No, not an online dating service … ResearchMatch is an NCRR-funded secure registry that allows individuals to sign up to receive alerts about clinical research in which they might be interested and for which they might be eligible — and researchers to sign up to find potentially eligible participants for their studies.

Currently, 40 of the 46 current CTSA sites are participating, and the registry will eventually expand to include non-CTSA institutions. As described in the NIH’s news release:

After an individual has self-registered to become a volunteer, ResearchMatch’s security features ensure that personal information is protected until volunteers authorize the release of their contact information to a specific study that may be of interest to them. Volunteers are notified electronically when they are a possible match and then make the decision regarding the release of their contact information. It also will promote choice as there are no obligations on the volunteer to participate in studies.

According to the ResearchMatch.org participant FAQ, “[approved] researchers will not be given access to begin looking for potential study Volunteers through ResearchMatch until approximately January 2010.” As further explained by the researcher FAQ:

ResearchMatch is a not-for-profit activity and is free for any participating site & their researchers. … Researchers at participating sites will be given access to register through the ResearchMatch system. Upon registration, researchers may request either feasibility or recruitment access … your access to recruit via ResearchMatch will last only as long as your IRB-study approval.

After you have been granted recruitment access, you will be able to search for appropriate matches amongst the non-identifiable ResearchMatch Volunteer profiles in the system. You will enter your study’s criteria in the ResearchMatch Search Builder which will yield a list of these potential matches. You will send out IRB-approved content in your initial recruitment message to these potential matches through ResearchMatch. The secure ResearchMatch clearinghouse will route your message to each of these potential matches and they will have the option of replying yes, no, or no response. Your study’s home page will feature all those Volunteers who say yes and show aggregate figures/charts demonstrating the response rate to your initial recruitment message. Once the Volunteer has authorized ResearchMatch to release their contact information to you, you will be responsible for managing this contact information as called for by your IRB-study protocol.

Vanderbilt, which maintains and whose IRB oversees ResearchMatch.org, also has its own DNA bank called BioVu, which includes leftover blood from all patients seeking treatment unless they opt out when signing the the Vanderbilt Consent for Treatment and Agreement to Pay form.

NIBIB has released the RFA for Phase II (Implementation) of its Quantum Grant Program - aka Medical Moonshots.

Letter of intent due December 22, application receipt date on January 22, 2010 (just misses the Jan 25 transition to enhanced shorter applications, so these use a 25-p research narrative … “typewritten” paper submission no less).

The goal is to achieve a profound (quantum) impact on the prevention, diagnosis, or treatment of a major disease or national public health problem through the development and implementation of biomedical technologies.

Total costs (i.e., direct plus indirect/F&A costs) for any single year (5-y project period) may not exceed $3M. NIBIB expects most applicants to request $1-3M in total annual costs.

Before you get too excited, only 1-3 awards will be made.

NIBIB made 5 awards in the Phase I competition “on stem cell therapies for diabetes and stroke, nanoparticles to help eliminate brain tumors, development of an implantable device to replace kidney dialysis, and a microchip to capture circulating tumor cells for clinical and research purposes” — but anyone can apply for Phase II funding so long as their research plan “demonstrates the potential for a quantum advance by the end of Phase II via substantial pre-clinical data or a first clinical implementation.”

How much of an advance? NIBIB envisions that the “technology being developed would overcome a major, present-day disease or national public health problem (i.e., leading categories of disease burden, high-mortality/morbidity diseases affecting more than 100,000 individuals annually, technologies that revolutionize over 200,000 procedures annually), or change the paradigm of prevention, diagnosis, treatment in the practice of medicine.” In 5 years. I guess $3M a year will do that for you. I can’t wait to read the way cool announcements in NIH Research Matters.

What I want to know is where NIBIB finds reviewers with the vision needed to foresee a paradigm shift and quantum advance in the practice of medicine within the next 5 years … and whether these reviewers are available to take a look at my 401K portfolio.

Lots more detail in the RFA. Happy reading.

Bit late putting up a reminder of this bit of fun – the annual Beloit College Mindset List. I think the most memorable Mindset List item for me remains #1 (covered today in the NYT) from the class of 2011:

1. What Berlin wall?

In fact, that whole 2011 list is one of my favorites for reminding me of the need to readjust my mindset (you can choose different years in the drop-down list at the top of the page). For 2013, we have:

2. Dan Rostenkowski, Jack Kevorkian, and Mike Tyson have always been felons.
13. The KGB has never officially existed.
23. The European Union has always existed.
35. Women have always outnumbered men in college.
36. We have always watched wars, coups, and police arrests unfold on television in real time.
38. Belarus, Moldova, Ukraine, Uzbekistan, Armenia, Latvia, Georgia, Lithuania, and Estonia have always been independent nations.
75. There has always been blue Jell-O.

Of interest to a select audience … one application per parent grant but no limit on the number of applications from a given institution. The big “have” institutions will have lots of these big core center awards and will no doubt get in line for an extra $1.2M+ for each of these facilities, complements of ARRA.

Today’s notice of Administrative Supplements to Support Core Consolidation provides up to $500,000 in equipment, up to $500,000 for alteration and renovation, and/or up to $200,000 (DC) for other costs such as personnel and supplies. The NIH plans to spend ~$15 million of ARRA funds by September 30, 2010 to support requests submitted in response to this notice. Participating ICs include NCRR (G12 plus all P and U awards), NCI (only Cancer Center Support P30s are eligible), NIAID (only CFAR P30s are eligible), NIAMS (only P30s are eligible), NIDDK (only P30s & P60s are eligible), NIEHS (only P30s are eligible), and NIDA (“particularly interested in consolidation that results in synergistic enhancement of existing research capabilities, while continuing current services”).

The Notice provides full application details. Applications are due January 13, 2010.

I took a pass in September on noting Les Costello’s piece in The Scientist entitled NIH R01s: No Longer the Best Science, in which he expresses concern over policies designed to increase funding to new/early stage investigators. This month, Walter Schaffer and Sally Rockey from OER (NIH’s Office of Extramural Research, which brings you the NIH Guide, Extramural Nexus, NIH Regional Grant Seminars, and all you need to know about grant application and management policies) respond with NIH Continues to Support the Best Science through R01s. {see Alison McCook’s comment below for the corrected subtitle to the Schaffer-Rockey piece.}

Essentially, Schaffer and Rockey lay out the history of NIH’s efforts to promote funding to new and early stage investigators (ESI) and the rationale for doing so:

When Dr. Costello [who "vehemently" objects to the new/ESI policy] received his first traditional NIH research grant (R01) in 1963, success rates were near 58%, and 35% of the competing R01s went to first-time recipients. … In 1977, the average age of new investigators was nearly 37, success rates had decreased to 28%, and the proportion of R01s going to new investigators had decreased to 33% … by 2006, less than 24% of the recipients of competing R01s were new investigators, success rates were below 21%, and the average age at first award of an R01 had increased to more than 42.

The first comment, however, keeps on with The Scientist theme about whether the NIH is funding the best science … not necessarily due to any potential discrimination favoring new investigators so much as penalizing amended applications by percentiling them separately (intended to reduce review burden by funding more A0s than A1s based on historical data showing that ~70% of A0s are eventually funded as A1s or A2s). The opening line probably sums up the scientific community’s mood though:

The angst over new and early stage scientists indicates a broader anxiety among established NIH investigators over what is seen as administrative meddling adding to an already capricious peer review process.

And then, of course, we have the forum over at Genome Technology asking Is Peer Review Broken? (review of grant applications and journal manuscripts). Clearly, CSR and OER need to keep the communication channels open for continued feedback on their enhancements to the application and review processes.

So asks the cover story by Meredith Salisbury for Genome Technology.

She starts the ball rolling in her accompanying editorial:

Get three scientists together, and it’s almost a guarantee that the conversation will eventually turn toward the vagaries of the peer review process. Be it for winning grant funding or getting a paper published, this system of relying on a handful of fellow scientists to select the most promising and influential research shapes — at least to some degree — every single researcher’s career path.

And then she gets 3+ scientists together, with the tone set right off the bat by Ferric Fang:

“For something that is of and for scientists, the peer review process is very unscientific,” says Ferric Fang, a professor of laboratory medicine and microbiology at the University of Washington. Whether it’s for papers or grants, having just a handful of people review someone’s work is statistically unsound, he adds. “If these [reviews] were data that you generated in your lab, you would say, ‘I don’t know what the conclusion of this is.’”

And per the suggestions made on grant review processes, apparently efforts to enhance peer review at the NIH haven’t gone far enough. A sampling to get you over to Genome Technology for the full report:

One hope is that having a larger pool of reviewers could help reduce the impact of any individual review, says Fang. Under the current system, “one bad review can sink an application.”

Another take on the grant review system in general is that focus needs to shift away from today’s model of specific proposals for short-term periods. …

Lawrence [Peter Lawrence at the zoology department of the University of Cambridge] would prefer a system where reviewers considered the track record of the investigator more than the details of the new research proposal (with special dispensation for new investigators). …

According to Fang, this concept of awarding funds on a track record basis would also serve the purpose of weeding out people who are very skilled at writing proposals but are less competent at actually performing the science.

Oh no! What’s a writedit to do?! Well, I am the first to acknowledge that no amount of skilled grantsmanship can make up for poor science, so I think, to a certain extent, this last concern can be dispensed with.

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.

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.

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.

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.”