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.
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.
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.
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，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。
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。
- “Transformative Concepts for Drug Design: Target Wrapping”, by Ariel Fernandez (ISBN 978-3642117916, Springer-Verlag, Berlin, Heidelberg, 2010).
- “Biomolecular Interfaces: Interactions, Functions and Drug Design”, by Ariel Fernandez (ISBN-10: 3319168495, ISBN-13: 978-3319168494, Springer; 2015 edition)..
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).
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.
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:
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).
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).
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:
(June 18th, 2014 4:51pm UTC)
Has anybody reported this to the institute?
(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.
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!
Ariel Fernandez (阿列尔·费尔南德斯, also styled as Ariel Fernandez Stigliano, CV linked and updated 5/18/2015) is a physical chemist and mathematician and the former Karl F. Hasselmann Endowed Chair Professor of Bioengineering at Rice University. He got his Ph. D. in record time from Yale University under the guidance of Oktay Sinanoglu (who recently passed away according to Yale News). Completed in less than two and a half years, Ariel Fernandez’ doctorate is believed to be one of the fastest awarded by Yale in its 300 years history (see Ariel Fernandez’ PhD Tree). Ariel Fernandez became widely known as the discoverer of the dehydron (脱水元) at the turn of the 21st century. His recent publications, and especially his latest book “Biomolecular Interfaces: Interactions, Functions and Drug Design” (ISBN 978-3319168494, Springer, available at Amazon), place him at the center of a veritable biotechnological transformation. We may term this transformation “dehydronic chemistry” because it explores the technological implications of the newly discovered chemical/catalytic role of dehydrons. This interview seeks to assess the significance of protein dehydrons (the structural defects that Ariel Fernandez discovered at the University of Chicago) for enzymatic catalysis (MarketWatch/Dow Jones & Co.). At the time when dehydrons were discovered, Peter Rossky, then the Marvin K. Collie-Welch Regents Chair in Chemistry at the University of Texas, Austin had this to say about the discovery to the University of Chicago News Office: “It’s a very radical way of thinking”.
Protein dehydrons have an established role as promoters of protein associations because they create poor interfaces with water. Biologists have become acquainted with this role of dehydrons ever since Ariel Fernandez’ Nature paper decisively revealed the importance of dehydrons in establishing the nonadaptive origin of interactome complexity. This crucial discovery was reviewed at Nature by science writer Philip Ball.
Chinese audiences were familiar with the more “standard” role of dehydrons as promoters of protein-ligand associations ever since the memorable lecture by Ariel Fernandez at Academia Sinica in 2008 sponsored by Wen-Hsiung Li as featured in the poster below:
The dehydron concept itself dates back to collaborative work between Ariel Fernandez and Harold Scheraga, published in the Proceedings of the National Academy of Sciences USA and work with L. Ridgway Scott, published in Physical Review Letters. Ultimately these concepts were translated by Ariel Fernandez and colleagues from M. D. Anderson Cancer Center into drug-based therapeutic agents with high specificity, as outlined in the patent “Mehods and Compositions Related to the Wrapping of Dehydrons” US 8,466,154. More recently, in another translation of the dehydron concept, Ariel Fernandez and the eminent cardiologist Richard L. Moss invented a drug-based treatment for heart failure.
This US patent number 9051387 describes the first therapeutic disruption of a protein-protein association using a man-made ligand, a challenge considered the holy grail in drug discovery. You may find this invention 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.
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.
The portrayal of Ariel Fernandez as a beacon of scientific innovation is not new (check out this review) but his latest contributions add a new spin to the story. People were familiar with Ariel Fernandez’s dehydrons and their role in driving protein interactions by causing interfacial tension for nearly a decade. Their recently discovered “chemical role” puts dehydrons again at the frontline of scientific innovation, as a recent journal cover in FEBS Letters attests:
The picture on display in the cover corresponds to Fig. 3 in Ariel Fernandez (2015) Packing defects functionalize soluble proteins. FEBS Letters 589:967-973.
WM: Almost every physical chemist and even people in related and distant disciplines is familiar with your name and with the dehydron concept. Yet, your name is coming up a lot more frequently lately, as attested by anyone who attended the Biophysical Society meeting and its Chinese counterpart (see recent profile in Baidu Encyclopedia). What have you been up to that seems to be eliciting so much attention?
Source: Baidu Encyclopedia.
Ariel Fernandez: If you open any book on Biological Chemistry and examine those enzymatic reactions you will be left with a certain discomfort. You feel that something is not quite right. The reactants do not behave exactly as you were told they would. Most such reactions involve trans-esterifications that require nucleophilic attacks. These reactions are unthinkable if the chemical participants would be in the bulk. You are then told that the enzyme is “special” and that it offers a special environment conducive to the reaction. But, what exactly is this special environment? What’s so special about it? That is the question I have addressed and the answer lies in the examination of the patterns of structural defects adjacent to the catalytic site.
To put it bluntly, enzyme catalysis is often viewed as a closed chapter in biochemistry or biophysics, where all the core issues have been essentially dealt with. Yet, problems related to the catalytic involvement of nano-structural features still hamper progress in the mechanistic understanding, and design of enzyme catalysts and inhibitors. Germane to these problems is the catalytic role of interfacial water confined by the nanoscale topography of the protein surface. That is exactly where I have now made substantive progress (I hope I got the story right). If I am right, much of the mechanistic literature on biochemical reactions would need to be rewritten, as the examples in my recent publication demonstrate.
Here you will find a voice presentation promoted at Elsevier, where I strive to get the point across.
WM: Are you saying those “defects” in the protein structure do more than shaping the active site?
Ariel Fernandez: I guess it all has to do with the realization that the structural defects in proteins known as dehydrons are endowed with a chemical role and participate as reactants in enzyme catalysis. Structural defects in proteins have a chemical function and that is news, maybe big news. [see Market Watch Press Releases]
WM: How can structural defects become reactants? I am somewhat familiar with heterogeneous catalysis in inorganic chemistry, where lattice defects in the crystal become crucial, but I guess you are referring to soluble proteins, quite another matter.
Ariel Fernandez: Yes, but there is a certain analogy. Dehydrons are ubiquitous at the active or catalytic site and intervene in the related enzymatic reactions by functionalizing the nano-confined interfacial water around them, locally inducing basicity at the interface. I have already conjectured this in a recent Communication and now proved it in a Letter (see also Ariel Fernandez’s blog).
WM: Sorry, now I am really confused. Why would the dehydron-promoted basicity enhance or even enable the enzymatic reaction?
Ariel Fernandez: Because the protein aqueous interface is essentially sculpted by the protein structure. The problem may be said to belong to the field of epistructural biology as I have outlined in my recent work. In this realm, one structural feature stands out: the so-called dehydron, a nanoscale defect that creates interfacial tension and thereby promotes protein associations. Dehydrons are backbone hydrogen bonds exposed to water due to nanoscale defects in the structure packing. Besides promoting dehydration, dehydrons also have a biochemical role that is proving to be exquisitely complementary: they turn nano-confined interfacial water into a chemical base, a proton acceptor. Thus, a dehydron in the proximity of a catalytic group purported to perform a nucleophilic attack enhances the catalytic potential of the latter through a chemical functionalization of vicinal water.
These two properties, combined with the fact that catalytic sites are invariably “decorated” with dehydrons, suggest a dual participation of dehydrons in catalysis: first, dehydrons prepare the solvent for enzyme activity and, after enhancing the enzyme nucleophilicity and turning the solvent into a better leaving group, dehydrons promote enzyme-substrate association in consonance with their dehydration propensity. This functional duality makes dehydrons both enablers and stimulators of enzyme catalysis. As you can surmise, this is an observation with paramount nano-biotechnological implications, especially in regards to what we may term “epistructure-based enzyme design”.
WM: There is of course structure-based enzyme design, people like Steve Mayo come to mind. Are you now proposing then “epistructure-based design”? On exactly what grounds?
Ariel Fernandez: Well, look at it this way: As dehydrons activate nearby catalytic groups to perform a chemical (nucleophilic) attack on the substrate, causing trans-esterification, they turn the nano-confined water into hydronium (H3O+, the product of proton acceptance). In turn, since the hydronium requires full hydration, it is easily removed from the active, thereby enabling enzyme-substrate association. This kind of dehydron-driven association is known as “wrapping”, and entails a thermodynamically favorable intermolecular “correction” of the structural defect. Thus, the dehydron may be regarded as a two-stroke molecular engine that promotes and sustains enzyme catalysis.
WM: Dehydrons promote protein associations, you are now saying they also have a chemical role and that both roles are complementary and essential to catalysis? Is that it?
Ariel Fernandez: Basically, yeah. This discovery may herald novel biomolecular design based on “dehydron enablers-stimulators”. These features may be created or removed though engineered mutations directed at fine-tuning the topography of the protein surface. In this way, we envision the possibility to activate or silence a catalytic site in a protein enzyme by respectively creating or annihilating its nearby dehydrons. On the other hand, novel drug-based enzyme inhibitors will emerge as dehydron agonists are targeted (wrapped) through engineered protein-drug associations. These possibilities were anticipated in my first book “Transformative Concepts for Drug Design: Target Wrapping” [here reviewed at Rice University]. They have been much further developed in my second book “Biomolecular Interfaces: Interactions, Functions and Drug Design” (foreword by Richard Moss, individual chapters here).
My latest book is in a sense a modern development of some work that I did back in my days at Yale jointly with my advisor Oktay Sinanoglu (see Ariel Fernandez’ PhD Tree), a peerless genius who recently passed away. Oktay Sinanoglu became the youngest full professor at Yale in its modern history, I believe.
WM: I see, we could now envision novel molecular designs inspired by the “epistructural catalytic stimulation”.
Ariel Fernandez: Precisely! and this “epistructural stimulation” will foreshadow a generation of nanoscale-optimized enzyme catalysts and pharmaceuticals.
WM: The work of Ariel Fernandez does not need praise. His marvelous advances have already been heralded by others, as is evident, for example, in a recent review published in Scientific American. [reproduced in Nature]. The novel type of drug design he has introduced was enthusiastically received by eminent physician scientists such as Thomas Force (Vanderbilt University) and was also covered in very promising terms for example in a review by Harvard oncologist George Demetri. Quoting Dr. Demetri:
“The first generation of kinase-inhibitory drugs such as imatinib and sunitinib have already provided patients with life-saving therapeutic options, and with tools such as those described by Fernández et al., 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”.
These seminal advances are further enriched in his recent work with a description of novel molecular design concepts that enable us to therapeutically disrupt protein-protein interfaces. This problem is considered to be a holy grail of molecular targeted therapy. Therapeutic opportunities stem from the design concepts of Ariel Fernandez. One illustration is provided in the potential treatment of heart failure by disrupting a myosin association with a myosin-regulatory protein, an invention with a pending patent by Richard Moss and Ariel Fernandez.
The work of Ariel Fernandez introduces considerable conceptual novelty rooted in fundamental knowledge that needs to find its way into the pharmaceutical discovery and development pipeline, in particular in the hit-to-lead and lead optimization phases. Paraphrasing George Demetri we conclude that the approach by Fernández and coworkers holds great promise for customized development of rationally designed therapeutic agents.
Ariel Fernandez, Editor for Metabolomics (profile)
“Residents and interns worked a lot of hours, and I wrote honestly about what it was like to be an intern. One of the deans wasn’t crazy about that. It reminded me that my core identity is as a journalist, constantly challenging things…Blogs are powerful and lower the publishing barrier.”
This post constitutes a bit of a digression but a justified one since the research I intend to discuss served as the basis for a professional paper recently exposed by junk journalism (see our previous entry). Here I vindicate Professor Ariel Fernandez (阿列尔·费尔南德斯), the discoverer of the dehydron (脱水元) and a remarkably creative and imaginative physical chemist and mathematician -as attested by his publications– who recently had his share of spats with the blog-based junk journalism. I am specifically referring to the coverage of the so-called “post-publication peer review” of one of the doctor’s papers in Nature (see the previous post). This paper was challenged by Joshua Cherry, a person of unreported and unverified employment at NIH. Joshua Cherry corresponded extensively with Ariel Fernandez before deciding to operate hiding in anonymity once Dr. Fernandez alerted him that he needed to learn the subject before writing reviews. The blog-based type of journalism that covered the Nature story is completely unedited, not subject to scientific peer review and not subject to the most elementary standards of science. Driven by angry nobodies seeking notoriety, the Marcus-Oransky blog lies outside the scientific establishment, actually doing a disservice to science. Internet enables the exchange of information at unprecedented levels, but it also enables any person, however deranged, to pour his or her madness, and make it universally accessible without even having to disclose his or her identity. Fortunately, the majority of scientists do not take such journalism any more seriously that they would take a blog on the healing powers of the pyramids.
The source of the picture on the left is this article at Yale Medicince.
Dr. Ariel Fernandez is no stranger to Chinese audiences (Wikipedia Biosketch for Ariel Fernandez in Mandarin). I first became acquainted with him in 2008, when he delivered a lecture (poster and announcement below) at the Genomics Research Center in Academia Sinica, Republic of China. His host at the time was none other than Wen-Hsiung Li, the James Watson Professor at the University of Chicago and a towering figure in the field of molecular evolution. On that occasion, Ariel Fernandez lectured on the exploitation of evolutionary concepts to optimize drug design, an extremely original idea. The lecture introduced the key concept of dehydron, a sticky structural defect in proteins that is not conserved across homologous proteins. This lack of conservation makes dehydrons crucial selectivity filters for drug discovery, an idea later fleshed out in Ariel Fernandez’s first book “Transformative Concepts for Drug Design: Target Wrapping“. It was a mesmerizing lecture.
Our second encounter took place in Hsinchu the next year, in 2009, when Ariel Fernandez began a series of visits to the National Tsing-Hua University sponsored in part by the Ministry of Education of the Republic of China (see illustration below). These visits hosted by Mathematics professor Sze-Bi Hsu led to the maturation of a revolutionary idea: introducing insights from structural biology into evolutionary biology, turning the latter more quantitative and precise. These thoughts eventually led to the Nature paper formerly coauthored by Michael Lynch. The seminal ideas by Ariel Fernandez at the National Tsing-Hua University, together with their ramifications in the field of aberrant aggregation-related disease, were enthusiastically reviewed at that institution, as shown in their “high-scope article” here.
Ironically, it was Michael Lynch who heralded these discoveries in auspicious terms. Thus, in 2009, Lynch had this to say to Rice University News and Media:
“One aspect of Ariel 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”.
The liason of Ariel Fernandez with the Republic of China seems to be a long-lasting one. We are indeed fortunate that he has become a frequent visitor to the Mathematics Division at the National Center for Theoretical Science. His lecture last year is still announced here.
It is not uncommon to see him announced on short notice, like in the poster below for an inpromptu lecture at Chiao Tung University on recent developments of the ideas he first brought to us at Academia Sinica five years earlier.
Dr. Fernandez, come back. We miss you!
Ariel Fernandez featured in Baidu Encyclopedia.
RECENT COMMENTS (SEARCH UNDER COMMENTS)
I love your inclusion of Oransky’s quote. In plain English it reads: SCIENCE IS HARD, TRASHING IT, AS WE DO AT RETRACTION WATCH, IS SO MUCH EASIER!
DECEMBER 6, 2014 AT 11:07 PM
WEISHI MENG says:
That is the translation, yes. Sad and tragic. It takes all kinds, I guess…
DECEMBER 6, 2014 AT 11:16 PM
The towering Dr. Ariel Fernández is very good looking (was he photographed by El Greco or does he really share the build of a Mantis religiosa?), and Oransky is clearly a nasty bon viveur, jealous of the big man and who needs to start jogging if he wants to compete in the same scientific and glamorous world as our hero.
Also Oransky, learn one thing: one always has a better side for the pictures. Discover which one is yours and use it in all photos. Learn something from the aristos you good for nothing former headshrink!
DECEMBER 9, 2014 AT 1:38 PM
As a glance at his CV reveals, Dr. Ariel Fernandez (阿列尔·费尔南德斯), the discoverer of the dehydron (脱水元), is a very creative physical chemist and mathematician, a key player in the recent biotechnology transformation. His research has been heralded in auspicious terms, as illustrated for example in this review published in Scientific American. The breadth of research accomplishments of Ariel Fernandez, ranging from abstract algebra to drug design is breathtaking and probably unheard of in science (see a linked version of his publication record). In his ResearcherID page, Thomson/Reuters estimated that Ariel Fernandez has published 485 professional articles, book chapters included. His innovative drug designs were enthusiastically received by eminent doctors such as Thomas Force (Vanderbilt University) and were also reported in laudatory terms, as shown for example in this review by legendary Harvard oncologist George Demetri. Quoting Dr. Demetri:
“The first generation of kinase-inhibitory drugs such as imatinib and sunitinib have already provided patients with life-saving therapeutic options, and with tools such as those described by Fernández et al., 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”.
In a recent collaboration with eminent cardiologist Richard L. Moss, Dr. Ariel Fernandez came up with a potential treatment of heart failure by disrupting a myosin association with a myosin-regulatory protein, a novel invention recently awarded the US patent 9,051,387. You may find descriptions of this invention at: US Patent and Trademark Office page, Espacenet page, University of Wisconsin-Madison, Ariel Fernandez Consultancy, Academia.edu, Ariel Fernandez’s professional page.
In spite of this stellar career and in spite of his efforts to fight cancer and heart failure, Dr. Ariel Fernandez is not impervious to slander. In the new era of post publication peer review, where anybody says whatever they like without even revealing his identity or his credentials, Dr. Ariel Fernandez has been the target of libel. In this note, Dr. Ariel Fernandez reflects on post-publication peer review in light of a recent attack by journalist Ivan Oransky, the self-proclaimed champion of scientific transparency, who has been recently named Science’s Garbage Man (Muellsammler der Wissenschaft) by the Swiss Radio and Television. In his post, Oransky mentions a Note that Nature Editors appended as Addendum to a Nature paper by Ariel Fernandez.
The source of the picture on the left is this article at Yale Medicince.
WM: Thank you doctor for agreeing to talk to us on such short notice. What was your reaction to the recent post by Ivan Oransky (and Adam Marcus) published in their blog in regards to your Nature paper?
Ariel Fernandez: It is hard for me to understand the motivation for such posts by Ivan Oransky and Adam Marcus and for some of the comments in their blog. The story is thin on reality. It reads like an attack. These people seem angry (they surely sound angry) and probably think they will get some credit for doing what they do. Meanwhile, the science establishment is not taking the needed leadership in regards to post-publication assessment and in regards to fixing the peer review system.
WM: Why do you think Oransky dislikes you?
Ariel Fernandez: I don’t think our paths ever crossed, I don’t even know him. I heard he is a doctor, and that he is smart. There are many wonderful things that a smart doctor can do, what Oransky is doing is not one of them.
WM: Can you tell us what are the news exactly?
Ariel Fernandez: The Addendum published by the Nature Editors on my paper [Ariel Fernandez, Nature 474, pages 502-5 (2011)] exposes a controversy between the two authors of the paper, former author Michael Lynch and me. This is hardly a news item. Lynch and I have a disagreement on the data and what it means. The Nature addendum is appended to the paper at the url:
I posted my own tutorial on the Nature paper, including the code, raw data and statistical analysis in compliance with the open data mandate. Anybody interested can help clarify the matter if he/she so choses.
WM: How did this problem originate?
Ariel Fernandez: As I recall, in November of 2011, a Joshua Cherry, a sort of contractor (?) at NIH/NCBI first contacted me indicating that he wanted to reproduce my data in the Nature paper. After exchanging dozens of mails, I offered him a tutorial, because I realized he had little or no background in biophysics. He rejected my tutorial and from then on began challenging my papers. Now, why would a person with no background in my field decide to challenge my papers is a mystery to me. This fellow Joshua Cherry is behind the attacks on my work and my person. He seems somewhat obsessed (?) with me for some reason. Now, from what I can see, Cherry has authored some reasonable papers on population dynamics, yet he invests heavily on the downfall of someone working in a field he knows nothing about?
WM: That is odd.
Ariel Fernandez: The most important lesson to be drawn from this incident requires that we all take the high ground and ask ourselves: How should post-publication peer review be conducted? I believe there is only one way which has been the way of science for centuries: If anyone feels the need to challenge a published paper, the person should send the comments to the journal where the original work was published, request that his/her comments be subject to peer review and if they pass peer review, the objections should be published side by side with the response by the original author for everybody to examine and draw conclusions. The rest, including Oransky’s blog, is just noise.
WM: Doctor, I heard rumors that you and I are the same person.
Ariel Fernandez: Well, let’s see. You surely sound quite different from me and I don’t have any Chinese ancestry to speak of…
WM: Thank you doctor, have a good evening.
Ten more minutes on the phone with Dr. Ariel Fernandez (12/2/2014)
WM: Did you read the comments at the blog run by Ivan Oransky and Adam Marcus?
Ariel Fernandez: I read a bunch, then it got too silly with the Meng-Fernandez duality and I took my dog for a walk. It made me sad that these people cannot seem to be able to take the high ground on the broad issues at stake.
WM: Yes, they seem to dwell on whether I am a real person or whether you are actually me, or dual realities, or God knows what. Totally immaterial, like asking whether the characters in Plato’s dialogues are real or fake and take away merit if the latter were the case (I prepared that one beforehand, by the way). So, what are the issues at stake?
Ariel Fernandez: As I see it, the only thing worth focusing on is the failure of the peer review system. If the system were water- tight, there would be no need for PPPR [post publication peer review], of course. There are core issues worth focusing on: lobbying, editor courtship, fake reviewers, and cronyism in the peer review system.
WM: Well, so what do we do then?
Ariel Fernandez: Many journals are simply too amateurish to lead in this crisis, and the absence of leadership in times of crisis, often leads to bad things as we all know too well. Opportunists take over, as history has shown time and again. A leadership void has been created concurrently with the peer review crisis and, quite opportunistically, the blog by Ivan Oransky and the other fellow fills in that void. It is a bad thing but it has managed to parasite over the space available, fits right in there. Tragically, everybody watches in complete stupor while these people run the agenda.
WM: OK, so what do we (you and me) do?
Ariel Fernandez: Well, we keep it up. We help them realize that there is a loftier pursuit than indulging in the trigger-happy nonsense of the blog. We try to educate the bloggers and commenters because we believe that there is a higher ground and that they can truly contribute. Oransky, for one, is possibly a very smart person and could do plenty of good.
WM: And the lofty pursuit is…
Ariel Fernandez: Help the establishment fix the peer review system by showing concrete failures of peer review and how we can learn from the mistakes to make improvements, how we can introduce better ways to safeguard the integrity of reported work with concrete working examples while fighting the problems alluded to previously. Above all, ensure that if and when PPPR becomes an absolute necessity, it is subject to the standards that science has upheld for centuries, since professional journals came into existence. In this pursuit there is no room for Ivan Oransky or the other fellow, or the commenters, unless they choose to get serious about fixing the system and stop being silly. Vulgarization of career mistakes and tragic turns of fortune is not going to get them anywhere (except in the eyes of the angry mob of losers in science who invest in the downfall of the winners). They need to help device clever ways to deal with and combat scientific corruption at its root.
WM: My pleasure again doctor, enjoy the rest of the day.