Cancer Cure Within Reach: Our Gratitude to Ariel Fernandez and Especially to Bert Vogelstein

 

Bert Vogelstein and Ariel Fernandez (aged 69 and 60, respectively).

The immune checkpoint blocker pembrolizumab (Keytruda, Merck) has proven most successful to treat solid tumors harboring a DNA mismatch repair (MMR) deficiency.  This striking result recently reported by Luis Diaz Jr., Bert Vogelstein and their collaborators was anticipated a couple of years before by Dr. Vogelstein, a towering figure in oncological research. Ariel Fernandez has now shown that it is possible to generate a drug-promoted phenotype mimicking the MMR deficiency in solid tumors and thereby engineer a generic hypersusceptibility to Keytruda. This sensitivity is achieved through drug-induced metabolic stress on DNA synthesis.

The striking results by Diaz, Vogelstein and coworkers prompted Ariel Fernandez to address the following question: Is it possible to induce the MMR deficiency in any solid tumor, for example through targeted drug-based therapy, and thereby enhance the cancer antigenic activity and diversity to turn the Keytruda-drug combination into a universal cure for cancer?

Ariel Fernandez, Trends in Cancer, 2017

As work at Ariel Fernandez Consultancy reveals, the answer to this question is a resounding yes. The key to the problem resides in identifying a signaling pathway that gets recruited to promote MMR and then identifying a kinase inhibitor that would block that pathway.  The MMR deficiency-inducing kinase inhibitor has been found at Ariel Fernandez Consultancy. The potential of such drug-Keytruda combinations as universal treatments for solid tumors deserves clinical evaluation. Collaborative work is underway at Ariel Fernandez Consultancy to validate this paradigm. This may well be a decisive step in cancer cure.

Related Reading

Ariel Fernandez: “Engineering Tumor Hypersusceptibility to Checkpoint Immunotherapy”, Trends in Cancer (2017) Published online September 4.

 

Advertisements

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…

Dr. Ariel Fernandez

   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.

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 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”.

 

Book Review: “Physics at the Biomolecular Interface” by Ariel Fernandez

“Physics at the Biomolecular Interface” is the latest book by Ariel Fernandez (阿列尔·费尔南德斯), the physical chemist and mathematician who developed the center manifold thermodynamics, unraveling the physical basis for the onset of life, and discovered the dehydron (脱水元), an idea that laid the foundation for the new field of epistructural biology. The hardcover is expected by June 8, 2016. The bibliographic information is as follows:

Title: Physics at the Biomolecular Interface

Subtitle: Fundamentals for Molecular Targeted Therapy

Series: Soft and Biological Matter

Author: Ariel Fernández

Publisher: Springer International Publishing, Switzerland

Hardcover ISBN: 978-3-319-30851-7

eBook ISBN: 978-3-319-30852-4

Number of pages: 483

Ariel Fernandez Book Cover

Physics at the Biomolecular Interface, the third book by Ariel Fernandez, is no bedtime reading. Conceptually intricate and highly interdisciplinary but cast in Fernandez’s beautiful supple prose, this monumental work is, without a doubt Fernandez’s opus magnum. It  provides the fundamental scientific framework and discourse to handle biological matter physics, exploring the evolutionary axis of biology from the physicist perspective. In the author’s own words:

…the biological functionality of a soluble protein can only be fully grasped when its aqueous interface becomes an integral part of the structural analysis. Furthermore, the acknowledgment of how exquisitely the structure and dynamics of proteins and their
aqueous environment are related attests to the overdue recognition that biomolecular phenomena cannot be grasped without dealing with interfacial behavior at multiple scales. This is essentially the dictum that guided the writing of this book.

Ariel Fernandez deals with biological interfacial phenomena in his own unique and transformative way. He introduces what he calls “epistructural tension“, a concept that relates to the reversible work needed to span the aqueous interface that envelops the structure of a soluble protein.  Epistructural tension is, he argues, key to biology when examined at the molecular scale since it steers molecular associations, drives protein folding and functionalizes water at the interface, prompting a substantial revision of biochemical mechanism. The impact of this concept reaches distant fields like enzymology, structural biology and pharmacological design, and the book exploits it within an incredibly broad spectrum of possibilities, spanning vast conceptual territory, from statistical physics to molecular-targeted therapy. For example, Chap. 1 introduces a statistical thermodynamics framework to handle the aqueous interface of a protein, while Chap. 17 describes the epistructure-based design of kinase inhibitors with controlled multi-target activity to treat cancer metastasis and overcome drug resistance. In spite of this astonishing latitude of interdisciplinary research, the conceptual progression remains smooth throughout the presentation, as the reader is guided by Fernandez’s characteristically supple prose.

Dr. Ariel Fernandez, 2016

Some highlights of the book certainly worth mentioning are:

• Provides a solution to the protein folding problem from first principles of physics (Chapter 3).
• Provides and validates a nanoscale theory of nanoscale water dielectrics (Chapters 1-5).
• Provides the first biologic drug to disrupt a protein-protein interface for therapeutic purposes, i. e. to cure heart failure (US patent 9,051,387, Chapter 16).
• Provides an epistructural filter to control drug specificity guiding the design of safer and more powerful drugs (Chapters 8-17).
• Emphasizes the role of Fernandez’s dehydrons as structural markers of molecular evolution (Chapter 6).
• Prompts the rewriting of several mechanistic chapters in Biological Chemistry as the catalytic role of protein packing defects is unraveled (Chapter 7).

The book can serve as a textbook, as originally intended, and also as an advanced monograph for practitioners in drug design or molecular-targeted therapy interested in the translational aspects of their art.

The book builds on original and highly meritorious research previously reported in professional journals by the author. Here are some quotes on different aspects covered in the new book:

On the discovery of the dehydron: “This is a very radical way of thinking. This is an experiment that actually backs up that radical way of thinking and that’s what’s striking about it.” Peter Rossky, interviewed by the University of Chicago News Office

On the pharmacological designs guided by epistructural patterns: “With tools such as those of Ariel Fernandez, the future certainly looks bright for constructing ever-better agents that can be combined safely and effectively to manage and eventually cure many forms of human cancer.” George Demetri, Review on the work of Ariel Fernandez commissioned by the Journal of Clinical Investigation

On the medical implications of the work of Ariel Fernandez: “The biggest message from this paper by Ariel Fernandez et al. is that a cardiotoxic cause can be identified and steered away from. There are hundreds of agents in development that could benefit from this research.” Thomas Force, interviewed by the Royal Society of Chemistry

On the Ariel Fernandez’s dehydrons as structural markers for molecular evolution: “One aspect of Fernandez’s research that is potentially groundbreaking is the observed tendency of proteins to evolve a more open structure in complex organisms. …This observation fits with the general theory that large organisms with relatively small population sizes — compared to microbes — are subject to the vagaries of random genetic drift and hence the accumulation of very mildly deleterious mutations… In principle the accumulation of such mutations may encourage a slight breakdown in protein stability. This, in turn, opens the door to interactions with other proteins that can return a measure of that lost stability. These are the potential roots for the emergence of novel protein-protein interactions, which are the hallmark of evolution in complex, multicellular species… In other words, the origins of some key aspects of the evolution of complexity may have their origins in completely nonadaptive processes.” Michael Lynch interviewed by Rice University News Office on the work of Ariel Fernandez.

On Biomolecular Interfaces, the previous title by Ariel Fernandez introducing epistructural tension for the first time: “In this book author Ariel Fernandez introduces conceptual advances in molecular biophysics and translates them into novel pharmacological technologies. In so doing, he creates a new discipline named “epistructural biology”, focusing on the reciprocal interactions between interfacial water and protein structure. The epistructural biology approach enables researchers to address core problems in molecular biophysics such as the protein folding problem. The book surveys powerful theoretical /computational resources in epistructural biology to tackle fundamental problems, such as the physico-chemical basis of enzyme catalysis and the therapeutic disruption of protein-protein associations. The latter is recognized by many as the biggest challenge in structure-based drug discovery. A multi-disciplinary approach is exploited to engineer drugs, enabling decisive advances in molecular medicine with a tight control of drug selectivity. This book may well be Ariel Fernandez’s greatest contribution and its conceptual insights will enlighten and inspire readers. The author is also a masterful expositor which makes the book a pleasure to read.” Valentin Andreev.

Another comment on the previous title by Ariel Fernandez: “First and foremost, this book addresses an issue that is very important in protein research, namely, the interactions between a protein molecule and its surrounding water environment. This very complicated relationship is often simplified or ignored in molecular modeling. Such an ill-considered strategy simplifies the model but leads to unrealistic predictions of molecular behaviour. By contrast, this book introduces the reader to Epistructural Biology, a model that covers various important aspects of the protein-water interaction. The model is explained with an articulate clear writing style and backed up with enough mathematics to put the ideas on a firm theoretical foundation. The book is suitable for advanced undergraduate and graduate students. To help the student assimilate the ideas, the chapters include several problems with solutions. This is an excellent introduction for students wanting to get a start in Epistructural Biology.” Forbes Burkowski.

“Biomolecular Interfaces may well be Ariel Fernandez’ most authoritative work. In Chapter 3 we find a semiempirical solution to the protein folding problem, in chapter 5 we find a way to disrupt protein-protein interactions for therapeutic purposes (a major challenge in the pharmaceutical industry), in chapter 7 we find Ariel Fernandez’ striking new finding: the catalytic role of packing defects in proteins, ushering a new biotechnology. The applications to drug design in the remaining chapters bring us many surprises, including a quantum mechanics development of the wrapping drug-target interactions pioneered by the author. Ariel Fernandez’ Biomolecular Interfaces is enjoyable and rewarding. Its conceptual richness, style, and breadth of interwoven disciplines, from Statistical Thermodynamics to Molecular Medicine, make it a valuable asset.” Xi Zhang.

To conclude, here is a biosketch of the author as provided by Springer:

Ariel Fernandez (born Ariel Fernandez Stigliano) is an Argentine-American physical chemist and mathematician. He obtained his Ph.D. degree in chemical physics from Yale University in record time. He held the Karl F. Hasselmann endowed chair professorship in engineering at Rice University and was a professor of bioengineering until his retirement in 2012. To date, he has published over 350 scientific papers in professional journals including Physical Review Letters, PNAS, Nature, Genome Research, and Genome Biology. Ariel Fernandez has also published two books Transformative Concepts for Drug Design (2010) and Biomolecular Interfaces (2015), both with Springer, and holds two patents (US 8,466,154 and 9,051,387) on biotechnological innovations. He is currently involved in research and entrepreneurial activities at various consultancy firms.

RELATED READING

ORCID Record for Ariel Fernandez

Selected publications of Ariel Fernandez

• Ariel Fernández, Tobin R. Sosnick and Andrés Colubri: “Dynamics of hydrogen-bond desolvation in folding proteins”, Journal of Molecular Biology 321, 659-675 (2002).
• Ariel Fernández and Harold A. Scheraga: “Insufficiently dehydrated hydrogen bonds as determinants for protein interactions”, Proceedings of the National Academy of Sciences, USA 100, 113-118 (2003).
• Ariel Fernández and R. Stephen Berry: “Proteins with hydrogen-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis”, Proceedings of the National Academy of Sciences, USA 100, 2391-2396 (2003).
• Ariel Fernández and Ridgway Scott: “Adherence of packing defects in soluble proteins”, Physical Review Letters 91, 018102, 4 pages (2003).
• Ariel Fernández, Kristina Rogale, L. Ridgway Scott and Harold A. Scheraga: “Inhibitor design by wrapping packing defects in HIV-1 proteins”. Proceedings of the National Academy of Sciences, USA 101, 11640-11645 (2004).
• Ariel Fernández and R. Stephen Berry: “Molecular dimension explored in evolution to promote proteomic complexity”. Proceedings of the National Academy of Sciences, USA 101, 13460-13465 (2004).
• Ariel Fernández: “Keeping Dry and Crossing Membranes”. Nature Biotechnology 22, 1081-1084 (2004).
• Ariel Fernández, et al.: “An anticancer C-kit kinase inhibitor is re-engineered to make it more active and less cardiotoxic”. Journal of Clinical Investigation 117, 4044-4054 (2007).
• Jianping Chen, Han Liang and Ariel Fernández: “Protein structure protection commits gene expression patterns”. Genome Biology 9, R107 (2008).
• Ariel Fernández and Jianping Chen: “Human capacitance to dosage imbalance: Coping with inefficient selection”. Genome Research 19, 2185-2192 (2009).
• Ariel Fernández and Michael Lynch: “Nonadaptive origins of interactome complexity”. Nature 474, 502-505 (2011).
• Ariel Fernández: “Epistructural tension promotes protein associations”. Physical Review Letters 108, 188102 (2012).

Converging Technologies at ProWDSciences: Protein-Water-Dehydron-Bingo!

Translational research involving converging technologies is clearly the way of the future for drug discovery and the pharmaceutical industry. At least, this is what we are being told by leading scientist Sangtae Kim in a recent NSF lecture on Converging Technologies. The great Sangtae Kim himself appears to have followed this mantra when he founded the biotech company ProWDSciences, where “ProWD” stands for Protein-Water-Dehydron. As the name informs us, ProWD Sciences is all about converging technologies. The idea is enshrined in the unfamiliar word dehydron (脱水元). Dehydron is the central concept of epistructural biology, a new scientific field developed by Ariel Fernandez to deal with the complex physics of the protein-water interface. To properly define dehydrons, a multiscale theory of biological water may be required, as Kim would say. Yet, as described in the book Biomolecular Interfaces, we may say that dehydrons refer to structural deficiencies in proteins that promote interfacial tension, are endowed with catalytic properties and serve as selectivity filters for drug design.  As the research of Ariel Fernandez suggests, the dehydron may well be the point of convergence of nanotechnology, biotechnology, molecular engineering and learning technologies, the sort of convergence that Kim described in his NSF lecture. Time will tell us how this technological convergence will enable the rational design of safer anticancer drugs with optimal selectivity control.

Ariel Fernandez (left) and Sangtae Kim toying with a dehydron-based molecular design at the Morgridge Institute for Research (University of Wisconsin-Madison)

On “Promoting an Open Research Culture”, Policy Forum, Science Magazine

On 26 June 2015, Science magazine published an article in its section “Policy Forum” entitled “Promoting an Open Research Culture”  (B. A. Nosek et al. Science, Vol. 348, pp. 1422-1425, DOI: 10.1126/science.aab2374). The article and two related pieces (“Self-correction in science at work”, and “Solving reproducibility“) published in the same issue seem to have been inspired by the perception that there is an irreproducibility crisis affecting science. In this regard, this is what Science Transparency has to say:

There is a perceived or real crisis over the reproducibility and transparency of scientific reporting. This crisis is surely being mismanaged by scientists, and they have only themselves to blame. Scientific pursuit requires a highly specialized training, and consequently, so does the assessment of the validity of reported science. Yet, while scientists figure out how to deal with the current crisis, they are allowing journalists like Ivan Oransky (named Science’s Garbage Man by the Swiss Radio and Television), defamation rings, and anonymous nobodies to tell them what to do. This is especially apparent in certain journals that keep listening to Clare Francis, Retraction Watchers or some of the pubpeers, who are in fact nobody’s peers. This nonsense where anyone says whatever they want and pours their anger on the internet, only fuels the current hysteria over fake science. More on this problem has been previously covered in Science Transparency.

As usual, Prof. Ariel Fernandez (阿列尔·费尔南德斯), the discoverer of the dehydron (脱水元), is on the mark in regards to this issue, and his pronouncement featured in Science is reproduced below in accord with Terms and Conditions on User Submissions to Science.

 

Dr. Ariel Fernandez . 阿列尔·费尔南德斯

Some journalists and some science outsiders have installed the belief that science is in the midst of a reproducibility crisis. These people are being listened to, at least by some editors, while they feverishly advocate for higher standards of transparency in regards to the way in which scientists conduct and report their findings. The underlying misconception that led to this delusional thinking may well end up sliding into hysteria if scientists keep taking advice from outsiders on how to conduct their business. The misconception sprouts from the odd notion that scientific publications are meant to report monolithic truths that must withstand the acid test of time. Nothing further from the truth, and while scientists comply and try to raise the bar on transparency and accountability, they better take steps to debunk the myth that research papers distill anything other than provisional assertions subject to endless revision.

Much of the science reported is a-priori likely and expected to be faulty merely on statistical grounds. John Ioannidis, a professor of medicine at Stanford University, wrote in 2005 a paper in the journal PLoS Medicine entitled “Why most published research findings are false” (http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.00…) where, using statistical arguments, he estimated that the likelihood that a scientific paper contains false results is nearly 50%. His analysis reveals that under a great diversity of conditions, most scientific findings are likely to simply represent “measures of prevailing biases”. This statistical study was conducted with the utmost rigor and prompts us scientists to regard research reports with lower expectations, more in the context of a progression of provisional attempts at attaining an independent pristine truth. And please, please, let us focus on running our business ourselves, or we will have no one else to blame for the current crisis, be it real or delusional.

Dr. Ariel Fernandez Stigliano is the former Karl F. Hasselmann Professor of Bioengineering at Rice University (Follow Ariel Fernandez on Twitter).

阿列尔·费尔南德斯（Ariel Fernandez，出生名 阿列尔·费尔南德斯·斯提格里亚诺, 出生于1957年4月18日）是一位阿根廷–美国双重国籍的物理化学家^[1]，1984年在耶鲁大学获化学物理专业博士学位，曾在马克思-普朗克研究所在诺奖得主Manfred Eigen和Robert Huber的指导下从事博士后研究，后在美国莱斯大学任Karl F. Hasselmann讲座讲授，期间曾指导来自两名中国的留学生张曦和陈建平的博士学位论文，2011年从莱斯大学退休后开始在瑞士的巴塞尔学院继续从事研究工作，同时创建咨询公司Ariel Fernandez Consultancy和AF Innovation为企业提供咨询服务。

职业生涯

阿列尔•费尔南德斯多个领域的顶级学术期刊上发表文章，包括：代数、动力系统理论、统计力学、化学物理、界面现象、药物设计、癌症治疗和结构生物学视角下的分子进化。他的部分发表成果被收录在Google Scholar Citations和ResearchGate。他曾在国际重要期刊上发表过350篇学术论文，包括：Proceedings of the US National Academy of Sciences, Annual Reviews of Genetics, Nature, Physical Review Letters, Genome Research，其科研成果曾被 Nature, Nature Reviews Drug Design, Chemistry World (UK Royal Society), Scientific American等著名期刊评述。阿列尔•费尔南德斯著有一部学术著作，持有两个药物治疗方面的专利。

阿列尔•费尔南德斯在药物设计领域的一部分最重要的研究成果属于转化医学。他建立了被称之为dehydron的物理化学模型用于描述蛋白质分子的一种结构奇点，并将此模型用于进行药物特异性筛选从而设计更为安全的药物。基于dehydron理论，阿列尔•费尔南德斯发明了分子工程中的“包裹技术”（wrapping technology）。“包裹技术”让药物设计人员能够根据蛋白质靶点的dehydron分布特点来设计药物，从而达到更好的特异性。“包裹技术”及其应用在阿列尔•费尔南德斯的著作“Transformative Concepts for Drug Design: Target Wrapping”(Springer-Verlag, Berlin, 2010)中有详细描述。

著作

• “Transformative Concepts for Drug Design: Target Wrapping”, by Ariel Fernandez (ISBN 978-3642117916, Springer-Verlag, Berlin, Heidelberg, 2010).^[2]

• “Biomolecular Interfaces: Interactions, Functions and Drug Design”, by Ariel Fernandez (ISBN-10: 3319168495, ISBN-13: 978-3319168494, Springer; 2015 edition)..^[3]

外部链接

• Ariel Fernandez Innovation
• www.profarielfernandez.com

1. ^ CV for Ariel Fernandez
2. ^ Ariel Fernandez Bibliography. [25 February 2014].
3. ^ Amazon link.
4. ^ 美国专利与商标局：Patent US 9,051,387.

 

___________________________

阿列尔·费尔南德斯 – Ariel Fernandez biosketch at Baidu Baike

Richard Moss and Ariel Fernandez Patent Treatment for Heart Failure

IN COMPROMISED HEARTS, muscle contractions are weakened as the protein motor myosin binds too tightly to its regulator MyBP-C. Richard L. Moss , the Senior Associate Dean for Basic Research, Biotechnology and Graduate Studies at the University of Wisconsin School of Medicine, in collaboration with Ariel Fernandez Stigliano, the discoverer of the dehydron (脱水元), invented a drug that disrupts this protein association, releasing the “molecular brakes” that cause heart failure. This invention constitutes the first molecularly targeted treatment of heart failure based on rational design. The molecular physiology that led to the discovery was elucidated by Richard L. Moss, while the underlying science behind the novel molecular design is described in Ariel Fernandez’s book “Biomolecular Interfaces: Interactions, Functions and Drug Design“, with a foreword by the co-inventor in the patent. The activities of Prof. Ariel Fernandez at the University of Wisconsin-Madison (Morgridge Institute for Resarch) enabled this collaboration that ultimately led to the invention. The patent assignee is the Wisconsin Alumni Research Foundation (WARF P120252US02).

Dr. Ariel Fernandez

You may read the press release for Richard Moss and Ariel Fernandez’ patent US9051387 featured in Yahoo, MarketWatch. in the original form submitted by Ariel Fernandez Consultancy to PR NewsWire, or prior to distribution in WebWire. There is also a video by Ariel Fernandez covering the science behind the invention.

US Patent 9,051,387
Inventors: Richard L. Moss and Ariel Fernandez, Awarded June 9, 2015

Ariel Fernandez Consultancy serves the biotechnology industry by harnessing fundamental discoveries to broaden its technological base. In line with this goal, Richard L. Moss in collaboration with Ariel Fernandez invented a new drug for the molecular targeted treatment of heart failure. The invention named “Inhibition of MYBP-C binding to myosin as a Treatment for Heart Failure” was awarded the US patent 9,051,387 on June 9, 2015.

The recently awarded US patent number 9051387 describes the first therapeutic disruption of a protein-protein association using a rationally designed man-made ligand, a challenge considered to be the holy grail in drug discovery (see Nature review by James Wells et al.). At the molecular level, the effect of the drug is the disruption of the association between the molecular motor myosin and its modulator MYBP-C by a competitive man-made ligand that binds to MYBP-C. The target was identified by Richard L. Moss, who also conducted the experimental tests, while the drug itself was created by Ariel Fernandez based on his translational ideas on rational design.

The basic scheme descriptive of the molecular action of the invention is shown in the following figure:

Dr. Ariel Fernandez

The main difficulty in designing the myosin-MYBP-C disruptor is that the 3D-structure of the target MYBP-C is not known. Thus the binding site had to be inferred by detecting regions of the protein in the twilight between order and disorder, using exactly the same methodology developed by Ariel Fernandez in Nature 474, 502-505 (2011).

This invention is featured at: US Patent and Trademark Office page, Espacenet page, Description by the University of Wisconsin-Madison, Ariel Fernandez Consultancy, Academia.edu, Ariel Fernandez’s professional page. This patent marks the dawn of the new paradigm for drug discovery based on epistructural biology, the new discipline introduced by Ariel Fernandez in the latest book Biomolecular Interfaces (Springer, Berlin, 2015).

RELATED READING

Prof. Richard L. Moss webpage at the University of Wisconsin-Madison

CV for Prof. Ariel Fernandez (updated May 18, 2015)

Follow Ariel Fernandez on Twitter

Retraction Watch, Clare Francis, the Mockery of the First Amendment and a Recent Court Order

The blog Retraction Watch plays a game both dangerous and revolting. By making a travesty of the First Amendment to the US Constitution, Retraction Watch has allegedly managed to generate and propagate slander while protecting the anonymity of their tipsters. A recent Court order indicates that this allegedly venal practice will eventually come to an end, possibly making Retraction Watch the target of massive lawsuits.

On the surface, Retraction Watch appears to be a broadcaster of post publication “peer reviews” (whose peers?) that prompt a reaction in scientific journals, motivating the publication of a note, expression of concern or even a retraction notice in case of invalid data. In reality, Retraction Watch is served by what allegedly constitutes a serial defamation ring. The ring often (not always) feeds on comments from angry people with no verifiable credentials, who are typically not the peers of any reputable scientist. These people hide in anonymity to launch their attacks. This modus operandi is of course the despicable way of cowards and is usually fuelled by sheer career frustration: “I am failing, so those who succeed must be phonies, etc.” The angry individuals publish their comments in tributary blogs like PubPeer or simply convey their “critiques” to Ivan Oransky or Adam Marcus, founders of Retraction Watch. These comments are then conveyed to the journals usually in coercive defamatory terms and often under the pseudonym Clare Francis. Clare Francis, or others serving directly the interests of Retraction Watch, allegedly threaten and intimidate the journals and institutions and use words highly reminiscent of Oransky’s style, such as: “many think of this as scientific misconduct”. This wording is naively intended to avoid the defamation lawsuit (not for long). Once Clare Francis or others allegedly on behalf of Oransky manage to elicit a reaction from the journal or institution allegedly under duress, Retraction Watch immediately jumps in and broadcasts the published note, expression of concern or retraction usually in defamatory terms. This leaves us wondering why Retraction Watch founder Ivan Oransky has been named Science’s Garbage Man by the Swiss Radio and Television (Muellsammler der Wissenschaft).

Ivan Oransky portrayed at Yale Medicine.

As they allegedly intimidate journals and institutions, Clare Francis or Oransky, or a person on his behalf, brings up PubPeer “investigations”, as if PubPeer were reporting investigations carried out by scientific peers. This in itself constitutes a gross distortion of reality. Thus, the Oransky clique allegedly intimidates the journals within a defamatory context that includes wording like “many people believe this constitutes misconduct”. Not surprisingly, many of these accusations prove to be incorrect, as PubPeer contributors are usually not scientific peers. Yet, a damage is done to the scientist reputation as Retraction Watch hastily publishes the journal reaction it has allegedly elicited through intimidation and coercion.

Most of the time (not always), the Retraction Watch tipsters only have a vested interest in harming the person they target. A case in point is Joshua L. Cherry, a presumed NIH software contractor embarked in a crusade against a specific researcher. The dishonesty of these tipsters is evidenced by the fact that they operate hiding in anonymity as they seek to destroy careers by feeding into Oransky’s blog. Joshua Cherry and others go even further: They seek institutional involvement and immediately inform Retraction Watch on any reaction. Oransky or his cohort of angry people (including the tipsters) then allegedly coerce the journals and institutions seeking to elicit a quick reaction which Oransky (Clare Francis, etc.) demands must be published. Once this is done, the note (expression of concern, correction request, etc.) is immediately disseminated to the general public by the blog Retraction Watch sometimes within a libelous context. This is done even before the results of a formal investigation are known or the validity of the accusations is scientifically established. The alleged slandering is serially committed by Retraction Watch and its associated ring and pipelined along the PubPeer – Oransky axis.

Recent developments, specifically, a court order, suggest that this alleged venality may soon come to an end, with dire consequences for Retraction Watch and its cohort. Prof. Fazlul Sarkar is a professor at Wayne State University who may have lost a generous job offer because of scathing comments about his research posted on PubPeer and channeled into the Retraction Watch defamatory apparatus. His attorney has asked a judge to reconsider last month’s decision not to release information about the site’s anonymous commenters. The brief introducing that motion identifies the PubPeer commenter with the pseudonym Clare Francis.

On March 19, a Michigan court ruled that PubPeer had to disclose identifying information about the PubPeer commenter, identified as the author of the second of the comments below:

Unregistered Submission:
(June 18th, 2014 4:51pm UTC)
Has anybody reported this to the institute?

Unregistered Submission:
(June 18th, 2014 5:43pm UTC)
Yes, in September and October 2013 the president of Wayne State University was informed several times. The Secretary to the Board of Governors wrote back on the 11th of November 2013:  “Thank you for your e-mail, which I have forwarded to the appropriate individual within Wayne State University. As you are aware, scientific misconduct investigations are by their nature confidential, and Wayne would not be able to comment on whether an inquiry into your allegations is under way, or if so, what its status might be. Thank you for bringing this matter to our attention”

In a supplemental brief filed on April 9, Sarkar’s attorney Nicholas Roumel informs the court that Wayne State provided the email exchanges quoted in the comment, and that they were between “Clare Francis” and Julie H. Miller, secretary to Wayne State’s Board of Governors. Thus, the court learned that on November 10, 2013 Clare Francis wrote:

“I am writing to you about multiple scientific concerns about the published work of Fazlul H Sarkar which have been aired on Pubpeer.”

“You can find the entries on Pubpeer here: …”

“Many of the entries mention things which amount to what many think of as scientific misconduct….”

Following the supplemental brief and after spotting the libel, the court ruled that PubPeer must provide the IP for Clare Francis to Roumel.

The blog Retraction Watch offered PubPeer’s attorneys the opportunity to comment, and they had this to say:

“We are deeply troubled that a scientist who exercised his or her right to anonymously report anomalies in scientific research is being threatened with possible liability. The First Amendment protects the right to speak anonymously precisely so that, in circumstances like this one, individuals can report on matters of public interest without fear of retribution. This case is especially troubling because it threatens to weaken the foundation of scientific research, which relies on honest feedback and criticism from one’s peers.”

No kidding! This statement cannot pass even the most basic scrutiny! Let’s see:

a)      Where is the proof that Clare Francis is the pseudonym for “a scientist who exercised his or her right to anonymously report anomalies in scientific research”? Clare Francis may just be the pseudonym for an angry person who hates Fazlul Sarkar or someone with a vested interest in his downfall (like the Retraction Watchers). There is not a shred of evidence that the reported anomalies were detected by a competent scholar, that they are scientifically sound or that they were generated by anybody even coming close to be named a peer of Fazlul Sarkar.

b)      Where is the proof that Clare Francis is reporting on a matter of public interest? It could just be that Clare Francis is simply the pseudonym of someone who hates Sarkar, envies his success, or has a vested interest in his downfall (to increase the readership of his blog), and this is surely a personal matter, not a matter of public interest.

c)       How do we know the slanderer of Prof. Sarkar is being honest? He is most likely dishonest. In fact, everything suggests the latter to be the case: honest people who do the right thing do not usually hide, they don’t need to, at least in countries under the rule of law like the US.

d)      How do the PubPeer attorneys know that Sarkar’s attacker is one of Sarkar’s peers? In fact, how do they know anybody at PubPeer is actually a peer of the scientists they are attacking? Clare Francis is not revealing his scientific credentials! Strikingly some journals took him seriously and a few still do.

e)      Given that the person using Clare Francis pseudonym is most likely dishonest, and not a scientific peer of Dr. Sarkar, we obviously cannot assert that the case weakens the foundation of scientific research in any way.

We remain hopeful that the alleged serial defamation ring and venal operation described in this post will soon be brought to justice. With the help of the journals that have been contacted by Clare Francis (or others serving the interests of Retraction Watch) we would be in an ideal position to recruit the necessary elements for formidable lawsuits that will bring to a halt this abominable practice.

RECENT COMMENT

LIPING XIE says:

First and foremost, who says PubPeer contributors are scientific peers of anyone??? Nobody has verified whether they really are!!! This is complete nonsense and the way Retraction Watch harvests and uses the PubPeer feedback is absolutely revolting!

UPDATE FROM MAY 24, 2015

It is odd that we continue to have this discussion on these nobodies taking shots at people doing research, Cardiff University in the UK already led the way and did the right thing. Its policy now in place as described here enables automatic dismissal of all the incognito attacks from PubPeer, Clare Francis, Ivan Oransky and their associated haters!