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On scientific censorship and ‘bitchiness’

My first paper was published in 1977, and despite many fights with referees they were mediated by committed and intellectually fair Editors (especially in the controversial field of bioenergetics); thus I suffered not a single rejection until ca 1995. This occurred when a paper we had submitted to the then European Journal of Biochemistry, following up some analyses in the same journal [1,2] that we were showing [3] to be overblown, was blocked by an Editor called Christensen who was far from neutral to the topic and did not wish to see our side of the debate published. Its correctness was hardly in doubt as it included an analytical mathematical proof. Obviously we merely published it elsewhere a bit later [4], and this finished the debate (with our analyses being entirely vindicated, and with cordial relations continuing to be maintained to this day among the scientific participants in the debate). Scientific truth will out.

Since then, I have noticed an increasing and very unwelcome trend by which anonymous referees seem to think it is OK to try and block papers they do not like, independent of the arguments, and compliant or lazy Editors who either share their views or cannot be bothered to do their job and mediate properly let them get away with it.

An example was a paper we sent off in 2006 pointing out the desirability of using proteomics to look again at the players in oxidative phosphorylation, given that younger scientists are completely unaware of the evidence (e.g. [5]) that suggests that energy coupling membranes are not just inert proton barriers and thus that it would be of value. This ms was successfully blocked by those who did not wish to see these views promulgated. At the time I did not bother to pursue it, but I have now put it on our website (pdf) for others to follow up.

Most recently, several of our papers were initially shafted in this way (we need not speak of grant applications), although of course they reappeared in essentially unchanged form elsewhere. One example is our SpeedyGenes paper [6] where first up it met a series of referees who clearly wished they had thought of it so blocked it. By contrast, a referee in the journal where it was finally published commented as follows: “Suffice it to say that this reviewer thinks that each claim is well supported by rigorous testing. Without any reservation, I will order primers and use this method rather than stick to our standard lab protocols.”

Even worse was the treatment of our rather innovative paper (now published at [7]) describing a rule that more than 90% of marketed drugs obey (quite important, one might think given the costs to Pharma of attrition, where in one journal the (shamefully anonymous) Associate Editor simply chose hostile referees then wasted our time until s/he could find no further intellectual arguments and finally simply said that s/he was merely declining to publish it. Very scientific. The same journal pulled a similar stunt with another one, so I shan’t be going back there in a hurry. For now I shan’t need to name and shame it in this blog, as at least the Editor-in-Chief was cordial and apologetic.

However, the worst of all in terms of naked scientific censorship was the following tale.

Readers will be aware of a literature debate about the relative extent to which drugs and xenobiotics cross intact biological cell membranes either (i) mainly by passing through whatever lipid bilayer may be present or (ii) by hitchhiking, more or less exclusively, on proteinaceous transporters present as part of intermediary metabolism (as we have recently reconstructed in both yeast [8] and humans [9]). We have set out the evidence favouring version (ii) in a number of articles [10-18], available here.

A separate group, variously constituted, has been highlighting their belief in the importance of mechanism (i) [19,20]. However, their latest version [21], published in a ACS journal called Molecular Pharmaceutics, is a rather personal attack, polemical in tone, including virtually libellous phrases that our views are ‘not a scientific principle (sic)’, and including (quote) various ‘demands’ of us. Given this, and as is clear from that paper, one might suppose that we would have had a right of reply, setting out for instance any of the (very numerous) factual errors in ref 21, and that it would also be published in Molecular Pharmaceutics so its readers could see both sides of the debate in the same journal. This will not be happening. The story (as per the Christensen episode) is as follows.

I sent our detailed and scholarly rebuttal to the journal, where its Editor-in-Chief is Gordon Amidon (who, as a matter of record, has published more than 20 papers with various of the coauthors of reference 21). It was assigned by his office not to the Editor most involved in transporters (whom I suggested) but to one Carston Wagner. Wagner’s reply read “Thank you for considering Molecular Pharmaceutics for your manuscript submission. Molecular Pharmaceutics is committed to promoting high standards in the fields that it covers (sic). Before deciding to send your manuscript for review I have read it and in my opinion, your submission would be better suited for a more specialized journal. Consequently, we must make decisions based on likely scientific impact and interest to our readership. Thank you for your interest in Molecular Pharmaceutics.” In other words he sought to block its publication and did not even deign to send it out for review. When I appealed to Amidon, and pointed out that there could not be a more specialised journal than the one in which he had let the authors of reference 21 publish the article to which we were replying, I was told by its ‘coordinating editor’ Kimberly Barrett that the original decision had been ‘rescinded’. It is not clear what that could have involved, as the subsequent response (from Wagner) included “Thank you for your recent response to the decision on your manuscript. I have reviewed your letter and manuscript again. Molecular Pharmaceutics encourages rigorous scientific discussion. However, your paper in it’s (sic) present form is a review of a review and is not acceptable as a scholarly review or perspective.” Amidon added “A review of a past controversy, with a strong bias is not in the best interest of science.” Presumably that is considered to be in contrast to the contents of reference 21.

This is transparently an attempt (not for the first time) to censor one side of the debate, and I consider the whole episode to be utterly shameful. Consequently, readers awaiting our response and its detailed scientific arguments will have (had) to wait longer, and look elsewhere for it (a paper covering some of this ground is now online at Frontiers in Pharmacology [22]). They will also have to make up their own minds about the editorial values of Molecular Pharmaceutics, and the consequent likely scientific rigour of any of the papers that it publishes. It is not a journal I myself shall be able to take seriously again, and anyone reading it should be aware of the above facts (to which I have carefully confined myself, using quotations from actual emails) and in the light of them should choose carefully where they might wish to publish.

Given a previous set of events set out in this blog, it seems that a rather distasteful trend in scientific censorship is emerging in some places, and one that is not good for science and its role in the evaluation and dissemination of scientific truth. This is one in which Editors, who seem answerable to no one with any real teeth, impose their own scientific agenda on a field without regard to the intellectual arguments. At least it is now possible to record the behaviour of journals on social networks, e.g. at SciRev.

In summary, certainly the existence of reference 21 sharpens the debate, as it helps to make clearer what the scientific issues are seen (in some quarters) to be. Indeed, based on the ‘discussion’ in references 19-21, I have now realised that it is will be useful to rehearse the most elementary ideas of the nature of scientific evidence (and the enormous differences between observations and scientific evidence), the basics of hypothetico-deductive reasoning, what an independent variable is, how to detect a circular argument, the (lack of) relationship between state variables and mechanisms, why correlations of dependent variables are not causations, the most rudimentary aspects of molecular enzymology, enzyme kinetics and enzyme specificity, and even the difference between what is an actual measurement and what is merely an inference.  Only with these to hand will one properly be able to judge the extent of any actual evidence that supports or has directly observed lipoidal bilayer diffusion in real biological cells with intact membranes. At present, so far as I can tell, the amount of this evidence is precisely zero.

However, an unrefereed blog is not the right place to present such material (though it is an excellent means for disseminating the above facts), so our latest scientific arguments on this topic have been and will be sent elsewhere for publication. Indeed, I am now in the throes of learning (by reading them) that the ‘widespread belief’ in the bilayer lipoidal diffusion of drugs (to which I have rather loosely referred) pervades the undergraduate pharmacy and related textbooks, with barely a mention of transporters at all. I think they will soon need to be rewritten.

[1] Cornish-Bowden, A. (1991). Failure of channelling to maintain low concentrations of metabolic intermediates. Eur J Biochem 195, 103-8.

[2] Cornish-Bowden, A. & Cardenas, M. L. (1993). Channelling can affect concentrations of metabolic intermediates at constant net flux: artefact or reality? Eur J Biochem 213, 87-92.

[3] Mendes, P., Kell, D. B. & Westerhoff, H. V. (1992). Channelling can decrease pool size. European Journal of Biochemistry 204, 257-266.

[4] Mendes, P., Kell, D. B. & Westerhoff, H. V. (1996). Why and when channeling can decrease pool size at constant net flux in a simple dynamic channel. Biochim. Biophys. Acta 1289, 175-186.

[5] Kell, D. B. (1992). The protonmotive force as an intermediate in electron transport-linked phosphorylation: problems and prospects. Curr. Top. Cell. Reg. 33, 279-289.

[6] Currin, A., Swainston, N., Day, P. J. & Kell, D. B. (2014). SpeedyGenes: a novel approach for the efficient production of error-corrected, synthetic gene libraries. Protein Evol Design Sel 27, 273-280.

[7] O’Hagan, S., Swainston, N., Handl, J. & Kell, D. B. (2014). A ‘rule of 0.5’ for the metabolite-likeness of approved pharmaceutical drugs. Metabolomics, in the press; DOI 10.1007/s11306-014-0733-z http://link.springer.com/article/10.1007%2Fs11306-014-0733-z.  

[8] Herrgård, M. J., Swainston, N., Dobson, P., Dunn, W. B., Arga, K. Y., Arvas, M., Blüthgen, N., Borger, S., Costenoble, R., Heinemann, M., Hucka, M., Le Novère, N., Li, P., Liebermeister, W., Mo, M. L., Oliveira, A. P., Petranovic, D., Pettifer, S., Simeonidis, E., Smallbone, K., Spasić, I., Weichart, D., Brent, R., Broomhead, D. S., Westerhoff, H. V., Kırdar, B., Penttilä, M., Klipp, E., Palsson, B. Ø., Sauer, U., Oliver, S. G., Mendes, P., Nielsen, J. & Kell, D. B. (2008). A consensus yeast metabolic network obtained from a community approach to systems biology. Nat Biotechnol. 26, 1155-1160.

[9] Thiele, I., Swainston, N., Fleming, R. M. T., Hoppe, A., Sahoo, S., Aurich, M. K., Haraldsdottír, H., Mo, M. L., Rolfsson, O., Stobbe, M. D., Thorleifsson, S. G., Agren, R., Bölling, C., Bordel, S., Chavali, A. K., Dobson, P., Dunn, W. B., Endler, L., Goryanin, I., Hala, D., Hucka, M., Hull, D., Jameson, D., Jamshidi, N., Jones, J., Jonsson, J. J., Juty, N., Keating, S., Nookaew, I., Le Novère, N., Malys, N., Mazein, A., Papin, J. A., Patel, Y., Price, N. D., Selkov Sr., E., Sigurdsson, M. I., Simeonidis, E., Sonnenschein, N., Smallbone, K., Sorokin, A., Beek, H. V., Weichart, D., Nielsen, J. B., Westerhoff, H. V., Kell, D. B., Mendes, P. & Palsson, B. Ø. (2013). A community-driven global reconstruction of human metabolism. Nat Biotechnol. 31, 419-425.

[10] Dobson, P. D. & Kell, D. B. (2008). Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov 7, 205-220.

[11] Dobson, P. D., Patel, Y. & Kell, D. B. (2009). “Metabolite-likeness” as a criterion in the design and selection of pharmaceutical drug libraries. Drug Disc Today 14, 31-40.

[12] Dobson, P., Lanthaler, K., Oliver, S. G. & Kell, D. B. (2009). Implications of the dominant role of cellular transporters in drug uptake. Curr Top Med Chem 9, 163-184.

[13] Kell, D. B. & Dobson, P. D. (2009). The cellular uptake of pharmaceutical drugs is mainly carrier-mediated and is thus an issue not so much of biophysics but of systems biology. In Proc Int Beilstein Symposium on Systems Chemistry (ed. M. G. Hicks and C. Kettner), pp. 149-168 – http://www.beilstein-institut.de/Bozen2008/Proceedings/Kell/Kell.pdf. Logos Verlag, Berlin.

[14] Kell, D. B., Dobson, P. D. & Oliver, S. G. (2011). Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Disc Today 16, 704-714.

[15] Lanthaler, K., Bilsland, E., Dobson, P., Moss, H. J., Pir, P., Kell, D. B. & Oliver, S. G. (2011). Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast. BMC Biology 9, 70.

[16] Kell, D. B., Dobson, P. D., Bilsland, E. & Oliver, S. G. (2013). The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so. Drug Disc Today 18, 218-239.

[17] Kell, D. B. (2013). Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening, and knowledge of transporters: where drug discovery went wrong and how to fix it. FEBS J 280, 5957-5980.

[18] Kell, D. B. & Goodacre, R. (2014). Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery. Drug Disc Today 19, 171-182.

[19] Sugano, K., Kansy, M., Artursson, P., Avdeef, A., Bendels, S., Di, L., Ecker, G. F., Faller, B., Fischer, H., Gerebtzoff, G., Lennernaes, H. & Senner, F. (2010). Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov 9, 597-614.

[20] Di, L., Artursson, P., Avdeef, A., Ecker, G. F., Faller, B., Fischer, H., Houston, J. B., Kansy, M., Kerns, E. H., Krämer, S. D., Lennernäs, H. & Sugano, K. (2012). Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discov Today. 17, 905-912.

[21] Smith, D., Artursson, P., Avdeef, A., Di, L., Ecker, G. F., Faller, B., Houston, J. B., Kansy, M., Kerns, E. H., Krämer, S. D., Lennernäs, H., van de Waterbeemd, H., Sugano, K. & Testa, B. (2014). Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition. Mol Pharmaceut 11, 1727-38.

[22] Kell, D. B. & Oliver, S. G. (2014). How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Front Pharmacol, in the press http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00231/abstract.