Cancer Research, Carlo Croce, Character Assassination, Civil Death, Clare Francis, Data Fabrication, Data Falsification, Defamation, Defamation lawsuit, First Amendment to US Constitution, Fraud, Ivan Oransky, National Institutes of Health, New York Times, NIH, NIH funding, Office of Research Integrity, Ohio State University, Paul S. Thaler, protected free speech, Research misconduct, Retraction Watch, Scientific corruption, Scientific publication

Stellar cancer researcher Carlo Croce falls from grace: hypocrisy in science

Last week The New York Times published a front-page story entitled “Years of Ethics Charges but Star Cancer Researcher Gets a Pass“.  The article grossly disparages Prof. Carlo Croce, a towering figure in cancer biology and genetics, and his home institution, The Ohio State University. It describes in some detail multiple accusations of misconduct and malfeasance that have been targeting Croce for years.

bio_croce

Dr. Carlo M. Croce, Ohio State University

We are told that Croce has been dodging grave allegations that he falsified data in research supported by more than $86 million in federal grants that have been awarded to him. The investigative task of the Times reporters was greatly facilitated by the fact that the records at Ohio’s courthouses and its university system are completely open to the public. And Ohio State University, which claims it had spent more money supporting Dr. Croce’s research than it had received in grants, was apparently totally responsive to requests for records.

The big problem with all this is that to this day there is no hard evidence of misconduct implicating Croce. Ohio State had repeatedly investigated Croce and cleared him of wrongdoing every single time. How disinterested these investigations were is of course a matter of debate.

Since Dr. Carlo Croce has not been proven guilty of misconduct by the preponderance of evidence, the public does not have the right to know about these investigations and he must be presumed innocent. The integrity of Croce’s career should have been protected. The New York Times article is actionable in Court.

The most astonishing aspect of the story is that neither government agencies nor Ohio State believed Croce would be seriously investigated for misconduct, since he is one of Ohio State biggest rainmakers. This bespeaks of a system corrupt to the marrow and draws a lesson that epitomizes the level of hypocrisy that plagues the science establishment.

Of course we wonder who sent James Glanz, the Times reporter, the documents that appeared in Mr. Glanz’s email inbox, in what his collaborator Agustin Armendariz calls three big dumps. This is anyone’s guess. The Times story mentions Clare Francis, the pseudonym for an agent for the blog Retraction Watch, whose brash nauseating style is reminiscent of Ivan Oransky’s writing…

In any case, that would be discovered in Court if and when Dr. Carlo M. Croce decides to take legal action.

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Blog, Character Assassination, Clare Francis, Defamation, Defamation lawsuit, Expression of concern, Hilda Bastian, lawsuit, Mass hysteria, McCarthyism, National Institutes of Health, NCBI, NIH, NLM, Office of Research Integrity, Paul S. Thaler, Post publication peer review, Post Publication Peer Review Scam, Reporting Retractions, Research Integrity, Research misconduct, Retraction, Retraction Watch, Scientific corruption, Scientific Misconduct, Scientific publication, Scientific Reproducibility

Handling scientific post-publication events: Legal action required

Hilda Bastian is an NIH contractor for PubMed Health and PubMed Commons at the National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine (NLM). She also seems to be a prolific science writer. Bastian recently informed the blog Retraction Watch that the NLM is planning a prominent display of Expressions of Concern (EoC) published by scientific journals. By her own admission, Hilda Bastian is not versed in scientific matters. Given what she intends to do, let us hope she is versed in legal matters, or at least willing to seek legal advice.

In the US, as in most societies under the rule of law, a person is deemed innocent unless proven guilty, and any suggestion that may affect someone’s reputation without hard proof constitutes defamation. By Bastian’s own admission, only about 25% of EoCs typically result in retraction. This begs the question: What do the authors whose papers received the remaining 75% of EoCs plan to do?

Lawyer Paul S. Thaler, a towering figure in scientific integrity may be the ideal person to assist such people determine their legal options. Paul S. Thaler made the following enlightening remark:

The first thing to remember is that the federal regulations, as well as the internal policies of most institutions, protect the confidentiality of respondents in research misconduct matters.  Thus, as a matter of federal law, institutions are prohibited from disclosing the identity of an accused scientist, except on a “need to know” basis, for example, to a member of the investigation committee, unless and until a finding of research misconduct is made.  These proceedings are not public as court is in criminal and civil disputes.  It is more comparable to proceedings against other professionals, such as lawyers, who are governed by their licensing organization.  Privacy in these matters is critically important as there is no public need to, or right to know, about professionals simply accused of wrongdoing.  What the public has a right to know about is a professional who has been found responsible for wrongdoing.  At that point, the public is alerted.  But because a professional’s reputation is so important to his or her career, the specter of an accusation can permanently stain that reputation and frequently the accusation is not well founded.  So the confidentiality of the process allows a full examination before the public is made aware.  We certainly do want to know about those scientists who have actually done something wrong that impacts science, but we do not, and should not, be concerned with those who are good scientists but caught up in a sometimes very political, internal dispute.

The bold section is crucial because it implies that EoCs are in all likelihood illegal, and so is the dissemination of such statements. The public does not have the right to know about mere accusations of wrongdoing, or suspicions of invalid data resulting in EoCs. According to Hilda Bastian such EoCs are likely to be wrong in 75% of the cases. For example, pseudonymous Clare Francis, the venal whistle-blower of Retraction Watch, has scored plenty of false positives eliciting EoCs mostly in the 75% of valid papers. Yet we are not aware that Retraction Watch or other related venues have been sued yet. Hopefully, Hilda Bastian will reflect about her plans and seek legal advice before charging ahead.

 

 

 

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Ariel Fernandez, Ariel Fernandez books, Ariel Fernandez Research, Ariel Fernandez Stigliano, Biochemistry, Biotechnology, Cancer Research, Dehydron, Drug design, Hasselmann Professor at Rice University, Journal of Clinical Investigation, National Institutes of Health, Physics at the Biomolecular Interface, Rice University, WaterMap

Ariel Fernandez’s Alternative “WaterMaps” of 2007 Look Much Like Precursors to WaterMap

Ariel Fernandez   Drug designers often implement molecular therapies to block malfunctioning proteins that are causing disease. They do so by creating small molecules that bind to the intended protein target when suitably delivered. The procedure has its risks as unintended targets (off-target proteins) may also be hit or impaired, especially when they are structurally similar (homologous) to the intended target. To achieve specificity and improve affinity for the intended target, practitioners in drug design often use WaterMap®, a product of the NY-based company Schrodinger. WaterMap is regarded by some as a gold standard in the field.

   What does WaterMap do? It identifies water molecules surrounding the protein target that may be easily removable as the purported drug binds to the target. Thus, a WaterMap of the target-water interface may provide the designer with valuable information to optimize a given drug lead. Since WaterMaps of homologous proteins are somewhat different, they may be used to tell apart homologs through selective molecular recognition. This much almost everyone knows…

   So, who pioneered these “WaterMaps”? One would assume Schrodinger scientists did, who else? Well, maybe they were not the first to get there. A similar method was published earlier and the Schrodinger folks may have not been aware of it. The facts as now described by Ariel Fernandez and Ridgway Scott in Trends in Biotechnology (2017) are that in May and December of 2007, Ariel Fernandez and coworkers published two papers on the local lability of interfacial water and contrasted the “dewetting propensity” patterns across protein targets to design anticancer drugs with controlled drug specificity. These papers are: Fernandez et al. Cancer Research, 2007, Priority Report, and Fernández, A., et al. (2007) Journal of Clinical Investigation 117:4044-4054. The former contains what Ariel Fernandez has named “local dewetting propensities” that surely look like precursors to WaterMap and were featured in the cover of Cancer Research for the May 1, 2007 issue. In December of 2007, in Figs 1-3 in Fernández, A. et al. (2007) Journal of Clinical Investigation 117:4044-4054, you may find the first “WaterMap” analysis of two proteins that needed to be differentiated through molecular recognition.

First "WaterMap" by Ariel Fernandez, probably a precursor to WaterMap.

First “WaterMap” by Ariel Fernandez, probably a precursor to WaterMap.

CANCER RESEARCH MAY 1, 2007 COVER LEGEND: Extensive exposure to molecular targeted therapy elicits mechanisms of drug resistance, typically promoting mutations in the protein target that lower the affinity for the drug inhibitor. Thus, protein kinases, the central targets for drug-based cancer treatment, avoid functional impairment by developing adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. Fernández et al. approach this problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target, quantified by the bar plot in the figure. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit, as shown in the bottom molecular displays. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening,cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance. Inspired by these findings, Fernández et al. envision a strategy for drug redesign that “corners” mutation-induced adaptation, so that the only recourse to avoid drug-promoted inhibition becomes a mutation that renders the target protein functionally inactive. For details, see the article by Fernández et al.on page 4028 in this issue.

   Evidently, the method introduced by Ariel Fernandez and highlighted in the figure caption above is a precursor, possibly equivalent, to WaterMap.  And here is a “WaterMap” by Ariel Fernandez, dating back to 2007, used exactly as WaterMap is used:

WaterMap by Ariel Fernandez (J. Clin. Invest., 2007)

“WaterMap” by Ariel Fernandez dating back to 2007 (The Journal of Clinical Investigation 117, 4044-4054, 2007, reproduced with permission).

Furthermore, it is likely that a 3-body energy contribution described in Ariel Fernandez’s books has been omitted in the standard WaterMap analysis of “counterintuitive” desolvation sites. Usual computations of the reversible work to transfer interfacial water to the bulk do not take into account that, as water is displaced by a nonpolar group upon ligand binding, nearby preformed intramolecular hydrogen bonds that were previously exposed to solvent (dehydrons) become strengthened and more stable. Thus, the nonpolar group may be designed to displace water originally hydrating a polar group only if the latter is hydrogen bonded to another polar forming a dehydron. “Wrapping preformed hydrogen bonds” in this way stabilizes the drug-target complex, thereby enhancing affinity. This is a three-body effect (nonpolar with polar pair) that Ariel Fernandez named “wrapping interaction”.

 

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美国国立卫生研究院, Howard Hughes Medical Institute, John Ioannidis, National Institutes of Health, NIH, NIH funding, Peer Review, Principal Investigator, Research grant, Study Section

Peer Review: Is NIH Rewarding Talent?

In a striking analysis published in Nature, Stanford University researcher John Ioannidis, the expert on metadata investigation at the Stanford Prevention Research Center, has seriously questioned the way the National Institutes of Health fund research proposals. He and his colleague Joshua Nicholson have argued in what seems like a rousing condemnation of the status quo that peer-review, the process by which study sections review and rank research applications, is totally broken.  The researchers argued that peer review at NIH (简称) encourages “conformity, if not mediocrity”, favoring proposals submitted by people who know how to network and play the petty games of academic sociology, rather than those by people who have original and potentially influential ideas.

These conclusions rest heavily on the observation that only 40 percent of scientists with highly cited papers (say, those with more than 1000 citations) are principal investigators on NIH grants. That is, those scientists whose peers value their work most highly are often not receiving NIH support for that work.

Of course, the analysis may be imperfect. Here is my critique for one: Using high citation level as a proxy for originality is probably not entirely correct (but then what is a good proxy for originality?). It is also possible that a good percentage of these investigators have not even applied for NIH funding in the first place. And, finally, they may have other sources of support for their research, most likely, the Howard Hughes Medical Institute (should we then conclude that HHMI funds more original research than NIH?).

It is perhaps true that the peer review system is broken. The majority of the authors of the most influential papers in medicine and the life sciences seem not to have NIH funding according to Ioannidis and Nicholson, and their funding rate is possibly less than average. Perhaps the most disturbing observation, the one that truly needs the closest scrutiny, is that study section members are almost always funded while their citation impact is typically low or average: they are not the high-impact innovators.

This leaves us with a sad reflection. Probably a truly innovative idea cannot be appreciated by the peers, while if peers can readily grasp it (to the level they are willing to fund it), it is probably not innovative.

NIH is seemingly aware of this problem and has earnestly tried to address these concerns introducing specific award categories such as the Pioneer and New Innovator Awards. Perhaps Ioannidis and Nicholson may be willing to evaluate the efficacy of these categories in capturing true talent.

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