So, with one FY of ARRA/stimulus funding behind us, where and how is it going? Nature has an economical infographic showing how 7 federal agencies are spending their R&D stimulus dollars and also includes brief commentaries by 6 experts on “what concerns them most about the US stimulus spending and … ways to ensure that it benefits research and society in the long term.” Many touch on the problems of feast-famine cycles in research funding and how these hit young researchers particularly hard. I suspect Michael Teitelbaum (Sloan Foundation)’s essay on “Incentives for universities do not promote sustainable behavior” will resonate with many regular readers of this blog.
Archive for October, 2009
Hellinga Controversy Expands
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Whereas Science was mum on the whole debacle when their article was retracted, Nature has taken a proactive analytic approach to the possibility that Hellinga’s 2003 Nature article (and a 2004 PNAS paper) may need to be retracted based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.
ORI Blog
As I mentioned earlier, ORI has ventured into the blogosphere, and a few recent posts caught my attention, such as the Meaning of RCR by John Galland, PhD, Director pf the Division of Education & Integrity. He concludes with a list of objectives for RCR training:
(a) Protect animal subjects, human participants, research personnel, and the environment
(b) Be honest and transparent, not deceptive (e.g., falsifying, fabricating, or plagiarizing data or deceitful attribution of authorship)
(c) Be fair by not introducing unwanted bias into research results, conclusions, or inferences (e.g., conflicts of interest and commitment, sloppiness)
(d) Be benevolent, not be malicious (e.g., thievery of ideas, unfair criticism during peer review for personal gain; exploitive of others)
(e) Be open to creativity and innovation
(f) Protect the public trust
I like (e) conceptually but cannot for the life of me imagine how typical RCR training would achieve this … hopefully not during lectures about falsification and fabrication.
Today I spotted a new post of personal interest on the Integration of RCR Education and Bioethics Education. Specifically, the question is posed,
What educational programs, what research environment can be fostered, at our institutions to help researchers with such decisions [e.g., fabricate data to secure grant funding needed to sustain research program & staff], or better yet, to help them never have to make such decisions?
Regular visitors will know that I monitor studies and analyses of procedural and distributive justice in the context of the research environment, such as the work of Brian Martinson, Melissa Anderson, et al.. Nice to see ORI giving a little thought to the research environment itself (and its administration) as a means for preventing misbehavior and worse. In discussing grant funding policy here at MWEG, some have suggested that institutions be required to pay the major portion of researcher salaries (hard money), and this would certainly be one way to foster a much more pleasant environment that would likewise be more conducive to the responsible conduct of research. If you have other suggestions, I am quite sure Dr. Galland would appreciate such comments on his blog.
Researchers “Unflinchingly” Grateful for ARRA?
The Chronicle of Higher Education has a commentary from our friends at AAMC entitled, Key for Future Investment: Researchers’ Response to America’s Recovery Act. And what is the proper response?
Researchers should continue to be unflinchingly positive about the opportunities that the Recovery Act has presented.
Unflinchingly. Indeed. The first comment submitted in response to this piece flinches a bit, certainly (“Unfortunately, most of the Recovery Act money was given to those who already hold NIH awards- so the rich get richer … I fail to see how this is going to provide much innovation, much added technology or job creation, and a stimulus to biomedical research other than that which already exists.”)
The authors urge beneficiaries of ARRA funding to demonstrate “thoughtful stewardship of those resources” so as to “bolster the nation’s future enthusiasm for science as a socially responsive and effective enterprise.” They caution that “future support for the NIH and research throughout the country could depend on whether Congress and the public perceive that scientists have taken appropriate advantage of [this] opportunity.” With regard to the reporting requirements on job creation and “other economic impacts of the grants”,
… such requirements will allow scientists to engage the public by putting in plain words the practical, present benefits from academic research, as well as potential future economic and societal gains that result … Some institutions already track the potential economic impacts and multiplier effects of research investments within local communities, such as job creation and the attraction of “high tech” health-sector jobs. … The willingness of researchers to create and improve upon such methodologies will reflect a commitment to be held publicly accountable for the generous public and private support they receive.
BICO already does this, and certainly, research, technology, health care, and education have replaced manufacturing and milling as the economic engine in our region – with spectacular success. But does that make universities here more worthy of increased federal funding? No, only the sound, peer-reviewed science that made such an economic transformation possible should be rewarded – here and elsewhere. As for public accountability … I guess you PIs should start disclosing those multi-million dollar bonuses you get every year.
But getting back to why we all should be “unflinchingly positive” about ARRA,
The act ends a five-year hiatus in real growth of the NIH’s budget, which had declined in inflation-adjusted terms by more than 14% since 2003. The recent rapid infusion of dollars illustrates the confidence of Congress in the ability of the NIH and other science agencies to play a vital, more immediate role as an economic engine essential to our national recovery. But those funds notwithstanding, the Recovery Act’s political significance for biomedical research goes far beyond material support, reflecting the trust of Congress and the administration in the medical and scientific communities as responsive and essential to long-term economic development and health.
I’m not sure ARRA ended the loss of “real growth” in the NIH budget, as the base appropriation will go up by just 1.3% for FY10 and probably not much more for FY11. If the impact of this unanticipated and hastily (frenzily) planned and implemented $10.3B infusion turns out to be mediocre at best (at least in the short-fuse time span acceptable to elected representatives), and if Congress therefore feels justified in maintaining flat-lined federal spending, this would seem to be akin to basing the future of the US research enterprise on the outcome of a pop quiz. Put another way, would someone who proposed this high-risk experiment as a pioneering or innovative project to demonstrate the value of research to US society have been funded?
On the other hand, a glimmer of hope for the Administration’s commitment to science. The NSF can be grateful to the White House for their concern over the Senate plan to reduce funding to the NSF and NIST (Natl Institute of Standards and Technology) by $200M and to “transfer … icebreaker operations and maintenance funding from the NSF to the Coast Guard.”
Findings of Research Misconduct
Little late getting this up, October deadlines and all …
Notice is hereby given that ORI and the Assistant Secretary for Health have taken final action in the following case:
Based on the findings of an investigation report by the Universidad Central Del Caribe and additional analysis and information obtained by ORI during its oversight review, ORI found that Jennifer N. Arriaga, former Research Assistant in a clinical trial project entitled Brief Strategic Family Therapy for Adolescent Drug Abusers, engaged in research misconduct in research funded by U10 DA13720.
Specifically, ORI found that Ms. Arriaga knowingly and intentionally engaged in research misconduct by fabricating 17 interviews and falsifying 10 subject incentive receipts in the trial. The interview record consisted of Timeline Follow Back information, confidentiality self-report forms, and urine drug test results.
