environmental perturbations; that was the rationale for choosing them in the first place. The discrepancy serves to highlight the risk in using the small molecule dyes as a proxy for ligand binding, without robust “orthogonal” characterization by a non-fluorescent method.

    4. I understand you mostly worked on the software side of things, right? The authors note that your computational model seems to work for the side chains. Why do you think it is only partly predictive? Does this mean you could make a few tweaks — or is this a big issue that will take a lot of work to resolve?

    That is a correct characterization of my involvement, although I did do some experimentation for the Nature 2003 paper (see #5). I have data (including a high-resolution crystal structure of a designed protein-ligand interface) showing that a computational methodology similar in its spirit to that described in Nature 2003 can be
    extraordinarily useful for prioritizing potential protein-ligand complexes. This designed protein-ligand interface was based initially on a computational model, and the first round of mutants tested showed pretty good activity. But this was refined by many rounds of directed evolution; it would have been very difficult to achieve the desired result without this. I believe that the most important take-home message is that it is important to combine rational & computational modeling with non-biased screening & selection methods.

    • Federale said

      As mentioned above.. I think this is a truncated statement. There is a reference in it to a #5 and then that does not appear…

  57. D Truck said

    I love how both of them give us their “take home message” for their shoddy-ass work. Lets turn lemons into lemonade!

    • noblesse d'epee said

      What I found redeeming among Looger’s comments was the following observation, which I interperet as evidence that he has learned a lesson from all of this, perceived (or real) arogance nonwithstanding:

      “I believe that the most important take-home message is that it is important to combine rational & computational modeling with non-biased screening selection methods.”

      Amen. Especially the “non-biased” part. Looger at least admits mistakes, and synthesizes a reasonable take-home message, whilst Homme takes no responsibility to the bitter end, and wafts about in his usual cloud of obfuscatory scientific flatulence.

    • D Truck said

      I didn’t find anything redeeming about Looger’s statement. Where’s the responsibility? He tries to make it come across as an honest mistake while focusing on his latest ground-breaking work. I don’t buy for a second any of their explanations and where’s the explanation of the in vivo results? Getting smoke blown up one’s ass may be a good way to describe the feeling.

      And we haven’t seen the most damning comment about “negative results” to put it in context.

      • noblesse d'epee said

        You make a good point. That section (#5) seems to be missing, hopefully by mistake. If I was in this situation, I’d try to handle my statements and disclosures a little more carefully than Looger. I’ve always thought that scientists, as a group, tend to be less savvy regarding public relations than the remainder of humanity.

        For whatever (perhaps irrational) reason, I still think that the tone of Looger’s statement is far more balanced and forthright than Homme’s. He directly admits that mistakes were made. One could argue that Looger, while he was working for Homme, should have brought his concerns about the “wet” data to committee members and/or should have refused to allow the papers to be published until these inconsistencies were addressed to his satisfaction. However, one must consider the vast assymetry of power which existed between Homme and his graduate students, and the former’s frequent recourse to immediate retaliation against those who even mildly challenged his pre-determined findings. Homme would likely have tried to have Looger thrown out of graduate school as a result of such a challenge. The faculty of Duke Biochemistry, for the most part, looked the other way when Homme terminated the employment of those who didn’t “perform” for him. Looger was a trainee. Homme is a PI with a reputation for exceptional ruthlessness. Should Looger have taken a stand? Perhaps. Would we have taken that risk if we were in his shoes at the time? I do not think that we are in a position to answer this question. This is a mentorship issue, and so long as his students were not feeding him falsified data (which they were not, as was established by a Duke investigation), Homme bears the ultimate responsibility for the validity of his lab’s published data.

      • D Truck said

        “Should Looger have taken a stand? Perhaps. Would we have taken that risk if we were in his shoes at the time? I do not think that we are in a position to answer this question.”

        I agree that we don’t know enough about the situation to incriminate or exonerate Looger’s actions at the time. He could be entirely responsible, or he could be completely innocent. However, from what I’ve heard so far, I’m not impressed with his _current_ abilities or attitudes as a scientist.

  58. This might be a good time to reiterate what actual scientific accountability looks like.

    Report of the Investigation Committee on the possibility of Scientific Misconduct in the work of Hendrik Schon and Coauthors [PDF].

    • Rob said

      Everyone here should note that the allegations against Schon first arose in 2002, and the committee to investigate the allegations first convened in May 2002. The report is dated September 2002. It took only 4 months to investigate the fraud and issue a final report.

      Duke has had an investigation ongoing since May 2008. It has been over a year, and yet the committee has yet to reach a conclusion. It is quite clear that Duke is dragging its ass, hoping that folks just forget about the Hellinga mess.

      There is no reason that it should take Duke this long to investigate the TIM results.

      • D said

        If a company that licensed any of this IP is threatening to sue then I imagine that Duke would be in no rush to complete the investigation.

      • Rob said

        @D-
        Yes, the downside of licensing and ventures….

  59. NicaracuanContra said

    Looger at it again! This guy is really quite a piece of work!

    That Hellinga is a scum bag has been proven beyond doubt, he is a waste of space, his science is baloney and his career is pretty much over. Now this Looger fellow must be brought to book.

    Full Disclosure: I have nothing personal against either Hellinga or Looger but a shitload of grudge against unscrupulous douchebags who masquerade as scientists by drumming up their “discoveries”, where honest hardworking self-critical scientist suffers from ignominy.

    • Kary Mullis said

      Hear hear.

      This whole business is pretty unbelievable. I hope we see editorial retractions of all Hellinga’s affected work soon.

  60. expat posdtoc said

    As someone who has worked with bPBPs, both sets of comments are plausible. However, that doesn’t explain their crappy interactions with colleagues. Furthermore, you guys REALLY need to separate these two interconnected issues.

  61. luna Halloween said

    Noblesse,

    Your questions:

    “Should Looger have taken a stand? Perhaps. Would we have taken that risk if we were in his shoes at the time?”

    are very profound. Taking a stand, when you love your work and have a family to support, is not easy. It is very difficult for graduate students, because they are unprotected, and might be equally difficult for young and seasoned professionals.

    Yet, I think we ought to think and device strategies to help people and ourselves to stand up. I don’t know how to do that but we, definitively, need to find ways to do it.

    Thanks

  62. D Truck said

    What always bothered me about Hellinga’s work, and what made it reek of BS from the start, is that it was never clear why he was able to get things to work whereas others weren’t. In other words, the technical advances that allowed them to reportedly design sensors and and enzyme weren’t discussed. Instead, much was made of irrelevant or obvious details. It’s the same thing in their statements above. For example, Looger concludes that it is important to follow rational design with a screen. Wow, that would have been a keen insight 10 or 15 years ago Looger! And then there’s Hellinga talking about how ibuprofen is a mild protein denaturant at high concentrations. Give me a break. If ibuprofen is denaturing proteins at the concentrations they’re using (which I doubt) then it’s a very strong denaturant (e.g. urea and GuHCl are used at high molar concentrations).

    Basically these guys come across a pretty crappy protein chemists.

  63. BigDaddy said

    The science is definitely crappy. The people also seem dubious! Yet one is an Endowed Professor and the other a HHMI Group Leader. Way to go!

  64. foo said

    *sigh*

    I only hope this doesn’t make people paint all labs in this field with the same brush. Some of us still think (and are banking our careers on) computational design as promising approach to develop proteins with new function.

    • D Truck said

      The Baker lab has apparently done careful, methodical science with excellent results, that provides an excellent counterexample to the Hellinga train wreck. Fortunately, that makes it difficult for anyone to make sweeping generalizations about those working on protein design based on this one blemish on the field.

      • noblesse d'epee said

        I agree with you regarding your comments about Baker and the protein design field in general. I just wish that David Baker would lose his inferiority complex with regard to Homme. Baker is a much better scientist, and ought to stop acting as if Hellinga is some sort of mentor/father figure. Homme is a fraud. Baker is a collaborative, rigorous scientist with a sterling reputation and paradigm-shifting accomplishments. Their names do not belong in the same sentence.

  65. David said

    Hellinga’s explanation to avoid retraction is that the in vitro experiments need fluorophore at the correct protein concentration. However, Hellinga completely ignores his own data showing binding in a cellular system. Hellinga reported that unmodified mutant PBPs bind their ligands in bacteria (without fluorophore modification). Without much more hand-waving this conflicts with his proposed explanation for the discrepancies with Hocker’s data.

    The fact that Hellinga ignores his own “confirmatory” cellular experiments is quite telling to me. Recall that Hellinga has also never even attempted to explain the results for NovoTIM in bacteria where the admittedly nonfunctional NovoTIM magically functioned in cells.

    • Exactly.

    • D Truck said

      hear hear

      • noblesse d'epee said

        Right on, David.

    • DickTracy said

      David, Send The Douche this email. Have any of you folks had The Douche in your dissertation/candidacy exam committee? Have you heard his argument on how experiments should NOT have tortuous logic? Maybe he forgot to follow his own mantra for a couple of manuscripts.

  66. DickTracy said

    A bit of investigative snooping around the Hellinga lab reveals he is busy junking old computer drives. WTF! If you dont believe me, go there and find out for yourself. The SOB will stop at nothing. I put a post-in on his door with the URl to this site. and a Happy reading smiley face.

    • noblesse d'epee said

      His lab should be sealed. I wonder if probable cause (in a legal sense) could be made for seizing these materials for Duke (or ORI’s) investigations? Tomorrow, I’ll go up there and have a look to see if I can confirm this. I hope that this isn’t true.

  67. D said

    Sounds like the Dukie mob is getting out its pitchforks and torches to go after Dr. Hellingenstein.

    I don’t think ORI has the law enforcement power to seize any materials. It is up to the school to do that. Although if any hard drives were bought with NIH money they are technically gov’t property. Of course if he knows the school is being sued and still destroys the drives that could be a problem.

  68. scotus said

    In the realm of a research misconduct investigation not being able to produce data is basically the same having not done the experiments in the first place and is taken as evidence of falsification. In fact, in the Schon investigation discussed elsewhere in many cases he just couldn’t produce data to account for the published work (along with pretending that unfeasibly precise theoretical data was really experimental data…).
    Trashing hard drives would not help Hellinga at all although I suppose he could be destroying all of the contradictory data that he ignored during the “cherry picking” process.

  69. David said

    From Nature News Comments:

    “Jeff Smith has contacted Nature requesting that the editors clarify that of the three proteins he tested, one signaled reproducibly in an in vivo assay and the other two did not signal reproducibly in the same assay. In his opinion this is quite different from the statement that ‘two consistently did not work.’ Additionally, he says that what convinced him that the one design worked was that another lab independently reproduced his results in another organism. Alexandra Witze 19 Oct, 2009”

  70. scotus said

    Does anyone know how much TIM activity is required to complement a TIM deletion strain? I understand that there are other “problems” with the “design” but Is it concievable that NovoTim could have activity thats below the limit of detection in vitro using even sensitive in vitro assays but still be functional in vivo (particularly when overexpressed with a strong promoter).

    It would help a lot if the primary data for these “in vivo” assays were made available. Perhaps they’re on one of the recently trashed hard drives?

    • I’d worry about that question only after another lab receives Hellinga’s strains, verifies that they are correctly constructed, and replicates the reported results.

      • noblesse d'epee said

        If there was a chance that the in vivo results could be replicated, don’t you think that the Hellinga Lab would have rushed to repeat these and thereby demonstrate to the world that complementation is indeed possible? Since last year’s retractions of the Novo-TIM work, I would be shocked (and disappointed) if Hellinga and colleagues did not re-try the appropriate in vivo experiments.

        I will drink every reagent in the shelves above my laboratory bench if Homme’s Novo-TIM can complement a TIM-deficient E. coli mutant, and can cover for a TIM knockout (in the presence of the appropriate positive and negative controls).

  71. Perplexed said

    On the solubility of TNT.
    Schreier et al (Fig 4) could not perform ITC with TNT.R1 “because the ligand TNT is insoluble in aqueous buffer”. Their ITCs were run at 100uM protein. For the CD spectra in Fig 1 they suggest TNT was accompanied by acetonitrile. In Looger et al ’03, Kd values are reported for TNT of up to 1.4 mM, with a detection limit for nitro compounds that “corresponds to affinities of ~10 mM”. Various references say aqueous solubility of TNT is 0.1-0.13 g/L or about 0.5 mM. So Schreier et al should have been able to get 1:1 molar data at 100 uM protein. Are the Looger ’03 values really just guesstimates or was acetonitrile used to further solubilize TNT for the assays? If so, that could certainly alter the fluorescence reads as well as invalidate Kd values. Something here doesn’t quite add up.

    • David said

      Inexperienced (or lazy) scientists have been known to dissolve a compound in one solvent (system) and then make dilutions into an aqueous buffer such that the dose-response curve has the original solvent varying along with the solute. The effects of any change from the solute may therefore be confounded by effects of the varying solvent. The Hellinga methods sections have insufficient detail, so there is no way to tell what they did.

    • Looger-logger said

      Fantastic point Perplexed!

      The Frenchie Noble Duke dude wrote: ” I will drink every reagent in the shelves above my laboratory bench if Homme’s Novo-TIM can complement a TIM-deficient E. coli mutant, and can cover for a TIM knockout (in the presence of the appropriate positive and negative controls).”

      Another Dukie lives to be 90…..shit!

  72. writedit said

    If Hellinga had been required to deposit his data in a public repository, would this all have come out sooner? Or is it only because Hellinga’s personality inspired others to call him on what he published? A letter in Science by David Allison points to an article in Nature Genetics showing that publicly deposited data (as required) supported the reproduction of published results for only 2 of 18 studies in Nature Genetics. Allison concludes in his letter “that effective implementation of data sharing policies requires resources to support implementation and monitoring.” Indeed. And then there is the cost of trying to reproduce studies … I wonder how many $s have been spent demonstrating the Hellinga data are not reliable.

    • D Truck said

      I don’t see how this would solve the problem. Hellinga would have just deposited the data in the supplemental materials of the paper.

  73. David said

    The Deputy Editor of The Scientist responded to my anonymous post with the following explanation of the Looger letter:

    Looger comments
    by Alison McCook

    [Comment posted 2009-10-22 13:28:56]
    Thanks for your question — Dr. Looger sent us a long list of responses to questions — for space concerns, I did not post the entire document.

    In one section of the remaining questions, Looger does make this statement, which may shed a bit more light on the Nature News comment:

    “There were a number of instances in which a given designed protein did not seem to bind its target ligand; these were not reported in the paper. Nonpublication of negative results is extraordinarily common in science; this did not seem inappropriate. The apparent failure rate was not such that it clearly pointed to any problems with the work.”

    Alison McCook
    Deputy Editor

    • D Truck said

      That additional sentence at the end doesn’t change the meaning to me.

      Weird that she didn’t post the entire statement though. Who has space concerns about an internet posting?

      • I think Looger is trying to refer to the times when experiments fail for technical reasons, but that area is not really gray in terms of what has come out of Hellinga’s lab. It is almost like they have taken cherry picking of experiments to the extreme. Perhaps the students in the lab viewed that slope as slippery. The culture of this lab seems to be extremely screwed up, and that flows from the top. DIsheartening to say the least.

  74. Dartmouth_Grad said

    I interviewed with Loren for the Janelia Farm position: he was successful, I was not. Two of his papers have been brought in question with the current spotlight on Homme’s work. Shouldnt Janelia reconsider their stance on hiring Loren? Why should I be not given the opportunity: I have better pubs, my credibility is better, my lab/mentor’s credibility is better! Someone who deny others the opportunity by claiming ability to do fantastic science on the basis of fraudulent papers should either resign voluntarily or be kicked out.

    • whimple said

      Bummer. I bet the people that lost out on Pioneer awards etc. feel similarly. Unfortunately the lesson seems to be that scootching right up to and possibly slightly over the fraud line pays real-world benefits. The NIH’s completely toothless sanctions for fraud aren’t helping here. They need to hit institutions where it counts: the bank account. Duke should be made to repay all grant support that used retracted publications as supporting documents, with interest.

  75. luna Halloween said

    Darmouth_Grad,

    I agree that denying opportunities to candidates by selecting and/or confirming those whose work and/or behavior are more than questionable should not be allowed.

  76. luna Halloween said

    Yes Wimple. You are right on. That money should go back where it came from and be redistributed to projects and people who have demonstrated and/or are willing to demonstrate a real commitment with science.

    NIH needs to stand up; otherwise, its commitment, “funding the best science”, will become a meaningless and doubtful slogan.

  77. D said

    If ORI investigates and finds Hellinga guilty of fraud (or Duke does and passes the info onto ORI) then NIH might get back some of its money. But, I get the impression that NIH prefers not to be the Science Police. And I agree with them. Proving scientific fraud is very difficult. Especially in the case of cherry-picking data.

    • noblesse d'epee said

      I strongly disagree, D. The NIH (or some other government agency of its choice) does need to be the “Science Police,” especially in egregious cases such as Hellinga’s where the home institution cannot be trusted. Too much taxpayer money is spent on research for there not to be oversight, and for there not to be significant sanctions when those resources are misused. Do you want to know why the public is not especially supportive of academia in general and basic research in particular? Look no further than that bloated fraud Professor Hellinga.

      I imagine that your distaste for “Science Police” is a hold-over from the days when ORI actually had “teeth.” The David Baltimore case caused, in my opinion, an over-correction by NIH. Yes, we don’t want zealots in the NIH operating some sort of scientific Star Chamber. On the other hand, the current lack of accountability, I think, is far more damaging to science than excessive vigilance would be.

      The cherry-picking of data is no more difficult to prove than other types of fraud. It is “results” fabrication.

  78. luna Halloween said

    Yes, I agree that NIH has too much in its plate to be the science police. But given the sentiments of the scientific community on the problems described here and elsewhere , is it not reasonable to expect that NIH requests both Duke and ORI to investigate and prove/disprove the community sentiments ???.

    Is it not NIH that, in good faith, gives away public money to outstanding researchers and institutions ? If the answer is yes, it is also expected, in my view, that NIH, in good faith, mediates the clarification of events directly impacting on scientists and other institutions. Competing for public funds includes also, in my view, the obligation to give back the awards when the rules of competition are not respected.

  79. There is some serious wishful thinking going on here. NIH is not going to “fix” the damage that Hellinga (through stupidity,carelessness, or malice) has done. The money is spent. It’s gone, as are various opportunity costs (i.e., Hellinga’s tenure track position has been occupied by Hellinga for several years.) The best that will happen is that a thorough and fair investigation will be conducted, and its results made widely available, and that appropriate remedies will be implemented going forward.

    Retribution (I’m using the word in its literal root form here, payback) is probably not, and probably should not, be in the cards. That’s not why NIH was created, it’s not what NIH is good at*, and there is just so much potential for things to get worse than they already are. Be very careful what you wish for, folks.

    *This is part of why ORI was created but there is ample evidence to suggest that they are not good at fulfilling their mandate, have done little to suppress actual fraud, and have in some cases caused quite a lot of collateral damage.

    • D said

      Personally, I prefer that Biomed science remains self-policing. As it should be. Will Hellinga ever get another NIH grant? Maybe, but the review panels are going to look upon his apps very skeptically. Will Looger remain at HHMI and be a success? It is possible, but he has a huge burden to overcome. As it stands now his lab sounds like a service core more than a research lab. Like Hellinga his work will under go extra scrutiny before it every gets published. Especially in Science, Nature or PNAS.

      This is their punishment. Scientific careers permanently tarnished by this scandal. Who will want to collaborate with them and have that tarnish rub off on them?

      Did some people get screwed in the process? Certainly. And it is unfair. But, NIH is not the fairness police. ORI is not the fairness police. Unless you believe in God and an afterlife, there is no fairness police.

      In the end it is up to the “community” and the institutions who employee them to met out retribution. Not NIH. And I hope never NIH. If you think administrative burdens are high now imagine what they will be like if NIH has to double check everyone’s work or follow up on every minor complaint about someone’s NIH funded work.

      • whimple said

        This is their punishment. Scientific careers permanently tarnished by this scandal. Who will want to collaborate with them and have that tarnish rub off on them?

        So, the appropriate penalty for committing a crime is… you’re not allowed to commit that crime anymore? How much punishment is that anyway?

      • @Whimple — you might want to think about the costs and consequences of “punishment.” There is no purging fire that takes away the rot and leaves the surrounding material uncharred. There is always collateral damage. The costs are never borne solely by the perpetrator, and instead ramify into the surrounding community. The question is how one deals with the rot while doing as little collateral damage as possible.

        I would like to suggest that “punishment” is precisely the wrong thing to be worrying about at this moment. We are scientists. The single most important thing — as in the case of Hendrik Schön at Bell Labs — is to establish as much of what actually occurred (the facts) as possible, with all due haste. In the case of Schön, the worst “punishment” that he received was that this report was prepared and published.

        If you haven’t read it, you really should. It is a classic. It will follow Schön for the rest of his life, and it will continue to haunt him after he is gone. For a scientist, there can be no more devastating punishment: a collective judgement by his peers that instead of advancing his field, he harmed it.

      • D said

        @Spiny….Ditto.

        @Whimple, as far as I can tell no crime has been proven to have been committed. You could suggest various laws have been broken but until something is successfully prosecuted in a court….well we have that whole innocent until proven guilty in a court of law thing here.

        These are all major ethical and professional lapses. So, unless the FBI gets involved, they have to be dealt with by the relevant professional communities. And from the tone of this message board they are.

      • whimple said

        No, the goal of a big fine is to punish the wrongdoer’s institution, not the actual wrongdoer.

      • noblesse d'epee said

        I agree with Whimple. In cases of institutional abetting of research misconduct, as appears to be occurring in the current Hellinga controversy, a figurative “stick” is needed with which the NIH might sanction the host institution if it has not engaged in good-faith investigations consistent with the NIH-required format and timeline. As it stands, Duke can tell the NIH, “We’re sorry, but we’ve chosen an investigation process which is in many ways orthogonal to both federal law and to NIH requirements.” The NIH might respond with a “sternly-worded letter.”

        Duke’s technology transfer office apparently thinks that Homme is worth a billion dollars in IP. Hellinga is a persuasive speaker, and has clearly convinced many decision-makers at Duke that he is a visionary — perhaps even a “wrongly-persecuted” visionary. Duke’s Medical Center administration has recently trumpeted its embrace of entrepreneurialism, and Homme’s triumphs mesh nicely with this effort. Duke does not care about Homme’s tarnished reputation; Duke thinks that it is on the verge of milking an IP cash cow.

        What might it take to ensure that Duke performs a proper investigation of Hellinga? Duke harvests several hundred million NIH dollars/year, and consistently ranks 3rd-5th in total NIH funding. I think that the threat of a massive fine, on the order of 10% of Duke’s annual NIH funding, is the only way to ensure Duke’s compliance with NIH rules and with federal law.

  80. luna Halloween said

    Thanks Spiny for your touch in realism and alert on wishful thinking. You’re right. People (just one example) whose retirement accounts were screwed by unscrupulous traders and the like will not get back their life’s savings.

  81. luna Halloween said

    I wonder whether the public visits this site. It would be interesting to hear what they think about “fines” on negligence by academic/research institutions. I agree that “ punishment” does not resolve problems in the best way; however, corrective measures seem to be the rule applying in all other spheres of our society. People get fines for speeding. And even get fines + weekend stays at correctional facilities for DUI episodes. I assume that those corrective measures are a reflection of accountability and intended to protect people’s life and promote civic behavior.

    That academic institutions might be immune to accountability or exempted of corrective measures when there is not full compliance is not that clear. Research is an essential educational component in academic institutions. Its essentiality is outlined not only by heavy taxpayers support but also by the great economic effort sustained by many American families with ever increasing tuition costs.

    Should we all expect better returns, in terms of training professionals and leading the best science, from all those efforts ?. Are we entitled to request reevaluation of actual procedures, policies, priorities when there is evidence of factual errors and omissions ?.

  82. D said

    @noblesse,
    What I am not sure about is the order of things. And who has what powers.

    I know that ORI prefers that the Institution investigate first. They then can either accept the school’s findings or declare it a whitewash and do it themselves. I think, that the only punishments ORI can met out are the debarment agreements. I am not sure at what point NIH steps in and asks for its money money back. Presumably after ORI is done.

    Of course anyone who was directly harmed by Hellinga’s actions could sue him and Duke via a Qui Tam lawsuit. The one describe below from the ORI annual report 2007 (http://ori.dhhs.gov/documents/annual_reports/ori_annual_report_2007.pdf) sounds very similar.

    United States ex rel. Bauchwitz v. William K. Holloman, et al. (Case
    No. 04-CV-2892) (U.S.D.C. E.D.Pa.). On June 30, 2007, the plaintiff and qui
    tam relator Robert P. Bauchwitz, Ph.D., filed a first amended civil complaint
    on behalf of the United States alleging that defendants William K. Holloman,
    Ph.D., Cornell University Medical College, Eric B. Kmiec, Ph.D., and Thomas
    Jefferson University violated the False Claims Act, 31 U.S.C. § 3729, et seq. The plaintiff alleges in this qui tam suit that the individual defendants made false statements and misrepresented research data in scientific journal articles, which were in turn cited by defendant universities in grant applications to obtain payment from the National Institutes of Health. The relator is seeking treble damages on seven counts of fraud, including civil penalties, attorneys’ fees, and costs. The district court ordered that the amended complaint filing be unsealed.

    • noblesse d'epee said

      Interesting post, D. I’d never heard of a qui tam suit. It seems that they are rare.

      Well, at least my Latin classes were good for something. 😀

      So, as I understand it, a qui tam suit allows one to sue on behalf of oneself (if one has standing in the matter, of course) AND on behalf of the taxpayers (specifically, the sovereign government) whose money Homme has so grossly wasted. Correct?

      Coming out of a recent meeting with Nancy Andrews, the Dean of Duke’s School of Medicine, I am not convinced that Duke can manage a properly-conducted investigation of Homme. The university has already long exceeded its own time-line for such investigations, whilst collecting a variety of procedural shortcomings. It would not surprise me if the Dean was attempting to arrange a face-saving whitewash of this whole fiasco. Homme deserves due process, but whatever investigation Duke has conducted is taking longer than most U.N. war crimes trials. Even if universities such as Purdue (“bubble fusion” scandal) have taken the better part of a decade to conduct similar investigations, Duke should not consider such a timeline to be acceptable.

      I was recently reminded that Dean Andrews did her graduate work with David Baltimore (MIT). Perhaps this connection explains her apparent reluctance to aggressively tackle the Hellinga debacle.

      While I think that it would be damaging to the university, Hellinga ought to be exposed in open court to a true adversarial exchange. Let the deconvolution of this mess be transparent and a matter of public record.

      • TheRoseCaptain said

        I find the disrespect being shown to the *VERY* experienced and accomplished Dean Andrews quite troubling.

        I am beginning to think that certain contributers to this blog are simply afraid of powerful women.

      • D said

        Disrespecting Deans (and Chairs, Provosts, Presidents, etc.) is a time honored tradition of academia. Again, no misogyny here.

      • noblesse d'epee said

        Oh, and I could care less that any of these people are women. Look around: half of the students/post-docs in this program are successful women. Sexism is so 20th Century. Brush that chip off your shoulder, RoseCaptain, and get with the times.

        I note however, how quickly you become defensive about your (putative) sex, Lorena Beese, and Dean Andrews. There’s no reason, in these times, to hide behind your sex, race, or sexual orientation. It has nothing to do with science, and should be ignored. We are all equal here.

      • D said

        Uranus…..sigh….Not only is what you say wrong and absurd but now everything discussed here can be put down to misogyny.

        Maybe RoseCaptain is actually psychic and could see the future postings.

      • writedit said

        I deleted the Uranus posting for its lack of relevance to this discussion and its inappropriate nature over all. (agreed it probably was a tongue in cheek comment … but still distracting and potentially inflammatory for a casual observer skimming through this thread)

      • noblesse d'epee said

        I suspect that Uranus’ comment was tounge-in-cheek. I completely disagree with it, however. Sex, race, etc. doesn’t matter in science. Why has this been inserted into the conversation? Just because Beese happens to be female. I think RoseCaptain herself is being a bit sexist.

    • noblesse d'epee said

      Dean Andrews is quite unimpressive, in my opinion. Such people deserve to be “disrespected,” especially when they preside over a mess such as this. Besides, she doesn’t have to sign my thesis, I won’t be asking for a job from her, and I frankly don’t give a flying fuck what she thinks. The important point is that she realizes that problems exist which urgently require her attention.

      • TheRoseCaptain said

        I find this all to be troubling, simply because there are no posts discussing the credibility of the male professors who have not joined this circus of a witch-hunt. Where are the posts questioning the interim-chair’s motives? Who is dragging his past out and trying to explain his reluctance to act? The Dean has decades of administrative experience and she has estabilshed herself as a strong, capable scientist – why must who she did her PhD with 30 years ago be pointed to as a reason for why she would stall…? Why is her conviction to treat this issue like a proper investigation, with proper due-process, being seen as reluctance and weak-willed?

        Academia is rife with gender inequality and dozens of recent studies have shown that the age of socially-accepted misogyny is *not* over. Strong women continue to fight a double-standard.

      • noblesse d'epee said

        I don’t care what Nancy Andrews has accomplished. I care what sort of leadership she shows *now,* in her *current* position.

        Dr. Mary Dwyer, an important (and in my opinion, heroic) *female* player in the Hellinga controversy, has been widely discussed here and elsewhere. Among Hellinga’s (and Beese’s) most persistent and vocal detractors at Duke is an eminent *female* professor who is internationally revered for her contributions to many fields of science.

        In these modern times, women and men see themselves as equals in this field. Sure, male professors and students are angry about Hellinga and Beese, but so too are the females — and in equal numbers. Your hypothesis of gender-bias in this whole controversy, Ms. Rose, is insupportable.

      • D Truck said

        No one cares about the interim chair of the department because he likely has about zero power in this situation. The dean, that happens to be female, is the one most likely calling the shots and therefore the one under the most scrutiny. No gender-bias necessary.

      • David said

        Mary Dwyer was a victim of unfair treatment along with a large number of women who left Hellinga’s lab unhappy. She was further victimized when she brought a complaint to the next appropriate authority at Duke and was brushed off before the Science paper was published. Thankfully she has found success and stability with a supportive adviser. If she were a man, do you think she would have been ignored? Where is Rose’s outrage for the many women who left Hellinga’s lab unhappy? I am sure the gender ratio is skewed. There is a pattern. Hocker’s paper seems a just dessert.

  83. scotus said

    I think a lot of scientists are very uncomfortable confronting misconduct issues.

    Earlier this week I was participating in a teleconference review. One of the reviewers led us through the process of copying and editing an image of a western blot from one of the applications that revealed a blank “control” lane was actually pasted on top of a blot that had bands in all of the lanes. Even then, some of the other reviewers were reluctant to call this a clear case of fabrication/falsification of data. Maybe this is the scientific equivalent of the “bystander effect”?

    I’m also very surprsised that Dean Andrews is willing to discuss the Hellinga business with anyone. Was this a one on one meeting or did she meet with the department or depatmental students/trainees together? Can you share any more details of what she said that makes you so skeptical about the progress and outcome of the “investigation”?

    • noblesse d'epee said

      Scotus,

      Photo-shopping data on a video-conference? Do people not understand what constitutes proper scientific procedure and reporting? I’m sorry that you had to observe that.

      To answer your question . . . It was a general meeting between the Dean and the Duke Biochem. trainees and post-docs. Faculty were not present.

      Andrews flatly refused to discuss the Hellinga issue, but many people brought it up despite this, in the context of problems related to our program’s public image and our thrice-failed search for a department chair, the hiring of much-needed new faculty, etc. I can understand the need for confidentiality, but Duke *did* issue a press release last summer telling the world that Homme had requested a Duke investigation of himself (albeit one with *very* narrow scope, probably designed with the help of legal counsel). Given the public nature of the genesis of the investigation, I see no reason for Duke refrain from providing public confirmation that (an) investigation(s) is/are ongoing.

      Another subject which the Dean would not address: Lorena Beese (Homme’s spouse/collaborator) using her control of crystallography resources to baselessly deny access to students who either a) signed a student petition requesting an investigation of Homme, or b) worked for her husband but switched labs before graduating, or c) rotated with her and were not willing to join, but are doing crystallography in other labs. Andrews needs to demonstrate leadership by ensuring equitable use of shared resources and compliance with federal law.

      Andrews assured us that Duke’s Biochemistry program is “world-renowned.” Indeed we are, for high-profile scientific and managerial misconduct.

      Some (though not all) members of the Hellinga and Beese labs expressed that they felt besieged under these circumstances. With a few notable exceptions, I don’t feel sorry for these students. The present situation is an obvious possible outcome of continuing to work for a charlatan or a sociopath, especially ones who synergize their awfulness.

      • TheRoseCaptain said

        noblesse,

        you failed to mention when you had a bonafide temper tantrum and stormed out like a five year old.

        Dean Andrews was behaving like a professional, and managed the situation appropriately.

        Your temper tantrum, however, was anything but professional.

      • D said

        But was the description of the meeting fair?

      • noblesse d'epee said

        I forgot, in PC-land people are not allowed to bring up controversial topics! The person who lost his temper must be terribly ashamed.

    • noblesse d'epee said

      Hmm. Sour grapes from one of Beese’s few remaining brown-nosers. You are making assumptions regarding who, exactly, I am.

      • TheRoseCaptain said

        D,

        That description *is* wholly biased. The information sent prior to the meeting stated it’s clear goals about what it was regarding. I don’t think it was a matter of being PC. The Dean politely and clearly stated that she not allowed, by due process, to not know about much of the investigation. It was also made very clear what the meeting was supposed to be about. She also declined to discuss the shared facility issue, as it was not in her jurisdiction and openly shared with whom we should talk to.

        It was disrespectful to continue to talk back and force a discussion, not just to the Dean, but also to the rest of the students. Not all students in the department have conceded to the witch-hunts that certain other students continue to fervently pursue. Most of us just wanted to learn about the topic at hand – the chair search.

        Noblesse,

        Perhaps I am wrong. However, your unique take on the goings-on of this department, your inability to let certain things go, and your distinct vocabulary, Noblesse, have led most people to identify as such. Perhaps everyone is wrong, as you are also making a wrong assumption as to whom I may be as well.

      • noblesse d'epee said

        Of course the dean has jurisdiction over shared resources.

        I rarely respect people based upon their title, including and especially university administrators, unless they demonstrate through their contributions and/or actions that they are deserving of my respect. This is a free country and the discussion with the dean had no stated agenda. Allowing confidentiality for Hellinga does not affect discussion of Beese’s management of shared resources. Pushing the issue (to the point of “talking back” to the dean) whether or not you personally find it distasteful, was the students’ right.

        I’m most flattered that you find my vocabulary to be “distinct.” Better to be distinct than to blend with the sheep-like masses.

  84. scotus said

    I’m not surprised the chair search is floundering. I can’t imagine anyone would want to inherit this train wreck.

    As I see it, what has been lacking all along is a whistleblower from within the Hellinga lab- someone with access to the primary data who could really spill the beans. Given the accounts of Hellinga’s behavior towards his “mentees” I can’t imagine he wouldn’t have upset someone to the extent that they would feel empowered to make a complaint. He must have been running a very secretive operation. I also think he has handled the situation cleverly by “neutralizing” Mary Dwyer with a preemptive counter allegation of misconduct and then essentially whistle blowing on himself with the investigation request.

    The Beese behavior you describe is troubling. Presumably this is causing conflicts with the mentors of the students who are being denied access to these resources. Is she really able to behave this way with impunity?

    • noblesse d'epee said

      “Is she really able to behave this way with impunity?”

      Yes, she has done things like this for years with apparent impunity. I’ve heard it argued that Beese’s damaging behaviors should be excused because she manages to turn out a Nature, Science, or Cell paper every few years. I’m tired of hearing the phrase, “she’s done awful things to people, but her science if very high-profile.” Retaliating against students who petitioned for an investigation of her husband, Homme Hellinga is, to borrow a phrase from computational chemistry, a local minimum in her energy function.

      I have to admit that Homme appears to have played his cards cleverly. However, he has made enough mistakes such that his “clever” ploys may spectacularly backfire upon him. The baseless and malicious accusation of Mary Dwyer is the best example of this. A friend of mine, who worked in the Hellinga lab for several years, predicted long ago that “Hellinga will hoist himself on his own petard.” Picturesque, isn’t it? Years later, it is becoming increasingly clear that Homme may have catapulted himself toward professional oblivion. He’s been his own worst enemy, garnering accolades which are now empty, and leaving the wreckage of others’ careers and education in his wake. If not for the collateral damage, I would almost — but not quite — feel sorry for him.

    • TheRoseCaptain said

      The truth of the “situation” with Dr. Beese is being blown out of proportion, and the story-teller is allowing his paranoia to taint any facts.

      Dr. Beese has never barred anyone out of retaliation from using a Duke resource. She does, however, ask that all students get properly trained, which does include sitting back and basically being an observer the first time you are there. ALL students, including her own, do this. It is to my understanding that Noblesse has mistaken her general request of all students as some sort of personal slight, instead of seeing it as the general safety precaution that everyone else also adheres to.

      • David said

        Rose,

        To ask any student to observe as a training exercise is not efficient and is not typical at other beamlines. Most people are trained while shooting their experiments. The fact that Dr. Beese’s putative training policy is not written anywhere is very troubling. The fact that many students past and present were told by Dr. Beese not to go on trips at all belies the assertion that students can ever be “trained” by observing others. This is a problem that has gone on for years according to friends who are no longer at Duke.

        Thankfully, I have heard that the Duke Administration is fixing this problem by establishing written protocols and procedures to be administered outside Dr. Beese’s sole control.

      • Rob said

        Please tell me how this training requirement is a safety requirement. Are you suggesting that an untrained student could bypass the safety features present at the beam line and endanger themselves or others? How exactly is this possible?

      • writedit said

        I’ve deleted names introduced if the original poster has not self-identified. Please do not out anyone, intentionally or inadvertently as part of this lively discussion. Thanks – writedit

      • noblesse d'epee said

        Beese does not have the right to decide how other PIs’ students should be trained. It is ridiculous and unwarranted for a student to go on a synchrotron trip — even their first one — to merely watch others collect their data. Such foolishness is orthogonal to the goals of scientific education, and to the mission of government-owned, education-oriented physics facilities.

        The salient point is this: Duke’s SERCAT time belongs to Duke, not to Beese. She should not be playing gate-keeper to it, especially since she’s established a clear pattern of making its use difficult for students against whom she has motive to retaliate. Three of these individuals happen to have signed the student petition regarding Hellinga. As further demonstration of Beese’s corruption, I point out that she tried to charge a laboratory in the Pharmacology Department ~30K for the use of Duke’s own beamline time! That behavior was super-unethical, super-illegal, and, unhappily for Beese, super well-documented. The re-sale of federaly granted institutional resources to raise cash for one’s research program is mind-boggling. Duke Biochemistry will not be a healthy program until Homme is dismissed, Lorena’s unethical and illegal activities are scotched, and transparent, equitable access to “shared” resources is established.

      • Pinko Punko said

        Beamlines tend to have their own training that all users must pass to be allowed access to the facilities as well as various security precautions.

  85. […] of his groundbreaking enzyme design study were withdrawn, sicne they could not be reproduced, read more about it here […]

  86. Perplexed Periplasmic said

    One key element of this controvery is the protein modeling. Schreier et al suggest that DEZYMER mostly predicted the observed side chain orientations of the Stn protein. But it clearly doesn’t bind its target. Schreier further suggest domain reorientation needs to be considered. The 2003 Nature and 2004 PNAS papers from Hellinga’s lab are somewhat vague but suggest “fuzzy” VdW and H-bond potential energies were used in ranking ligand binding as well as QSAR. In the PMPA study, electrostatic contributions were apparently not considered. Can someone well versed in drug design or protein-ligand binding simulations comment on this work? Much more sophisticated methods are known such as combined QM/MM, force field calculations with explicit solvent (water) molecules, solvation/desolvation methods, etc;. Is the comparison with unbound or open domain orientation structures neccesary for this approach to work?

  87. David said

    Noblesse,

    Correct me if I am wrong, but Duke efficiently investigated and exonerated Mary Dwyer in well under three months. The fact that the Duke investigation requested by Hellinga himself in July 2008 has dragged on without an end in sight strongly suggests that Hellinga is in deep trouble. If he were innocent and going to be exonerated, surely the investigation would be done and his exoneration announced. The longer it drags on and the more PNAS papers published that trash his research, the clearer it becomes that he cannot be exonerated.

    I heard about the ibuprofen binding MBP work some time back. It was evidently declared a failure by Hellinga (along with those who worked on it). I doubt it will be published, ever. Any journal that gets such a manuscript should independently contact all the authors listed to make sure they agree with the manuscript and to confirm no other authors were left off the manuscript.

    • noblesse d'epee said

      David,

      I concede that your hypothesis (Homme’s drawn-out investigation = big trouble for him) may be correct. Another, not inconsistent, possibility is that Duke may simply be stalling for time. I imagine that the committee investigating Hellinga would have found diverse and damaging evidence even in the early months its efforts. If the committee is following NIH guidelines, it is legally obliged to follow all available leads related to the alleged misconduct. In Homme’s case, we might expect these to be numerous. I suspect that if she chose to, the Dean could ask for a preliminary report from the committee and could decide to dismiss Homme on the basis of crimes already unearthed, and in anticipation of an even more extensive, damning report. Allowing the investigation’s time-line to vastly exceed that required by the NIH suggests deliberate stalling. If Duke is, as some have speculated, being sued in connection with Homme’s IP licensing, I think that the administration would wish to delay a finding for as long as possible. On the other hand, a friend recently pointed out that “one should not assume malevolent intent when incompetence will suffice.”

      I am troubled by the issue of the yet-unpublished (and probably unpublishable) ibuprofen-binding protein data being floated as some sort of “exoneration” of Homme. It could be, at best, a red-herring distraction for the investigative committee. I have heard from reputable sources, as you have, that the ibuprofen data are vehemently disbelieved by a subset of that work’s putative co-authors. But an investigative committee may end up expending time and effort considering these unpublished and contested data. The whole concept is patently silly: a secret committee investigating secret scientific data that it may lack the expertise to interpret. It’s like the Spanish Inquisition, but without the excitement arising from the hazard of life and limb.

      If Hellinga wishes to demonstrate that his secret “exonerating” data are real, then he should post them for public perusal. For structures, the PDB’s should be accompanied by both electron-density maps AND by the original x-ray reflection data. I agree, David, that the ibuprofen-binding protein data are unlikely to withstand scrutiny. Moreover, even in the unlikely event that these were kosher, they would not explain the rancid streaks of fraud running through many of Hellinga’s other findings, nor his horrific managerial wrong-doings. One can only hope that the cold wind of justice will flush Homme out of Duke, and the full litany of his crimes into the sunshine of public scrutiny.

    • D Truck said

      The ibuprofen work is just shifting the goal posts and shouldn’t even be considered in assessing how the two (or more) Dwyer, Looger, & Hellinga papers were so screwed up. Hellinga cannot exonerate himself by showing that some of his other work is correct.

      Although Dwyer was cleared in the enzyme paper, will she be under fire again for the Looger paper, especially since it sounds like she actually did the bench work? And will Looger also be investigated like Dwyer was?

      Also, wouldn’t it be public knowledge if Duke was being sued over Hellinga “IP”?

      Finally, I think the name of Hellinga’s program, DEZYMER, appears to be accurate.

      • noblesse d'epee said

        D Truck, I agree wholeheartedly with your first point, and I discuss your second in a posting below.

        For the issue of Duke possibly being sued over Homme’s IP. One can imagine multiple scenarios wherein such lawsuits might be under seal (at least in their earlier stages). I don’t know if this would prevent the plaintiff and defendant from being named in the published filing. Perhaps someone with relevant legal knowledge can comment on this.

  88. scotus said

    Presumably the crux of the Dwyer “investigation” was that Hellinga alleged that data in the science paper were fabricated or falsified and she was able to prove that they were not to the satisfaction of the committee. One would imagine that this could have been accomplished quite quickly. What I’m not clear about is what precise allegations are being investigated by either the Hellinga-requested investigation or any other “double secret” investigation that Duke is also running. Does anyone know? I think its very unlikely that Duke is going to conduct an expansive “Schon-like” scrutiny of the entire Hellinge oeuvre. A more focused investigation would be more feasible. Misconduct is essentially a zero tolerance offense. As has been discussed here extensively, a careful examination of the TIM complementation experiments would probably be sufficient to obtain a conviction.

    • noblesse d'epee said

      I imagine that any committee *currently* investigating Hellinga would have access to the documents and recorded testimony from Dwyer’s 2007 investigation. I understand that she was able to make her case in a way that left no doubt as to the nullity of the charges made against her. I disagree with D. Truck; Dwyer and Looger are unlikely to be implicated in any sort of wrongdoing in the PBP work. My understanding is that the data that the students collected (which Hellinga then re-interpreted, assembled, and published) were legitimate measurements. Whether they were done with the appropriate controls, and whether they were processed/reported in the correct manner, is a mentorship issue. The graduate student authors were dependent upon Hellinga to mentor them, and to tell them whether their controls and statistics were done properly. If the students gave him honestly-collected and unfiltered data (which, for various reasons, I am confident that they did), and he had no objection to those data, then the responsibility for those published data’s accuracy ultimately rests with Hellinga.

      Look, I must emphasize that Hellinga ran an *extraordinarily* secretive and dysfunctional operation. For the work in question, there were multiple authors who had little interaction. Homme gathered data from various parties, made decisions about which data were “noise” and which data were “good,” and assembled the final story. The work was so compartmentalized, and the scientific atmosphere in the lab so toxic, that the students were not in a position to easily see the “big picture,” nor were they in a strong position to challenge Homme’s “interpretation” of their data as presented in his manuscripts. As I discussed in a previous posting, challenging Homme, even for legitimate reasons, would have ended these students’ scientific careers. Students and employees who even modestly challenged Hellinga’s scientific “approach” tended to be rapidly terminated or driven off. What would we have done in their position? I, for one, am not sure. For this reason, I think that responsibility rests primarily, if not exclusively, with Hellinga.

  89. scotus said

    So are you saying that Hellinga operated in a way that allowed him to “filter” data while maintaining plausible deniability about having knowledge of contradictory or inconsistent data? So, for sake of argument, he might have been shown 100 sets of TIM complementation data in which the Novo Tim was inactive but then in one case where whoever was doing these experiments saw an apparent complementation effect (maybe they got the strains mixed up) and he decided that was “good” data and the rest was as you put it “noise”?
    Generally speaking misconduct investigations focus on uncovering fabrication or falsification of data which is usually relatively easy to prove. The scenario outlined above woudn’t fit the definition of fabrication or falsification. It is reckless disregard for established scientific standards and intellectual dishonesty of the worst kind but it is not misconduct. What specific allegations of misconduct defined as fabrication or falsification have been made against Hellinga? Maybe an inability to define what needs to be investigated within the established parameters is why the investigations are taking so long?

    • whimple said

      Yes it is misconduct. It is falsification by omission.

      • scotus said

        You’re absolutely correct of course but I am struggling to find details of any closed research misconduct cases that were decided soley on the basis of omission of data. None of the more dodgy data in the Science paper is accompanied by any statements about reproducibility or being representative of repeated experiments..

    • noblesse d'epee said

      I disagree. Picking one non-representative data set out of 100 is misconduct, if no valid scientific or statistical reasons can be given for discarding the other 99. I agree with you that a tussle over what committee members consider “misconduct” could be lengthening proceedings.

      • D said

        I disagree with noblesse’s disagreement. I think it of like Football replays. The call on the field (reviewers agree to publish) stands unless the replay shows “incontrovertible visual evidence” that the play should be overturned. So, barring missing data or clearly forged figures, I don’t think Duke will be able to overturn the call (prove misconduct ). Whether it occurred or not.

        Certainly they will not be able to do to the satisfaction of a judge and jury. Which is where this will go if Duke tries to boot him based on what has been shown so far.

        Instead, they will make it clear to him that his research career at Duke is over and unless he wants to spend the rest of his career teaching 2-3 undergrad courses a semester he better find a new job.

      • noblesse d'epee said

        You make a good point, D. However, I maintain that our predictions are dependent upon where the threshold of tolerance lies. Your football metaphor is analogous to “beyond a reasonable doubt,” when indeed “the preponderance of evidence” will suffice for civil action. I think that Duke could easily convince a jury that the preponderance of evidence points to Hellinga engaging in research misconduct worthy of his dismissal from the university.

      • scotus said

        Although the penalties involved are civil rather than criminal, from a scientific standpoint these investigations are basically the equivalent of a capital murder trial. The tolerance level among faculty appointed to conduct the investigation is likely to be rather high because the penalty is so severe (certainly a lot higher than it would be if the investigation was being conducted by a panel of Duke Biochemistry graduate students…)

      • noblesse d'epee said

        If this controversy is examined in civil court, which is likely, it won’t matter whether professors consider the proceedings to be equivalent to a “capital murder trial,” or whether students clamor for Hellinga to be beheaded on the flimsiest of pretexts. In many ways, I think that Homme’s career is already ruined. His most important works have been demonstrated to be either shoddy, dishonest, or both. I’m more concerned that an investigation addresses the managerial issues in this case, e.g., Hellinga making malicious/unfounded/reckless claims of misconduct against his student.

  90. scotus said

    So in order to establish that misconduct ocurred it would be necessary to prove that Hellinga had access to and was fully aware of the contradictory data and that he did not have good reason to discount these data in favor of other data that fit with his wishful thinking. Do we know that this Is this the basis of a formal charge of research misconduct being investigated at Duke? The point I’m trying to make is that this will be harder to prosecute than an open and shut case where the data that are being challenged just don’t exist or were made up.

    • noblesse d'epee said

      It would not surprise me if Dwyer was cleared of misconduct explicitly *because* she was able to prove that “Hellinga had access to and was fully aware of the contradictory data.” That is why I believe that conviction of Hellinga is inevitable (albeit unlikely to happen quickly for reasons of high-stakes academic politics).

  91. scotus said

    I agree but at the same time I am not aware of any closed research misconduct cases in which a finding of research misconduct was made soley on the basis of selective reporting of data. Maybe someone else around here can think of one? That was the point I was clumsily trying to make in my original posting.
    Depending on how much plausible deniability Hellinga had built into his system for interacting with his lab workers it may be hard to nail down just how much he knew (even though we all know that as both PI and mentor it was his responsibility to know everything). Hopefully there are electronic records that can be accessed. At the same time one could imagine that Hellinga has all kinds of “explanations” for why he decided to ignore contradictory and/or inconsistent data. Its even possible that in some cases inconclusive data were excluded for legitimate reasons. I’m just saying that this is probably why the whole mess is taking so long to resolve and even if/when the Duke investigation is over I can’t imagine there won’t be a series of appeals.

  92. Duke’s own Graduate School Responsible Code of Research states the following:

    “50.102 Definitions. Misconduct or Misconduct in Science means fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research. It does not include honest error or honest differences in interpretations or judgments of data.”
    http://gradschool.duke.edu/academics/degree_reqs/rcr/about.php

    So assuming something resembling actual data actually exists somewhere in Homme’s lab, are we really talking here about “honest error or honest differences in interpretations” ? Maybe a shrewd operator might even see this as a loophole.

  93. “Misconduct or Misconduct in Science means fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research. It does not include honest error or honest differences in interpretations or judgments of data.”
    http://gradschool.duke.edu/academics/degree_reqs/rcr/about.php

    • noblesse d'epee said

      My favorite sentence of Duke’s RCR description in your linked page:

      “The commitment of Duke faculty and administrators to RCR education has helped to foster an institutional climate in which the ethical dimensions of research are taken seriously.”

      Yeah, right.

      If we students have to take these “ethics” classes as a prerequisite to earning our Ph.D.’s, then the faculty should complete similar coursework in order to become eligible for tenure.

  94. writedit said

    Apropos comment from Bruce Alberts in Science:

    My first piece of advice for graduate students is to begin research training in a laboratory led by a person with high scientific and ethical standards. It is by talking to people in that lab or those who have previously trained there, and by consulting other scientists in the same field, that one can gain this important insight.

    • noblesse d'epee said

      It is good advice that is too rarely heeded. There is a tendency for incoming graduate students to feel (often with the encouragement of devious professors such as Hellinga) that they are special, and that they will be “different” than their “loser” peers who currently populate the lab/department. New students should be wary of such delusions, and of any professor who encourages such thinking.

  95. Wiki Dude said

    Hellinga should be outed like Yossi Schlessinger http://wikileaks.org/leak/joseph-schlessinger-2009.pdf

    • scotus said

      Murder victim Annie Le was a graduate student in Schlessinger’s department….perhaps she knew too much?

      • If that’s not a joke, scotus, it’s asinine. If it is a joke, it is indecent.

  96. scotus said

    It was intended to be a jibe at people who think the Schlessinger/Imclone patent case is in any way relevant to our discussions about Hellinga’s research misconduct. Yes, it was in poor taste.

  97. David said

    An interesting editorial appears here about scientific ethics & conduct:

    http://www.ft.com/cms/s/0/8aefbf52-d9e1-11de-b2d5-00144feabdc0.html

    Good quotes:

    “Science may be objective; scientists emphatically are not. This episode illustrates what too many universities, professional societies, and research funders have irresponsibly allowed their scientists to become. Shame on them all.

    The source of that shame is a toxic mix of institutional laziness and complacency. Too many scientists in academia, industry and government are allowed to get away with concealing or withholding vital information about their data, research methodologies and results. That is unacceptable and must change. ”

    “The issue here is not about good or bad science, it is about insisting that scientists and their work be open and transparent enough so that research can be effectively reviewed by broader communities of interest. Open science minimises the likelihood and consequences of bad science.”

    From the closed source code of Dezymer to the drawn out “investigations” Duke may be conducting, I think the editorial could apply just as well to the Hellinga controversy.

    • D said

      Sadly, now that so much money and fame is involved in major scientific breakthroughs, it is no longer possible to assume the good honest intentions of your competitors or even colleagues. Yes, science is mostly self-correcting but look at the costs involved in the self-correction.

      Maybe if the Universities where fraud happened had to cover ALL of the costs of the fraud (including the several years of dead end research by others) they would be a little more vigilant.

  98. I really don’t think that scientific papers which are centered on software should be publishable without source code. Without the source it is not possible to interpret the experiments, and it is not possible to independently replicate them, either.

    The reporting of methodology together with results is at the very core of the scientific method. Failure to do so makes the enterprise something other than science.

    • Rob said

      @Spiny-
      I agree with you 100%. It amazes me that source code is not a requirement for publication. I just don’t understand it. Method are supposed to be open and shared. Sharing source code should be viewed in the same light as sharing a reagent or construct. If you publish work based upon code, it should be fair game.

    • maurice said

      It does no make sense to require that people publish their code. It is the underlying algorithm that has to be adequately explained in the paper, not its particular implementation on a computer. Besides, a clever, efficient implementation of an algorithm can have tremenduous commercial value. Why give it out for free?

      • noblesse d'epee said

        If one publishes data derived from the implementation of an algorithm in a peer-reviewed journal, and the reproduction of those data are dependent upon the detailed methods by which that algorithm is employed, then the reveleant code should be made public. Hellinga and his ilk cannot have it both ways. If he wants to keep his progams proprietary, then he cannot publish their output. It is easy to forget that taxpayes have footed the bill for that bastard Hellinga’s “proprietary” implementation. The data so derived, which are not reproducible without his code (or as it now appears, even with it), have mislead his field at the cost of untold millions, and the waste of numerous careers. I don’t know about you, Maurice, but I hold that scientists who take public money are ethically bound to disclose all of their methodologies in their publications. Those who do not, or who cannot, deserve to face a furious public — which, given the desperate economic times — might rightly put an end to the shenanigans of charlatans like Hellinga who cause hard-earned tax money to evaporate into clouds of fraudulent results. Burning stacks of hundreds would be more productive than funding Hellinga. At least the former produces warmth.

  99. maurice said

    Yes, US taxpayer money funds research in US universities, but that does not imply that the details of this research have to be made available to everyone in the world. There are national interests at stake in such cases. Imagine that H & L’s code did work. Should–say–the Chinese have full access to sophisticated energy minimization code developed in US universities at US taxpayer expense?

    • D said

      National Security interests….puh..lease. Are you telling me that Hellinga wouldn’t have sold it to the Chinese if they offered him enough money? Should the Federal Government classify as top secret all federally funded research? That is a very weak argument.

      Hellinga could have provided the code for research/non commercial use. Just have everyone sign a MTA (Material Transfer Agreement) and promise not to use it to make money. This is done all the time with very valuable IP.

      The essence of science is repeatability. So, if no one can repeat your work because you withhold essential materials then it is not science.

      As far as money is concerned, The Bayh-Dole Act is pretty clear that the inventor has exclusive rights to make money off of Federally Funded research (http://www.cptech.org/ip/health/bd/). So that can’t be an excuse either.

      The bottom line is that if a scientist doesn’t want to share he shouldn’t expect to be able to publish his work in science journals or ask for grants from the NIH or NSF. Go to the venture capitalists or DoD for your money.

      • maurice said

        “Hellinga could have provided the code for research/non commercial use. Just have everyone sign a MTA (Material Transfer Agreement) and promise not to use it to make money.”

        Sure. Did anyone in the academia ask Dr. Hellinga for the software and was refused? It seems to me that the accusations against Hellinga & Looger (especially) are getting a little bit unfair.

      • D said

        I am not sure. I am just pointing out that a solution was possible. But, I would be surprised if no one in the field asked for it if it was as amazing as it was originally claimed to be.

      • noblesse d'epee said

        People in academia *did* ask Hellinga for the Dezymer software, and he usually refused to provide it. Given that the software doesn’t work, perhaps he was doing them a service. The point is that Hellinga’s behavior is orthogonal to the spirit and principles of honest scientific research. What Hellinga has done to his field, to his former students/post-docs — these things are “unfair.” Accusing him of being a fraudulent jackass, given the weight of evidence, is not.

    • Former Hellinga Student Here said

      That’s right! Maybe Usama Bin Laden could potentially use DEZYMER to make a protein more potent than ricin, with no antidote available! For example, his mighty protein engineers could construct a protein that would specifically bind to and inactivate human testosterone and produce more Hellingas in the US (do all male charlatans have high-pitched voices?). And those Chinese, constantly stealing the US secrets, shame on them! (just being sarcastic here, in case intelligent FBI are reading this)

      Ok, now to the sane on this thread: Hellinga’s DEZYMER code was very closely guarded by a mighty computer password – only Looger and Hellinga himself had access to the code. The rest of the grad students and postdocs were running the code blindly, but “in good faith”, to get the predicted a.a. sequences so that they could begin their monkey work – inserting 15 mutations in a 1kb DNA segment for each construct. I once took a look at the “user manual” for that piece of crap software, and it was very obvious that Hellinga had written in the most user-unfriendly fashion. Now I see why.

      Homme’s philosophy of training graduate students was nothing but using his students as wet lab monkeys. Any attempts by the students to learn more about computational biology and DEZYMER in particular were frowned upon by “The Man”. Unfortunately, charlatans like Homme will never be punished at Duke as long as they are able to keep landing those sweet grants. We’ll just wait until Hellinga well dries out.

  100. maurice said

    “People in academia *did* ask Hellinga for the Dezymer software, and he usually refused to provide it. ”

    Wow. Very unusual, and clearly did not gain him any friends. What’s interesting is that the algorithm correctly predicts protein conformation, but not functionality. Wonder if a few tweaks could fix that.

    • noblesse d'epee said

      Maurice wrote: “. . . the algorithm correctly predicts protein conformation, but not functionality. Wonder if a few tweaks could fix that.”

      It’s a good point, and part of the tragedy of the whole Hellinga episode. As you say, there may be simple improvements that would be blindingly obvious to people looking at Dezymer from the outside, but that the Hellinga group, through its proximity to the problem, has missed. I like to contrast the trajectory of Hellinga’s development of Dezymer with David Baker’s work on Rosetta. The latter demonstrates the value of having open and transparent (academic) access to software for protein design.

      I think that the modeling of dynamic conformational changes (for example, induced fit) is still in its infancy. We really don’t understand how even simple proteins fold. Conformational correctness alone, I suspect, will be insufficient to design most ligand-binding and/or enzymatic functionality into most scaffolds. With tunneling, long-range intra- and inter-molecular forces, dipoles, etc. to consider, consistent development of designed enzymes is still best approached in a modular manner (David Baker) and/or with assistance from directed evolution. As our understanding of protein dynamics — from a quantum-mechanical perspective — improves, and computing power continues its exponential expansion, more generalized protein design will be within reach. That’s why basic research, especially in semi-neglected fields such as protein folding, is so important. We must better understand Nature in order to successfully mimic its processes.

  101. maurice said

    Is it just me, or there has been a significant spike in the number of reports of scientific fraud in Sci & Nature papers? IMO a groundbreaking paper in Science or Nature is not going to get you automatically hired anymore. In fact, it is likely to hurt one’s chances, especially in the private sector, as hiring managers have probably grown skeptical about extraordinary claims made in Nature & Science papers.

    There are only a few fraudster assholes and lots of honest scientist suffer. As always, the few bad apples spoil it for everybody.

    • D said

      I was wondering about that too. Anyone keeping score?

      • writedit said

        Nature had a little piece noting that high-impact journals have higher retraction rates – they publish sexier science at the cutting edge (sensational but inaccurate), and often that edge crumbles off when the data cannot be replicated.

        I think the up-tick in fraud/misconduct reports is in part like the increase in cancer incidence … we catch it more often due more sensitive tools … and in part due to the fierce competition for limited resources … as Brian Martinson et al. would attribute to issues of procedural/distributive justice (or lack thereof) and mentoring effects. Plus, with the Internet, dissemination is much wider. How many grad students, postdocs, faculty, writedits et al. read ORI reports printed in the Federal Register in years past?

  102. TrainedInPharmacology said

    It’s time to reform the way scientific data are published such that all the raw data are available. In times past, this wasn’t possible due to space issues in printed journals. Now journals are online and the raw data/code can be listed as supplementary information, with almost unlimited space.

    A large influence on how data are interpreted is how the scientist chooses to present it. A reviewer or another scientist reading a published work is usually very limited in ability to do an independent analaysis of data (e.g. You get graph, not the raw numbers. You get a cropped image, not the whole image. You get “representative” data/images, not all the data/images). There’s no practical reason why it has to be this way anymore, thanks to the internet and pdf.

    I review GLP studies and scientific reports by others that summarize GLP studies. The majority of the time, I mostly agree with the summarized report, but I always have the option of (and frequently do) going back to the raw data and presenting it a different way, which can lead to a different conclusion.

    I am not saying that academic labs should be required to do GLP studies (which are expensive), but I do think that there needs to be some consideration of how to make the raw data easily available for all to peruse (in most cases,the taxpayer paid for it, it’s not confidential business information, and its not a national security issue). This also prevents the unfortunate scenario of not being able to “find” raw data when there is a question…since raw data would be required to publish.

  103. scotus said

    “Hellinga’s grey waves of hair encircle a cherubic face just beginning to show its age”

    http://www.the-scientist.com/2010/1/1/19/1/

    “A former student still working in the department (who declined to be named) shared Bloch’s sentiment, noting that, “A tense meeting [in September] resulted in a lot of students speaking out about the administration’s inability to do anything about Hellinga’s treatment of Dwyer.”

    I wonder who that could be?

    • noblesse d'epee said

      “I wonder who that could be?”

      Not I. I’m still a student in the program.

      • noblesse d'epee said

        I was, however, at the “tense meeting” in September, and a later and even more “tense” open-house with the Dean in November. The object was to impress upon the administration the students’ concerns about the Hellinga situation, how it affects our program’s reputation, etc. The 2008 student petition was mentioned in both meetings.

    • David said

      It was also not me. I would point out that in the “tense” open-house with the Dean in November, many students and former students still in the program voiced concerns about the lack of an efficient resolution to the controversy. Many of us have had awkward questions about the controversy at job interviews and postdoc interviews. I hope that some closure is coming soon. The committee must be done with their report by now.

  104. Mentorless said

    Serge Lang fought fraud and quackery in academia most of his life. He came up with, “The Three Laws of Sociodynamics:

    The first law of sociodynamics
    (a) The power structure does what they want, when they want; then they try to find reasons to justify it.
    (b) If this does not work, they do what they want, when they want, and then they stonewall.

    The second law of sociodynamics
    An establishment will close ranks behind a member until a point is reached when closing ranks is about to bring down the entire establishment; then the establishment will jettison that member with the least action it deems necessary to preserve the establishment.

    The third law of sociodynamics
    It’s like the video games: one can’t shoot fast enough.”*

    For sure, the second law applies to Duke’s & NIH’s handling of Dr. Hellinga.

    * Serge Lang “Challenges” (New York: Springer-Verlag, Inc; 1998), p. 797.

    • noblesse d'epee said

      Yes, Mentorless, Serge Lang would have fought for Hellinga to face justice. Consider, however, what became of Lang. It seems that he died a outcast, pilloried by the mandarins of academia, and discredited in the eyes of the public. Such is the fate of those who challenge the status quo, especially that which prevails behind the ivory ramparts. To work for honesty and transparency is an exercise in charging windmills. You would do well, Mentorless, to ignore the writings of would-be reformers such as Serge Lang. You will only be disappointed by the impossibility of his crusade. I assume, Mentorless, that you are a graduate student somehwere. I advise you to finish your thesis work, to leave academia, and to make money in industry or government. Academia is not worth saving. Its spineless denizens cannot summon the courage to police their own; let them wallow in their moral squalor. There are more useful ways with which to fritter away your life.

      • D said

        Are you speaking of Serg Lange the mathematician who also refused to believe that AIDS is caused by HIV despite the mountain ranges of evidence?

        I am not sure that he is such a great example.

      • noblesse d'epee said

        Well, his bizzare AIDS denialism certainly — and deservedly — sullied his legacy. Most of his other battles were commendable.

      • D Truck said

        Yeah, fights against the status quo aren’t always justified. From what I’ve seen, being an academic biomedical researcher is one of the best jobs out there. Hellinga’s BS and Duke’s inability to clean it up don’t change that in any way.

      • noblesse d'epee said

        D Truck, do you speak from experience? Looking around at the wreckage of (former) assistant professors’ careers in my department, it seems to me that being an academic biomedical researcher entails a constant scramble for arbitrarily-awarded grants, tenure “points,” and Science/Nature/Cell papers. One works extremely long hours for laughable pay, pouring one’s soul into one’s work, only to have a 50/50 chance of being denied tenure and slinking off to teach Chemistry 101 for $30K/yr. There are few second acts in this business. I suppose one doesn’t discover this until one nears 40, and has lost the most vigorous years of one’s life working as a species of trainee, only to be cheated of a real career at the end. I’d rather take my chances in the free market, thank you.

      • D Truck said

        Yeah, I’m speaking from experience. There is a fair amount of pressure in this job, but it can also be very rewarding. But it’s not for everyone. If you think there’s something out there that’s a better fit for you, then you should go for it. However, I believe you do have a skewed viewpoint, which I guess isn’t surprising given what Duke Biochem looks like these days.

  105. D said

    Noblesse,
    Academia is tough and some real jerks exist as powerful members of it. But, I disagree with your especially harsh assessment. Although I don’t know many folks at Duke, my experience is that for every big time rotten ass jerk there are 9 genuinely good folks who want you to succeed.

    My beef is that most senior folks know that for every 10 Post-docs or PhD-level grad students they train there are maybe 2 or 3 tenure track jobs available. They do not do enough to get that point across and support their students in finding equally satisfying careers outside of the Ivory Towers. That is the secret shame of academia.

  106. maurice said

    Anyone here familiar with the concept of reproducible research, as advocated by Davaid Donoho and others at Standford? Not sure how easily this can be applied to life sciences publications though.

    From http://www-stat.stanford.edu/~wavelab/

    “The idea is: An article about computational science in a scientific publication is not the scholarship itself, it is merely advertising of the scholarship. The actual scholarship is the complete software development environment and the complete set of instructions which generated the figures.

    We make WaveLab available to make the full content of our scholarship available, enabling others to understand and reproduce our work.”

    • writedit said

      Computational biology could follow this model to a certain extent, and for otherlife sciences papers, the methods should be sufficientlydetailed that someone could reproduce the same results. Of course, thatis what led to the first Hellinga retraction, when John Richard at SUNYBuffalo couldn’t replicate the Science paper findings. Many lifesciences journals now stick methods at the end or as supplementalonline material, though, which downplays the need to ensure thereported data are reproducible (should someone invest the time andeffort to do so … ).

  107. foo said

    I would argue that while nearly every computational protein design paper suffers from a lack of detail to ensure reproducibility (not just Hellinga’s, but many, many others including those of Baker, Mayo and ours), posting source code and instructions is not a sufficient solution. Protein design still takes a fair dose of intuition – intuition as to whether a computational solution makes sense, whether van der Waals or rotamer energies are being weighted appropriately – whether outcomes ‘look’ right.

    It is difficult to express this aspect adequately, just as it is difficult to convey the art and skill aspects of protein purification, histology analysis of tissue slices or tissue culture.

    There is no easy solution to reproducibility – although expansive, 100 page supplements to your science or nature articles are a step in the right direction for those who are patient and motivated.

  108. David said

    Hellinga’s latest paper is out in PNAS. Edited by David Baker. Completely unrelated to the projects/methods that led to controversy.

    One wonders how long until Hellinga publishes the vindication of Dezymer and/or the retraction of his work called into question by Hocker. I previously thought something should come out by the end of 2009. The deafening silence on this controversy – from Hellinga, from Nature, and from Duke’s investigation is most troubling in March of 2010.

    • noblesse d'epee said

      Ah David, we’ve learned that if powerful individuals and institutions deny the existence of problems for long enough, those troubles eventually go away! (/sarcasm) I agree with you regarding the Hocker findings. A decent interval, in which Homme might be reasonably expected to explain his 2003 Nature findings, has nearly passed.

    • Timmah said

      It is quite likely that they will never address the papers in question, due to cost and effort related issues in a now personnel-depleted and cash-strapped lab. A good case for comparison involves a claim of a cyclic peptide with protease activity. This finding was later debunked by Corey, et al (Cyclic Peptides as Proteases – A Reevaluation; PNAS 1994). However, to the best of my knowledge, the original report in question was never officially retracted, and everyone eventually dropped the issue. Similarly, the Hocker paper will probably stand alone as the final word on the Hellinga receptor designs. In the meantime, another protein design group (perhaps Hocker) will demonstrate consistent, reproducible success in receptor design, and the field will move on (But this time, with feeling! A one and-a two and-a…….). This possible outcome will greatly displease the truth and justice crowd, but it would take a very strong argument to convince me that another round of retractions will achieve something greater that the first. Although, I admit that it is somewhat puzzling to see recent protein design review articles that cite the receptor papers without reservation (for example, Nanda and Koder; Nature Chemistry 2010).

      • noblesse d'epee said

        I suppose that I’m in the “truth and justice” crowd. Homme’s fraudulent work must be retracted — all of it — and he must be driven from respectable science. Let him go search for the Philosopher’s Stone, the Elixer of Life, etc., and join the ranks of creationists, flat-earthers, and other fringe PhD-holding quacks. Maybe FOX News will hire him as an “expert guest” on occasion.

        Consider what Hellinga did. He maliciously tarnished the career of one of his former students. He knowningly mislead many research groups and thererby wasted people’s time — destroying a resource so finite and precious. An example must be made of him. “Big science” has become unacceptably corrupt, and many other Homme Hellingas screw over their collaborators, abuse their students/staff, fudge data in major ways, and generally do all of this with impunity. Enough. A stand must be taken against this malfeasance and waste. Editorial retraction of Hellinga’s fraudulent 2003 Nature paper would be a good start. Duke Med.’s Dean Nancy Andrews firing his sorry ass would be even better. But the Dean is too busy attending politically-correct academic summits and basking in her over-promoted mediocrity to do what is right. She’s just another hack who has sold her soul to be an academic administrator. Homme has little to fear at Duke.

        The problem with academic science is that it tends to attract the introverted, the indecisive, and the spineless. Many academicians hope that the Hellinga issue will resolve itself. In their dispassionate pursuit of science, such individuals lose sight of the human element of their work. I do not believe in karma, and I am skeptical of divine judgement. Justice must be meted out here, now, or it will never happen.

      • Z said

        Noblesse:

        This is not “big science”. It is ordinary science that happens to have had lots of funding because it happens to be sexy (not a good term I know). I suspect in a community at large sense, Homme will shrivel, but it will be Hell in Nanaline for while. Poor Dave and Jane to have to put up with this crap.

      • noblesse d'epee said

        Z wrote: “Poor Dave and Jane to have to put up with this crap.”

        ::sigh:: Those two, in their genteel and under-stated way, stand above most of their colleagues as true educators, and in this case, Duke Biochemistry’s professorial “noblesse d’epee.” Why must such decency and sense of justice be so rare among their peers?

      • Nancy Andrews is certainly not a hack. You had me on almost any other topic, noblesse, but you’ve gone too far.

      • noblesse d'epee said

        Pinko Punko,

        I’m sorry to have disappointed you. I recognize that Andrews appears to be a solid scientist and a good clinician. I’ve personally experienced her “leadership” (both from afar, and from “up close”), and I am unimpressed. Andrews has a compelling life story, which is surely an inspiration for many. Unfortunately, this doesn’t make her an effective administrator. When one considers that she’s paid somewhere in the vicinity of 0.6 million/year as Dean, one expects decisive and effective leadership. As is often the case in academia, the very qualities which make her a good scientist seem to make her an awful manager of people. Andrews appears to think that she walks on water, and she brooks no dissent. To have apparently become isolated in power and surrounded by sycophants so early in her tenure does not bode well. Perhaps “hack,” is too strong . . . however I might characterize her current status, it is not good. Of course, the preceding is just my opinion. Hopefully, for all parties involved, my assessment of Andrews is proven completely wrong. I would honestly welcome that outcome.

  109. scotus said

    If the Hellinga lab is now “personnel depleted” and “cash-strapped” at least something positive has been accomplished.

    If I recall one of Hellinga’s reasons (provided to “The Scientist”) for not being able to rapidly re-evaluate the protein designs debunked in the Hocker paper was that he would have to resynthesise the fluorescent probes used to monitor ligand binding to the proteins. I wonder if the new approach described in the recent PNAS paper could be of use here?

    • Former Hellinga Grad Student said

      Is that the reason he provided to The Scientist? Most of the fluorescent probes used are quite common and can be ordered via Sigma or Fisher. There was a group of fluorophores with code names U…. – they were synthesized by a collaborator at UConn. That’s the lamest excuse ever! Hellinga knows that he cherry-picked data to fit his religious belief in Dezymer and he will never try to ‘reproduce” experiments he knows did not work in the first place. Let’s just stop being so naive for a moment.

  110. David said

    It will be interesting to read a piece on the “Hellinga Controversy” in the Duke student newspaper, The Chronicle, coming out later this month. I am sure the link will appear as soon as the article is published. I understand that many people have agreed to be interviewed on the record for the first time. I hope this article will provide an update/timeline on the investigation publicly requested by Professor Hellinga. I think it is telling that Dwyer’s exoneration was swift, but Hellinga’s verdict is much delayed.

  111. Federale said

    This brief article is interesting.
    http://www.the-scientist.com/blog/display/57297/

    Notably, the FERPA claim with respect to confidentiality since the issue involves a student.

    However, in this situation with Prof. Hellinga, the student is not admitting misconduct. The student was entirely cleared. But, FERPA may get claimed in order to shroud the process in secrecy.

    If only Duke, Prof. Hellinga, and ORI could come to a swift agreement similar to the people in Indiana. Unlikely, I know.

    • noblesse d'epee said

      In a hypothetical case wherein transparency is favored by the student parties to an academic investigation (that is, students whose FERPA-protected information is employed in the investigative process), could said students choose to explicitly waive their FERPA rights?

  112. Rob said

    Duke’s student newspaper, The Chronicle, has a nice article on the Hellinga Investigation.

    http://dukechronicle.com/article/questions-linger-about-hellinga-case

  113. Gordon Klintwrth said

    This case has lingered on for an unusually long time. Surely the Duke panel investigating the case should be able to come to a verdict by now. Why has the investigation gone beyond the usual 312 days set by the University’s polica? If Duke can not resolve the issue now perhaps an external committee with appropriate expertise should be appointed. It seems to be time to wrap up the case.

  114. scotus said

    The suggestion in the Chronicle article from Prof Richardson that perhaps Hellinga should not take students in the future to save the department from the “hassle” of having to warn people of the dangers of working in his lab on an annual and individual basis was priceless.

    I wonder if Hellinga’s attempts to restrict the scope of the investigation by complaining against himself have backfired and what has actually happened is that a more expansive investigation was started. For example, I can’t imagine that Hellinga’s complaint requested an investigation into the Novo TIM complementation experiments but I also can’t imagine that any perceptive faculty member involved in the investigation would not immediately identify these as something that needed to be looked into.

    Of course, goodness only knows why this has taken more than two years.

    • noblesse d'epee said

      Wesley Byerly, the “Misconduct Review Officer” in the Hellinga case, wears another “hat” at Duke: he is paid to be the “Associate Dean for Research Services.” In the latter capacity, he controlled the budget for the (now cancelled) structural biology center offered to Hellinga and Beese as a retention bribe. Why Byerly hasn’t recused himself from the Hellinga case, despite a more-egregious-than-usual conflict of interest, is anyone’s guess. But it doesn’t look good.

      As all NIH-funded Duke graduate students had to take “ethics” seminars taught/directed by Byerly, I’ve seen him in action. It’s just my personal opinion, but my impression of him, long before I knew about Hellinga et al., was of a Misconduct Review Officer who seemed like a partisan “good old boy” of Duke Medicine. He did not inspire confidence. Significantly, we graduate students’ ethics training consisted (the year that I took the courses) of a detailed dissection of the David Baltimore scandal. I recall that our “discussions” were gently guided toward the conclusion that Baltimore and his laboratory were victims of an overzealous ORI. Perhaps not coincidentally, Dean Andrews was one of Baltimore’s star students. It is pure conjecture, but I would not be terribly surprised if Andrews and Byerly are attempting a whitewash of the whole affair.

      • Mentorless said

        noblesse d’epee:

        Wow! Great comments!!

        I guess your course’s, “detailed dissection of the David Baltimore scandal” was managed so as to exclude documents deleterious to Baltimore et al. I would be interested to know the syllabus.

      • Mentorless said

        For instance, was Dr. Baltimore’s 9 September 1986 letter to Dr. Herman Eisen part of the “dissection?” Eisen was the only person assigned at MIT to look into Dr. Margot O’Toole’s allegations. The letter was discussed at length in one of Rep. John Dingell’s hearings. Amazingly, the HHS Appeals Board ruling/decision that exonerated Dr. Thereza Imanishi-Kari cited the letter as evidence of a misunderstanding!!

        The letter can be found here:
        http://www.gatewaycoalition.org/files/Gateway_Project_Moshe_Kam/modules/module2.html
        (Go to “resources.”)
        So also can Lang’s analysis of the case – which also discusses the letter.

      • noblesse d'epee said

        Mentorless,

        I’m pretty sure that the Eisen letter was not included. I’d post the materials online if I still had them. Alas, I threw them out years ago. I do recall that Rep. John Dingell was presented as a “bad actor” in the whole affair. It was cast as a “grandstanding politician meddles in scientific affairs” scenario. That may have been partially true, but there was clearly more to the story. Thanks for the link.

  115. Federale said

    Interesting tidbit that just came out…

    http://www.the-scientist.com/news/display/57386/

    Also, the reading for the Duke Ethics training used to be the book ‘The Baltimore Case’ by Daniel Kevles. There was some short attached article to it, which not only failed to adequately protray the book, but also whitewashed the complexity of the underlying problems and processes.

    Nice pickup on the linkage between Dean Andrews and Baltimore. That should send a chill through many peoples spine…

    • Mentorless said

      Federale:

      Well, Professor Daniel Kevles’, “The Baltimore Case: A Trial of Politics, Science, and Character” (New York: W.W. Norton & Co., Inc.; 1998) IS a whitewash. Probably, the, “short attached article to it” was one of the few critical reviews. I agree with Tina Gunsalus’ description of the book as an, “homage to Baltimore.” Here is a list of them:

      Gunsalus, C.K. (1999) Review of Kevles’ “The Baltimore Case…” New England Journal of Medicine 340(3): 242 (21 Jan.);
      Greenberg, D.S. Letter (ScienceWriters, Spring 1999, p. 26);
      Shashok, K. (1999) The Baltimore affair: a different view. International Microbiology 2(4): 275-8 (Dec.);
      Lang, S. “On A Yale Kevles Appointment” (paid advertisement) (Yale Daily News, 3 Feb. 2000, pp. 6-9);
      Moran, G. (2002) Review of Kevles’ “The Baltimore Case…” J. Information Ethics 11(1): 90-3;
      McCutchen, C.W. (2002) “The Baltimore Case” Misrepresents a Major Piece of Evidence. J. Information Ethics 11(1): 5-6.

      • Federale said

        My apologies. I did not intend to imply that I agreed with the analysis in the Kevles book. Just pointing out that the materials seemed to be uniformly useless.

        However, imagine, hypothetically, that someone at Duke would have the gall to tell departmental faculty the following…

        “I would like to again remind all Department faculty that it remains Duke policy not to discuss or respond to any inquiries regarding confidential research misconduct cases. As previously indicated, all inquiries regarding these cases should be forwarded to Doug Stokke in the Medical Center News Office.”

        Think that ever happened in the Baltimore case?

      • noblesse d'epee said

        I suspect that Federale’s post refers to an e-mail sent by a senior Duke administrator in an attempt to muzzle the Duke Biochem. faculty regarding the Hellinga scandal. Could this have something to do with professors’ recent comments regarding this issue and published the campus newspaper (see link)?

        http://dukechronicle.com/article/questions-linger-about-hellinga-case

        Why not post the whole e-mail, with the sender’s signature line? E-mails and letters become the property of their recipients, and can copied and forwarded at will.

      • sabrosa said

        Here’s the e-mail I got:

        From:
        Date: Thu, Jun 19, 2008 at 9:23 PM
        Subject: Petition regarding Professsor Hellinga
        To:

        Colleagues:

        I enclose a petition (attached PDF) concerning the recent controversy surrounding Duke Biochemistry Professor Homme W. Hellinga and his former
        student Dr. Mary Dwyer. I offer my thanks to the colleagues whose ideas and proof-reading brought this document together.

        Those of us who prepared this petition ask, as a favor, that you take time to read and carefully consider it. Should you wish to sign it, I will keep the signature page in my laboratory ().

        If you would like me to stop by your lab or office, please let me know. The deadline for subscribing this petition is next Friday, 30 June.

        Best Regards,

  116. scotus said

    I’ve been wondering what in the Chronicle article could have prompted the email discussed in Federale’s post.

    One thing did catch my eye:

    She [Prof. Richardson] said, however, that she would not question the sincerity of those currently serving on the committee.

    “They definitely take their job very seriously,” Richardson said.

    These statements imply that the identities of the faculty serving on the investigating committee are known (at least to Prof Richardson).

    Is this the case?

  117. noblesse d'epee said

    This July, two years will have elapsed since students petitioned Duke to investigate that charlatan Hellinga. It will have been nearly three years since Prof. John Richard discovered the first (of multiple) example(s) of Hellinga’s dishonest science. The pace of the investigation directly violates Duke’s (and NIH’s) formal academic misconduct procedures. Medical Center Dean Nancy Andrews and her despicable toady “Dr.” Wesley Byerly have tried to muzzle students and faculty who have publicly questioned their gross mishandling of this case. Duke ought to demonstrate support of fundamental scientific ethics by taking decisive action in what is obvious academic misconduct by Hellinga. Instead, the university engages in cover-up. The Dean and her minions have “outrageous ambitions” indeed . . . regarding “damage control.” Fuck them all.

  118. Rob said

    Yet another example of an academic misconduct investigation that did not take 2 years:

    http://blogs.discovermagazine.com/badastronomy/2010/07/01/climategates-death-rattle/

  119. scotus said

    This one took “only” four years to resolve and ended with a criminal prosecution and voluntary payment of $50K restitution (with the “incentive” of a possible $100K fine and jail time).

    http://news.sciencemag.org/scienceinsider/2010/06/scientist-turned-in-by-grad.html

    • noblesse d'epee said

      Well, Duke’s total awareness of the Hellinga scandal has exceeded three years, while the formal investigation has surpassed two. This trajectory is consistent with Dean Andrews being incompetent, or corrupt, or both. Duke should, for once, attempt to take a stand in favor of something other than its perceived financial interests. The university will not get one red cent of alumni support from me. But hey, I’m only a scientist, and will therefore never accumulate sufficient wealth to have much influence. That’s left to the many Duke-educated Wall Street securities brokers (crooks). Now that I think about it, Hellinga is our home-grown Madoff of research. He’s certainly fleeced his investors. He should be sent to join Bernie in “Club Fed.”

  120. scotus said

    A milestone or sorts is fast approaching:

    http://projectreporter.nih.gov/project_info_details.cfm?aid=7485777&icde=4499482

    At the end of the month the 2 year no cost extension of Hellinga’s DP1 grant will end leaving him with no active NIH grant support.

    • Mentorless said

      I may be wrong: but I don’t think no-cost extensions of NIH grant funding are limited to 2 years. Or am I wrong?

      • noblesse d'epee said

        I think that you’re correct, Mentorless. Remember, however, that Homme has/had significant funding from the D.O.D., specifically the Office of Naval Research. Since our military doesn’t notice when it is fleeced of $ billions, I doubt the $ millions lost on the Hellinga misadventure have appeared on the radar. Nor is there an easy way to see how military funds are allocated. Homme could still be pulling in enough government cash to keep afloat.

      • SG said

        1 year is automatic. 2 years you have to ask for. I have not heard of a 3 year extension. I guess it is possible but you’d have to justify why you still haven’t spent all of your money with 2 additional years. You are not allowed to hoard cash and do no work.

    • scotus said

      It would be very unusual for this to be extended for a third year.

      Irrespective of his possible sources of DOD funding, being unable to sustain active NIH support after the significant investment of a prestigious DP1 award is a humiliation of sorts for Dr Hellinga.

      • noblesse d'epee said

        Mild academic humiliation is not enough. Hellinga and Potti are still Duke faculty; these jerks retain their relatively high-paying, respectable positions. As I’ve said before, examples must be made of these betrayers of scientific trust and thieves of scarce funding. Some will argue that punishment is not a deterrent, that the pathology(ies) shared by these two charlatans render their would-be emulators unresponsive to outside pressures. That may be true, but I still believe that the safest route (for Duke, for science) is dismissal. While Duke’s trustees are in the cutting mood, this is an excellent opportunity to mow down a swath of DUMC’s administrative overgrowth, starting with fraud-abettors (and dismal leaders) Victor Dzau and Nancy Andrews.

  121. Rob said

    Durham’s media has been absolutely silent on the Hellinga debacle. The did, however, take note of another pompous liar in the medical center ranks:

    http://www.newsobserver.com/2010/07/17/585434/duke-scientist-placed-on-leave.html

  122. […] 19, 2010 at 2:20 pm · Filed under Biomedical Research Ethics, Research News This morning, Rob commented on the lack of local media coverage of the Hellinga case but the quick reporting of Duke’s […]

  123. scotus said

    Presumably Duke has the relevant biosketches on file and can quickly determine if these questionable credentials were listed or not while simultaneously documenting if these credentials are bogus.
    This seems like an open and shut case to me.

    Why on earth would anyone do this? Did he think that somehow claiming to have been the recipient of a prestigious award would give him a competitive advantage in the grant review process? Is Dr Potti unusually insecure?

    • writedit said

      Please see separate discussion of Potti case at http://wp.me/p2wrc-R9, which includes links to Nature Medicine’s coverage of Duke’s review of data handling errors related to Potti’s work (& relevant clinical trials).

  124. noblesse d'epee said

    Nope. Hellinga’s still a James B. Duke Professor of Biochemistry.

  125. scotus said

    So does this mean he’s leaving Duke?
    Is his wife leaving too?
    Does KIST have some sort of a formal arrangement with Duke like the National Univesity of Singapore does?

  126. David said

    Seems that Duke Prof Potti resigned. Perhaps Hellinga will resign as well.

  127. Homerhell Linger said

    Homme will never resign, he gets a lot more grants than that Potus guy.

    • scotus said

      What exactly are all these Hellinga grants? He doesn’t have any active NIH support. How is he funding his research?

  128. writedit said

    Update: The [Duke] Chronicle reports: “The University has reached a resolution in its two-year investigation of biochemistry professor Homme Hellinga has been reached. But Duke officials contacted last week declined to discuss the outcome.”

    What a shocker … (thanks to inside tip)

    • Maurice said

      > But Duke officials contacted last week declined to discuss the outcome.

      How can they not discuss the outcome? This is not about Hellinga’s personal affairs, it is a matter of public interest at the university. The students pay their teachers salaries and are entitled to know if there are any problems with any of these teachers. WTF? Can the Duke leadership be any more misguided and make any more mistakes?

  129. David said

    It seems to me that Dr. Hellinga wrote about a project to design ibuprofen binding into MBP (see October 20, 2009 above). He wrote, “We have completed the experimental observations for this work, and are finishing a manuscript describing it.” How long does it take to write up work that might salvage your reputation? Was it ever submitted to a journal? Has no one reviewed this work? How does he get away with these delays?

    • noblesse d'epee said

      Despicable, utterly despicable.

    • noblesse d'epee said

      I’m not surprised. In academia, one can be an obvious charlatan, yet survive to fight another day. Take note, young scientists. Do you really want to be a professor? One would have to have agar for brains to devote one’s life to a system doomed to be dominated by sociopaths and frauds.

      • D said

        Of course on the other hand, once you progress high enough you can commit crimes and get mulit-year paid vacations as a reward. Sounds like a great benefit to me.

  130. Federale said

    If Hellinga is found innocent by NIH rules, as is indicated in the C&EN article upon a careful read, then there is a duty to repair his reputation. This would require Duke to say something to the public.

    However, if this be true and Hellinga is found guilty based on Duke rules, then one could envision the deafening silence we have now as Duke hashes it out with Hellinga and decides what (if anything) they will do next.

    • David said

      For convenience, the C&E News article is here:

      http://pubs.acs.org/cen/news/88/i51/8851news4.html

      Duke repaid NIH for Potti’s funds. It appears they will not be repaying any of Hellinga’s funds to NIH or DARPA.

      While I appreciate the quote of Louis Metzger, I think the critical request of the student petition involved Hellinga’s arguable mistreatment of Dr. Mary Dwyer, former Hellinga graduate student and current (at the time) Duke Postdoc. By not responding to this aspect of the student petition, Duke has thus condoned the treatment she received by Hellinga surrounding the retracted work. It seems to me that the University could hardly have take “appropriate action to address any concerns identified” with Hellinga. If there were not any problems uncovered, exonerate him. If there were problems, the “appropriate action” for the good of Duke, academia, and all current and future graduate students is to point out what went wrong and how to prevent it from happening again. Anything less is a coverup.

  131. Rob said

    Meanwhile, Precision Biosciences, which licensed the work of Hellinga and is headed by former Hellinga p-doc Jeff Smith, has racked up some more grants based on some of Hellinga’s technology.

    I hope this holds up. If you remember correctly, Smith was on the TNT work that got retracted.

    http://www.bizjournals.com/triangle/news/2010/12/16/durham-firm-lands-3m-in-grants.html

    • noblesse d'epee said

      The conception and development of Precision Biosciences’ technology was done independently by Hellinga’s post-docs, possibly without Hellinga’s knowledge, and didn’t make use of Dezymer or other HH technology. Hellinga’s involvement in the company is probably part of an agreement by which Smith and other former Hellinga post-docs left the laboratory with the PI’s blessing. Apparently, the guys at Precision Biosciences don’t have much to do with Hellinga.

  132. D Truck said

    Dick Brennan of MD Anderson is the new Duke chair according to the Chronicle article. I assume his partner Maria Schumacher will also be coming along – will be interesting to see how these two interact with Beese – Hellinga, et al.

  133. David said

    Hellinga tried to design an enzyme into a structure. Unfortunately, he neglected to do all the controls to prove it, AND the reviewers let him slide with a sloppy paper. Here is a new paper that has many controls in it. Rather remarkable study. Still, they never claim anything beyond what their data show.

    I like this quote: “We also purified several of the de novo proteins. (To avoid contamination by the natural enzyme, purifications were from strains deleted for the natural gene.)”

    Hellinga could learn something from reading it:

    De Novo Designed Proteins from a Library of Artificial Sequences Function in Escherichia Coli and Enable Cell Growth

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015364

  134. David said

    As it has not yet appeared here, Duke newspaper editorial from Jan. 13:

    The last paragraph is exactly what I believe: “If Hellinga has done nothing wrong, he has nothing to lose from the release of a report that clears his name. If he has done something wrong or simply made an honest mistake, the University stands to gain the trust of many by admitting it.”

    http://dukechronicle.com/article/hellinga-case-demands-resolution

    Hellinga case demands resolution
    By Editorial Board
    January 13, 2011

    For the past two years the University has been investigating the research conduct of Homme Hellinga, the James B. Duke professor of biochemistry, who was forced to retract two published papers in 2008 after peers called his research into question.

    The investigation left a lot of scorched earth—it tarnished the reputation of Mary Dwyer, one of Hellinga’s graduate students, and resulted in Hellinga’s research being publicly questioned in Nature magazine.

    In December, The Chronicle reported [7] that the University concluded a review of Hellinga’s research conduct. Unfortunately, we know nothing about the review’s findings.

    The Hellinga case provoked an interrogation of Hellinga and Duke across the scientific community—a community that extends far beyond the walls of the Gothic Wonderland. A private, internal resolution does nothing to bring closure to this very public issue. A true resolution demands that the University release the findings of its review.

    Under federal regulations, the University only has to release the findings of the review if Hellinga is found guilty of research misconduct as defined by federal law. If Hellinga’s conduct violated University, but not federal standards, the University does not have to release the findings of the review.

    Keeping the review’s findings secret makes sense from a public relations standpoint. Hellinga is a distinguished researcher and Duke has an interest in protecting him. Sweeping the review under the rug could also avoid increased media scrutiny of the University in general.

    But public confidence cannot be restored through secrecy. The Hellinga review affected a lot of people. It dragged an innocent graduate student’s name through the mud, giving prospective and current graduate students reason to doubt Duke’s commitment to protecting its graduate students. Likewise, Hellinga’s peer scientists have good reason to doubt the credibility of his future research findings and, more importantly, the credibility of the University. Duke endorsed and rewarded that scientist’s efforts and now refuses to clarify whether research errors occurred.

    For these groups to have their confidence restored in the University and its review processes, they need to know what Hellinga did wrong and what steps the University is taking to chastise the professor and prevent future misconduct.

    Knowing that a review has been completed is not enough. As it stands, we have little reason to have faith in the purity of Duke’s review process. A recently released report on Duke’s review of Anil Potti’s research revealed [7] that the Duke administrators decided not to pass on information about discrepancies between the raw data and the data Potti reported. A review of Hellinga’s conduct might be similarly flawed.

    Protecting public confidence in the scientific process is vital. People rely on scientific conclusions to make critical decisions—whether or not to vaccinate their children; whether or not to turn conceptual research into a clinical trial. Individuals cannot evaluate this research on their own—they must make leaps of faith. Because they must place blind faith in the science, there is much at stake in protecting the integrity of the scientific process.

    If Hellinga has done nothing wrong, he has nothing to lose from the release of a report that clears his name. If he has done something wrong or simply made an honest mistake, the University stands to gain the trust of many by admitting it.

    • writedit said

      Thanks for posting this, David. Yes, one would think Duke would have learned from the Potti case that their internal reviews might not be as rigorous as they need to be.

  135. mysticdog said

    As the first grad student Homme threw under the bus, I am not surprised by any of this. Ego, ego, ego. I guess it is vaguely gratifying to see I wasn’t the only one…

  136. […] was recognized as a rising star at the time although much of his research has turned out to be, at best, irreproducible). I was hoping to go back to my office to google the awardees because I had not heard of them or […]

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