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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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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