House of Commons - Science and Technology

Select Committee on Science and Technology Written Evidence

APPENDIX 104

Memorandum from Dr Alexei Koudinov

1. INTRODUCTION

1.1 Author background information

I am M.D., Ph.D., neuroscientist, biochemist and editor. For over a decade I have been involved in Alzheimer's disease research and the basic science on the role of fats in brain function, memory, and brain disorders. I have published more than one hundred refereed articles, scientific correspondence items, and meeting abstracts, and lead the free-access no-publication-charge international peer-review scholar publication, Neurobiology of Lipids (ISSN 1683-5506) that I founded and publish since April 2002. My dual expertise as neuroscientist and electronic journal publisher provides the grounds for two parts of my personal written evidence for the inquiry on Scientific Publication by Science and Technology Committee of the UK Parliament. Part I of my written evidence is provided below.

1.2 Competing interest declaration

I declare that I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience Guidelines for Responsible Conduct Regarding Scientific Communication. I am a founding, managing and publishing editor of the Neurobiology of Lipids, an unpaid position. Neurobiology of Lipids (ISSN 1683-5506) has no affiliation with any professional association, publisher, industry member, commercial enterprise, public, educational or government organization. The viewpoint presented in this written evidence is my personal view.

2. EDITORIAL AND PUBLISHER CORRUPTION

2.1 Conclusions to draw

A. The unfair practices of major scientific journals (including representing conventional subscription-based publishing system journal Nature; Science magazine; Elsevier's Cell Press Neuron and Cell; Elsevier's Brain Research; and free access Journal of Clinical Investigation) illustrate editorial and publishing institution corruption, and their apparent inability to serve public interest.

B. The presented evidence show that questioned journals serve a private interest, and that there is no working mechanism to force these journals or their publishing institutions to amend things and thus observe their own broken self-declared ethical guidelines.

C. Described events (particularly an unpublishing a correspondence item at Science's SAGE KE, and the rejection of article at Dialysis & Transplantation after objections from marketing department[345]) additionally illustrate the lack of true editorial independence from the publisher, publishing institution (American Association for the Advancement of Science in case of Science's SAGE KE) or other bodies (The journal marketing Department in case of Dialysis & Transplantation).

D. There is a boring timing match between amyloid treatment, severe deterioration of UK Alzheimer's patient; and the preslump sales of shares by Dennis Selkoe, academic professor and director of Ireland-based Elan corporation.

2.2 Recommendations

A. To introduce rules to protect public interest of biomedical publication;

B. To introduce rules on personal responsibility and penalties for those helping to conceal the dishonesty by others in biomedical publications;

C. To introduce rules to safeguard true independence of editors of biomedical publications;

D. To investigate whether there is a secret deal between hiding for two years experimental amyloid treatment failure, severe deterioration of Alzheimer's patient in a UK clinic, the following sales of shares by Elan Corporation Alzheimer's expert Dennis Selkoe and other Elan insiders, and the consequent disastrous turndown of Elan.

2.3 Preamble

Editorial material of one of the major world medical journals, Nature Medicine, wrote in 1999: "Science, and biomedical science in particular, is competitive, and for many is a pursuit that generates considerable passion and emotion. No wonder, then, that competing scientists working in the most competitive disciplines occasionally come to blows . . . Research into . . . Alzheimer disease seems to suffer more than most in this respect. Judging by recent events, this reputation seems justified..." [346] This events were summarized in an accompanying Nature Medicine essay, [347] and in two earlier general media reports, a Wall Street Journal's "Did ties to Alzheimer's test maker sway NIH report?" [348] and The Boston Phoenix's "Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health",[349] a reading material for students taking a course on Medical Ethics at Case Western Reserve University.

Another major general medicine journal, UK-based British Medical Journal (BMJ) in a recent Education and Debate essay stated that "journals are caught between publishing the most relevant and valid research and being used as vehicles for drug company propaganda".[350]

The facts provided below indicate that the major worlds' general science and neuroscience journals impede not biased scientific development of the research into the causes and treatment of Alzheimer's disease, obstruct public interest and their own guidelines, and apparently serve one's secret private interest. It is explained how such wrongdoing i) is associated with a severe competing financial interest of Alzheimer's expert Dennis Selkoe, a hero of Wall Street Journal and The Boston Phoenix reports; and ii) could cause a severe deterioration of at least one Alzheimer's patient in England.

2.4 Journal Nature

In April 2002 I was forced to enter struggling to protect my fields' unbiased developed after UK-based journal Nature (Macmillan Publishers Ltd, Registered No. 785998, England; a "prestigious, long-running multidisciplinary journal and a must-have for libraries", as defined on 6 Oct. 2003 by The Guardian) published the article[351] co-authored by Harvard professor Dennis Selkoe. Prof. Selkoe is known as an Alzheimer's field lead authority and an architect of a decade-long amyloid hypothesis. This hypothesis blames a small protein called amyloid beta as a cause of Alzheimer's disease. The hypothesis dominated the stage for more then a decade and retarded the development of many other promising approaches. [352] Nature article favored Selkoe hypothesis. What the article failed to report was apparent financial conflict of interest by Selkoe, and the balanced discussion that amyloid beta is an essential brain chemical, as was convincingly shown by others. [353]The accompanied Nature News report[354], however, announced in the title that "smoking gun found for Alzheimer's'. I covered both issues in my correspondence arising item submitted to Nature. Nature editor asked me to present evidence of Selkoe conflict, and finally rejected my communication. The rejection response included the following determination on an allegation of a not disclosed competing financial interest by Dr. Selkoe: "regarding the competing financial interests statement, Dr Selkoe no longer has has any connection with the companies you list because of the 1997 ruling by Harvard University prohibiting such connections among its faculty members. Selkoe's amyloid-beta vaccine patent was independent of Elan/Schenk's." [355] This belonging to Nature scientific correspondence, along with some evidence of Selkoe conflict, appeared as a Rapid Response in British Medical Journal on 15 May 2002. [356]

In August 2002 Dublin-based The Sunday Business Post in two publications[357] confirmed that Dr. Selkoe is not only Harvard Professor, but also Elan Corporation Director, and "Elan Alzheimer's expert in pre-slump share sale". Growing fast internet search capabilities allowed me to discover in mid-summer 2002 publicly available US Security and Exchange Commission (SEC) information on sale of shares by Dennis Selkoe and other Elan insiders. This sale of shares happened a year before the company publicly announced poor results in its' trial of amyloid-based Alzheimer's disease treatment with a vaccine. [358] I also discovered another apparent conflict by D. Selkoe, an award in 2001 the major American Alzheimer's Potamkin Prize to Elan scientist Dr. Dale Schenk. This prize is managed by American Academy of Neurology (AAN) Potamkin Prize selection committee chaired since 1999 by Professor Selkoe, who's service as Director for Elan was not disclosed in any AAN document. [359]

As previously requested, I delivered the information on Selkoe conflict to Nature, and asked Nature to disclose Dr. Selkoe conflict to meet the journal own published guidelines. [360] The response of Phillip Campbell (dated 11 September 2002) serving Editor for journal Nature and Editor-in-Chief for Nature publications seemed missing the point of the latest publicly available info. Dr. Campbell stated: "My colleagues have examined the situation with patents and we are also satisfied that our conflict of interest guidelines have been adhered to." [361]

I believe that the above statement contradicts Dr.Campbell other official statement that "there are circumstances where selection of evidence, interpretation of results or emphasis of presentation might be inadvertently or even deliberately biased by a researcher's other interests"?[362]

Moreover, just three months later Nature published an Insight: Review article by Dennis Selkoe and his business partner, Dr. Howard Weiner with no competing interest declaration. [363] This article entitled "Inflammation and therapeutic vaccination in CNS diseases" is of particular relevance to Dr. Selkoe and Dr. Weiner amyloid entrepreneurship described in details in my correspondence "[Alzheimer's] Amyloid beta road show" commenting on another article co-authored by Weiner and Selkoe in Journal of Clinical Investigation (see below). [364]

Most lately Nature published another Insight:Review article by Selkoe entitled "Folding proteins in fatal ways".[365] In this article D. Selkoe expanded his amyloid theory to other brain proteins and other neurodegenerative diseases. However, there were no competing interest disclosure made by Nature despite the fact that Nature is fully informed about it, and because amyloid hypothesis is the basis of Selkoe's Elan Corporation Alzheimer program.

Based on the above I can not call the conduct by Nature other then corruption. I therefore have no reason to believe to the response by Nature editor Dr. Campbell on my inquiry whether "Dr.Selkoe served as a referee for the Nature `99 article by [Elan] Schenk et al. [366] (that was the basis for [Alzheimer's] vaccine development) and other Alzheimer's/amyloid related articles submitted previously to Nature." [367] In his e.mail reply of Sept. 11, 2002 Dr. Campbell stated: "It is a strict policy of Nature that we do not discuss the identity of referees involved in our decision making. However, I can assure you that there is absolutely no basis for any suspicion that Dr. Selkoe might have abused his position as a possible referee." [368]

I believe that it is in the power of The Science and Technology Committee to request Nature to disclose their Alzheimer's amyloid vaccine articles referees. I further believe that such disclosure will confirm the drawn conclusion on Nature editorial corruption, and that there were no solid scientific grounds to publish the article by Elan's Dale Schenk and colleagues. This article triggered an unusually fast track `development' of Alzheimer's amyloid vaccine, that could cause the severe deterioration of a patient in a UK clinic following amyloid treatment (see below).

2.5 Science Magazine by AAAS

Science is the major international general science scientific journal (published by the American Association for the Advancement in Science, AAAS with an UK office[369] ) that was called by The Guardian (6 Oct. 2003) a "major US player and perhaps the most widely read science journal in the world." Unfortunately, the conduct by Science and AAAS illustrate another example of editorial and publishing institution corruption related to Alzheimer's disease research. The facts are provided below.

On one hand on my inquiry[370] Science promptly handled the non-disclosure of competing interest in a 19 July 2002 review article by Hardy and Selkoe. [371] Similarly to all mentioned above articles in Nature, the Science article represented a unipolar view of the amyloid beta protein as an Alzheimer's disease culprit and failed to provide a fair discussion of amyloid beta as essential brain chemical. The correction note published in Science on 27 September 2002 stated:

"The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics" by J. Hardy and D. J. Selkoe (19 July [2002], p. 353). The review should have been accompanied by the following conflict of interest declaration: "Dr. Selkoe is a founding scientist of Athena Neurosciences, now Elan PLC, and a Director of Elan." Science had failed to send the disclosure form at the time the manuscript was received."

The latter part of the correction transferred the non-disclosure responsibility from Dr. Selkoe to Science, indicating the magazine voluntary acceptance of the editorial misconduct (see my full correspondence[372] with Donald Kennedy, Science Editor-in-Chief, for further details).

Just one month after the publication of the correction, however, on October 25, 2002, Science published another article by Selkoe that served to modify amyloid cascade hypothesis in favor of a specific physical form of amyloid, called oligomers. [373] It was a viewpoint article in a Science theme issue "The dynamic synapse" distributed free of charge at the 32nd Society for Neuroscience Annual Meeting, November 2-7, 2002, in Orlando, Florida, a major world forum for neuroscientists. This article (similarly to the mentioned above another Science article by Hardy and Selkoe) had no discussion of amyloid beta as good molecule. It also failed to provide honest disclosure of the competing financial interest by Selkoe and simplified the case by calling Dr. Selkoe "a consultant to Elan Pharmaceuticals, plc" in the last reference.

On my call for a true disclosure of competing interest by D. Selkoe, Harvard Professor, Elan Corporation Director, and "Elan Alzheimer's expert in pre-slump share sale"[374] Science Editor-in-Chief determined that "Dr. Selkoe's statement [that he is "a consultant to Elan Pharmaceuticals, plc"] is a sufficient announcement of what some might perceive as a conflict." [375]

On April 22, 2003 I brought attention of Science Editor-in-Chief to another case of the violation of the Science and AAAS (American Association for the Advancement of Science, a publisher of Science) disclosure policy in another article on Alzheimer's disease amyloid oligomers. One of the senior authors of April 18, 2003 article on amyloid oligomers, [376] Dr. Carl Cotman failed to disclose that he is a co-founder, scientific director and consultant of the Cortex Pharmaceuticals, a company that has Alzheimer's disease as one of its' research areas. [377] This time Donald Kennedy did not reply on my non-disclosure alert and yet failed to publish a correction to fix this instance of the AAAS and Science policy breach. Science also refused my correspondence item describing experimental and data interpretation flaws of the article by Kayed et al. Such scientific flaws were also noticed and publically sounded by Vincent Marchesi, Editor-in-Chief of The FASEB Journal.

Furthermore, on June 13, 2003 Science published a presidential address by Floyd Bloom, AAAS board chairman, [378] an immediate predecessor of Donald Kennedy at the post of Science Editor-in-Chief, and the sole Editor-in-Chief for Elsevier's Brain Research journal series (see below). This contribution included two-paragraph section on "Complex genetic diseases of the brain". Defining "new strategies for the treatment of Alzheimer's" Dr. Bloom particularly mentioned "vaccines for absorbing the bad fragments of APP" (a chemical precursor of the amyloid beta protein) and "enzymes to block the abnormal proteolysis" [of APP yielding amyloid beta]. The related bibliography included citations of the above mentioned article by D. Selkoe in the Science theme issue, [379] and the article by vaccine developer Dr. Schenk of Selkoe's Elan Pharmaceuticals, plc. [380] What this Science publication by AAAS top official did not mention was Dr. Bloom competing financial interest.

The above issues were addressed in my correspondence with Science provided in my June 16, 2003 "Open letter to Donald Kennedy, Science Editor-in-Chief: AAAS, Science, Alzheimer's disease and academic dishonesty".[381] This letter also informed Science Editor-in-Chief that Floyd E. Bloom, AAAS Board of Directors Chair and Scripps Research Institute professor has competing financial interest as founder and CEO of Neurome, Inc. [382] Dr. Bloom did not disclose his financial interest in his Science "Presidential address. Science as a way of life: perplexities of a physician-scientist"[383] that AAAS made available free to all with no barrier for access (!) and that official AAAS news release called "Healing U.S. Health Care. AAAS Board Chairman Floyd E. Bloom calls for U.S. health care reform." (AAAS News release 13 June 2003). [384]

There is another instance of financial conflict non-disclosure in articles on Alzheimer's disease that informed Science did not inform readers about. This is the article by Monsonego and Weiner in the Science theme "Brain Disease" issue (31 Oct 2003) [385] that apparently aimed free distribution among the global neuroscience audience at the Society for Neuroscience Annual Meeting 2003. I covered the above systemic wrongdoing by Science in my letter to colleagues, [386] that generated November 7, 2003 response by Cambridge-based Peter Stern, Senior Editor of the Europe (UK) Office of Science: "Dear Dr. Koudinov, thank you for relaying your concerns to us. We have already started an investigation into that matter." Despite of this response by Peter Stern Science did not make public the competing financial interest by Howard Weiner. The typos correction, however, was published for the Science article by Monsonego and Weiner. [387]

Likewise, Science did not handle other non-disclosure cases described above, indicating that this is an editorial corruption, not incidental error. The facts described below further suggest that Science corruption may be endorsed by the leadership of AAAS, the publisher of Science.

2.6 Is Science Magazine editorial misconduct endorsed by publisher leadership?

Let facts talk, so a reader of this section will justify himself/herself whether editorial misconduct by Science is endorsed by the American Association for the Advancement of Science (AAAS) leadership.

As noted above one of the Science articles that missed competing interest declaration was authored by Floyd Bloom, immediate past Editor-in-Chief of Science, AAAS Board of Directors Chair[388] 2003-2004and Scripps Research Institute professor, and founder and CEO of Neurome, Inc. [389]

Additional financial conflict of interest by AAAS official is illuminated in a news reports associated with the April 15, 2003 article published in the Proceedings of the National Academy of Sciences USA[390] (PNAS USA) having Floyd Bloom as senior author, and Neurome, Elan and Scripps Institute as organizations where this research was performed. [391]

Quoting Floyd Bloom at the Press Release of Neurome: "Using our newly developed tools for visualizing brain structures, we were able to completely reconstruct the brains of the mice that model human Alzheimer's disease," said Floyd E. Bloom, M.D., Founding CEO and Chairman of the Board of Neurome and Chairman of the Department of Neuropharmacology at The Scripps Research Institute. "In fact, embedded in the brain reconstruction, we generated a 3D reconstruction of the deadly deposits of amyloid, showing for the first time, how the amyloid deposits precisely correspond with key memory circuits -- the same key memory circuits that are affected early in human Alzheimer's disease..."

The Neurome web site[392] discloses further details of Dr. Bloom competing financial interest coming out of the collaboration between Neurome and Selkoe's Elan corporation: "The research partnership with Elan has an initial term of 3 years and may generate up to $4 million in service revenue for Neurome, together with shared ownership of the diagnostic and therapeutic applications of the genes, circuits and mechanisms identified in the research. The partnership will utilize Neurome's technologies to analyze a mouse model of Alzheimer's Disease with the goal of identifying and exploiting molecules and pathways relevant to diagnosis and treatment of the disease. The partnership will analyze Elan's proprietary mouse model of amyloid deposition in an attempt to answer a variety of scientific questions regarding amyloid deposition."

2.7 Did Floyd Bloom's Neurome and Selkoe's Elan joint venture affect AAAS and Science integrity?

Based on the above facts, I do think so. Moreover, there is an apparent unwillingness of AAAS to investigate and amend things, as illustrated by AAAS unpublishing my Open letter to Science Editor-in-Chief addressing the above issues. This letter was published on June 16, 2003 as a scientific correspondence item on Science article by Floyd Bloom[393] at an editorially independent division of AAA Science called Science's SAGEKE. During seven weeks (till unpublished at the beginning of August 2003) this letter was read by more then one thousand online readers, indicating significant readers' interest. An unpublishing of the letter, however, did not preclude its' unlimited availability at my own web site. [394]

In his recent Science editorial[395] Editor-in-Chief Donald Kennedy wrote: "we have tried to give authors more guidance about disclosure, and we'll continue to help our readers make their own informed judgments." The above facts indicate that what Dr. Kennedy says is a letter of intent, not the policy Science adhered to. [396]

Contrasting with Dr.Kennedy editorial the above facts show an apparent unwillingness of AAAS Science to inform readers about not-disclosed financial interests by Science authors, and AAAS Science obstruction of a disclosure made by others.

The situation is most dramatic because there is apparently no way to force AAAS (or Nature, as described in paragraph 2.4) to amend things. I therefore hope that the Science and Technology Committee inquiry will consider my recommendations, and will help to enforce by law editorial misconduct elimination and personal responsibility and penalties of those helping to conceal the dishonesty by others (see paragraph 2.2 above). This is especially important in biomedical publications as described below.

2.8 DID INDUSTRY TIE BY AAAS LEADER AFFECT THE CONTENT OF AAAS PUBLICATIONS?

There is another far-reaching implication, a concern of the content quality of a major worlds' general science journals, as illustrated below.

In 2000 AAAS published the special Science issue entitled "The Best of Science—Neuroscience".[397] This special issue was available for purchase at the Society for Neuroscience Annual Meeting 2000 held 5-8 November 2000, New Orleans, LA. Among other articles "The best of Science—Neuroscience" issue included the article "Alzheimer's Disease—Genotypes, Phenotype and Treatment" by Dennis Selkoe (published earlier as Science perspectives article[398]), and "Special introduction from Floyd E. Bloom, Editor-in-Chief of Science", according to the AAAS advertisement leaflet distributed at the New Orleans SFN Meeting 2000.

"The Best of Science—Neuroscience" "limited-edition volume" of Science is also mentioned at the AAAS Annual Report 2000 Membership page. [399] Quoting right side bar of this page: "Publications The Best of Science-Neuroscience. This new publication includes the best work published in this field from the pages of Science. This collection of cutting edge articles and research reports covers circadian rhythms, neurodegeneration, aging, and more."

Based on the facts described above one may doubt that this issue presents a true "best of science". One may further ask: Is AAAS inclusion of the article by Selkoe in the "Best of Science—Neuroscience" volume a support of Floyd Bloom business partner ? The latter seem true, based on an unfortunate time-match of the distribution of the Science's "The best of Science—Neuroscience" at the 30th Society for Neuroscience Annual Meeting (5-8 Nov. 2000) and Floyd Bloom's Neurome announcement of "financing from... [Selkoe's] Elan Corporation..." and "research partnership with Elan Corporation's pharmaceutical subsidiary to study neurodegenerative disorders" (20 October 2000, as announced in The Scientist daily news report[400] "New companies to commercialize neuroscience discoveries").

The next question come then: Do Science articles on Alzheimer's amyloid hypothesis (by Selkoe, [401] by Kayed et al. [402] by Bloom, [403] and by Monsonego and Weiner30 quoted above) serve to add a commercial value to Neurome, a company of Professor Floyd Bloom, an AAAS board of directors chair ?

If so, there is no wonder that another Science article[404] (covering presented at Stockholm World's Alzheimer's Congress 2002 wide range of Alzheimer's research projects expanding far beyond amyloid story) limits its' abstract (supposed to be fair representation of the article content) to the following amyloid beta endorsement: "STOCKHOLM--Alzheimer's researchers gathered here last month with a sense of urgency and optimism about possible treatments--and perhaps preventions--for the mind-robbing disease. The 4000 attendees heard about progress on several fronts, including possible vaccines and treatments aimed at either blocking formation of b amyloid, a small peptide thought to trigger the loss of brain neurons, or at dissolving the abnormal b-amyloid deposits that are a hallmark of the disease. This special focus also explores a debate over which drugs to test in a prevention trial."

2.9 THE LACK OF EDITORIAL INDEPENDENCE AT AAAS PUBLICATIONS: A CASE OF AAAS SCIENCE'S SAGE KE

As noted above (see paragraph 2.7 "Did Floyd Bloom's Neurome and Selkoe's Elan joint venture affect AAAS and Science integrity ?") my "Open letter to Donald Kennedy, Science Editor-in-Chief: AAAS, Science, Alzheimer's disease and academic dishonesty"[405] was published on 16 June 2003 in an online journal of AAAS Science called Science of Aging Knowledge Environment or Science's SAGE KE. Despite of being the subscription based service by AAAS this wonderful web site provides unique opportunity for scientists in biomedical disciplines related to aging to meet colleagues and to provide scientific correspondence items on almost any article published elsewhere. I published at Science's SAGE KE several scientific correspondence items that had total readership of 8,588 on February 1, 2004 (referenced at my web site scientific correspondence page[406]). My scientific correspondence published in Science's SAGE KE includes quoted above "Open letter to Science Editor-in Chief...", my "Open letter to Public Citizen's Health Research Group on Alzheimer's disease research"[407] (also published at British Medical Journal[408]), and the letters reporting the provided below facts on Elsevier Cell Press Neuron ("Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure?" [409]) and the Journal of Clinical Investigation ("Amyloid beta road show, or had the lure of profits corrupted Alzheimer's neuroscience"[410] ).

The latter letter "Amyloid beta road show..." [411] was unpublished by SAGE KE along with my "Open letter to Science Editor-in-Chief..." [412]. SAGE KE editor Kelly LaMarco in the e.mail letter of 8 August 2003 wrote: "Dear Dr Koudinov, Thank you for your recent postings in SAGE KE. Unfortunately, I have had to remove your comments from the site. We cannot post in SAGE KE letters that are addressed to the editors of other journals. We are happy to post comments on scientific findings. But we cannot post comments that criticize the editorial policies of other journals. Perhaps you can send your comments directly to Dr. Marks. Best wishes, Kelly LaMarco Editor, SAGE KE".

This response seemed explaining the reason to unpublish my 5 August 2003 letter on 1 August 2003 Journal of Clinical Investigation article co-authored by Selkoe. I, therefore, revised this correspondence and re-published it again with minor helpful revisions by Kelly LaMarco.

There were, however, no way to revise my Open Letter to AAAS Science Editor-in-Chief Donald Kennedy, also unpublished on this occasion, after this letter (published on 16 June 2003) generated in seven weeks the readership exceeding one thousand. I preferred to re-publish this Open letter at my web site where it is freely available. The Acrobat .PDF imprint of the Open Letter originally published at Science's SAGE KE is also available and is provided below (Appendix 2).

As SAGE KE user I enjoyed editorial management of this great online serial. I was, however, bothered by the following note in 8 August 2003 e.mail letter by Kelly LaMarco (see above): "Unfortunately, I have had to remove your comments from the site."

I do qualify this statement by AAAS Science's SAGE KE editor, an editorially independent publication (ISSN 1539-6150) as an indication of a pressure exerted on SAGE KE editors, and a break of SAGE KE editorial independence.

No question the responsibility for such apparent editorial independence break rest with AAAS, a publisher of SAGE KE, not SAGE KE editors.

One may find convincing that there is a reason for publisher pressure on SAGE KE editor, a competing financial interest by AAAS top official, described in the unpublished letter (see paragraphs 2.5-2.7 above for details).

2.10 ELSEVIER BRAIN RESEARCH

Another eye-catching example of editorial and publisher wrongdoing is the case of Elsevier Brain Research named by UK Gardian[413] the most expensive UK library serial offering "a comprehensive look at events in neuroscience". In June 2003 I informed Eric Merkel-Sobotta, Elsevier Corporate Relation Director, that Brain Research Editor-in-Chief, [414] Dr.Floyd Bloom (who also serves the sole Editor-in-Chief for the whole Brain Research journal series[415] by Elsevier) has not disclosed competing financial interest as illustrated above (see paragraphs 2.5-2.7 above). Since then Eric Merkel-Sobotta seems not bothered by the fact of impaired academic integrity by one of the most expensive Elsevier title. His only reply on my alerts (that I send him on several occasions since the publication on 16 June 2003 my Open letter to Science Editor-in-Chief that disclosed the conflict by Floyd Bloom) was 18 December 2003 e.mail note associated with my 17 December 2003 SPARC OA Forum posting "AAAS Science and academic integrity—breakdown of the year?": "Would you please be so kind as to remove my name from your cc: distribution list? I am already on all of the usual listservs, and so do not need to receive your information separately. Thank you very much for your cooperation. With best regards, Eric Merkel-Sobotta". No other action were taken.

2.11 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA (PNAS USA)

Proceedings of the National Academy of Sciences USA (PNAS USA) is a flagship journal published by the National Academy of Sciences USA.

Paragraph 2.6 above is mentioning that "additional financial conflict of interest by AAAS official is illuminated in a news reports associated with the April 15, 2003 article published in the Proceedings of the National Academy of Sciences USA (PNAS) having Floyd Bloom as senior author, and Neurome, Elan and Scripps Institute as organizations where this research was performed.

It is important to note that PNAS article does not have competing interest declaration, as it is required by the Uniform Requirements for the Manuscripts submitted to the Biomedical Journals, [416] and that it was "contributed by Floyd E. Bloom".[417] PNAS information for authors[418]explains that the record "contributed by Floyd E. Bloom" indicates the manuscript submission to PNAS through Track III mechanism. It further says: "Track III: An Academy member [PNAS is a National Academy of Sciences USA publication] may submit his or her own manuscripts for publication. Members' submissions must be accompanied by the name of knowledgeable colleague(s) who reviewed the paper, along with the review(s)". Is this an abuse of the PNAS submission policy associated with competing financial interest non-disclosure by Floyd Bloom?

I brought the above concerns to Nicholas Cozzarelli, PNAS Editor-in-Chief, in an e.mail letter (20 June 2003) on my Open letter to Science Editor-in-Chief and the above PNAS publication, and informed Dr.Cozzarelli of several other correspondence items quoted at length of this written evidence. In reply I received several confirmations from PNAS, including the one from Daniel Salsbury, Editorial Manager (21 Oct 2003) and Diane Sullenberger (5 Nov. 2003) similarly expressing thanks for my e.mails, . I am not aware, however, that PNAS come to a determination on the case described above.

2.12 JOURNAL NEURON BY ELSEVIER'S CELL PRESS AND OTHER CELL PRESS TITLES

The non disclosed conflict by Selkoe (described in paragraphs 2.4 and 2.5) and others links the editorial corruption matter with a major neuroscience journal Neuron by Elsevier's Cell Press, as summarized below and described in details in SAGE KE letter "Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure?" [419] and in BMJ letter "22 May 2003 Neuron article on Alzheimer's : "valid research" or a "drug company propaganda"?.[420]

In my correspondence[421] with Neuron in August 2002 I requested editorial investigation and disciplinary action to punish Dennis J. Selkoe, non disclosure of competing financial interests in prior Neuron publication, and while serving Neuron editorial board member. Shortly thereafter I received a reply from Neuron senior scientist (currently serving a senior editor) Stacie Weninger. Dr. Weninger wrote to me: "I wanted to thank you for bringing this matter to our attention. We take these issues seriously, and we will look into the matter further".[422] Since then Neuron did not come to any action [that I expected to be] commensurate with the pattern of Dr. Selkoe misconducting academic nondisclosure dishonesty, as it is advised by the US Office of Research Integrity. [423] Moreover, February 2003 Neuron article by Sharon et al. [424] again hided D. Selkoe (a senior author) competing financial interest, disclosure that is required by the academic ethics and the uniform requirements for the manuscripts submitted to the biomedical journals.

Furthermore, on 22 May 2003 Neuron published featured article by Zurich researchers entitled "Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease".[425] The article was endorsed with the favoring Neuron commentary co-authored by Neuron editor Kenneth Blum. [426] The commentary conclusion enthusiastically stated that "the findings presented are important in providing further evidence for the validity of the prevailing working hypothesis, the Amyloid Cascade Hypothesis".

I (as well as many other scientists) did not share the optimism of the Neuron article and associated commentary. Others found that "the title and some of the conclusions of this study are not yet justified." I called both contributions "a bias in favor of the expired amyloid dogma-based Alzheimer's therapy approach" due to the experimental flaws and the authors' apparently false statement on the financial interest in Selkoe's Elan.

Hiding authors' competing interest Neuron article by Hock et al. and its' accompanying endorsement by the Neuron editor commentary serve an evidence for a conclusion in the British Medical Journal Editorial on financial interest in medicine: "coverage is much more valuable to drug companies than advertising, and scientific studies can be manipulated in many ways to give results favourable to companies." [427]

Since May 2003 there is no action taken by Neuron, Elsevier or Cell Press, indicating that there is an apparent corruption, and that Neuron and its' publishers self interest (or ones' private interest?) dominates the public interest of an unbiased development of Alzheimer's neuroscience.

Neuron practices seems also exercised by another Cell Press title, worlds' major biomedical journal Cell. An example follows: On 27 December 2003 I informed Cell Editor Emilie Marcus and Cell Press CEO Lynne Herndon that two `breakthrough' articles[428] in 26 December 2003 issue of Cell miss competing interest declaration by senior author, Dr. Eric Kandel. Dr. Kandel is a Nobel laureate, a Chairman of the Scientific Advisory Board and principal scientific founder of Memory Pharmaceuticals, [429] and a reviews editor of Cell Press Neuron. The requirement for the disclosure of the conflict of interest is set in the Cell Conflict of Interest policy, [430] so, the break of it deserve the response. Again, there is no response over the past six weeks, however.

As in case of Nature and Science there is no working way to force Cell Press to amend things.

2.13 JOURNAL OF CLINICAL INVESTIGATION

The story of the Journal of Clinical Investigation (JCI) is based on the 1 August 2003 article by Monsonego et al. [431]The major flaw of this report is the failure to provide a true competing financial interest declaration for senior authors, Dr. Dennis J. Selkoe and Dr. Howard L. Weiner. The Monsonego et al. article footnotes' conflict of interest disclosure says that "the authors have declared that no conflict of interest exists." This statement is not true, as I described in mentioned above 5 August 2003 scientific correspondence letter "Amyloid beta road show or has the lure of profits corrupted Alzheimer's neuroscience".[432]

This letter, however, was unpublished by Science's SAGE KE based on the editor reasoning that SAGE KE "cannot post comments that criticize the editorial policies of other journals" indicating Journal of Clinical Investigation unhappiness with my letter. I, therefore, revised this correspondence on a JCI article and submitted it again. SAGE KE editor email of 12 August 2003 stated: "We have now posted a slightly edited version of your letter. JCI has elected not to respond.", indicating that JCI is fully informed about my disclosure of the false competing interest declaration in the article under discussion. There is no correction published at JCI since then, so, any reader of the article by Monsonego, Weiner, Selkoe and others at the free-access JCI web site remains dis-informed about the competing financial interest by the authors. See it yourself at the provided link. [433]

2.14 ALZHEIMER'S PATIENT SEVERE DETERIORATION IN A UK CLINIC

One of the recommendations of this written evidence is to investigate whether there is a secret deal between hiding for two years experimental amyloid treatment failure, deterioration of Alzheimer's patient in a UK clinic, the following sales of shares by Elan Corporation Alzheimer's expert Dennis Selkoe and other Elan insiders, and the consequent disastrous turndown of Elan. Such events match was reported by me to the Federal Drug Administration (FDA), US Securities and Exchange Committees (SEC) and noticed in the recent Sunday Times article "Selkoe's sale of Elan shares referred to SEC".[434] I am not aware that any action was taken to date by FDA or SEC.

The estimation of dates is based on 17 March 2003 Nature Medicine report "Neuropathology of Alzheimer's disease after immunization with amyloid-beta peptide: a case report"[435]

Let me quote the first paragraph of this Nature Medicine article. This quotation indicates that this Alzheimer's patient was immunized and become deteriorated before Elan Phase 2 clinical trial was launched, thus raising the question whether drug development regulatory bodies were properly and timely informed of this patient severe deterioration:

"A 72-year-old woman with a 5-year history of gradually progressive memory impairment presented with worsening confusion and disorientation. Her Mini Mental State Examination (MMSE) score (23/30) represented a three-point deterioration in two years. She had global cognitive impairment and satisfied the National Institute of Neurological and Communicative Disorders and StrokeAlzheimer's Disease and Related Disorders Association's criteria for probable AD, with no cardiovascular risk factors and a modified Haschinski score 4. Therapy with rivastigmine tartrate, a cholinesterase inhibitor, resulted in improvements in the Alzheimer's Disease Assessment Scale cognitive section (ADAS cog), MMSE, clock drawing and verbal fluency, but ten months later she had returned to baseline levels on all these parameters. The patient was then enrolled in a randomized, double-blind, multiple-dose immunogenicity study of Ab42 (AN-1792; Elan Pharmaceuticals). She received her first injection, containing 50 microg of AN-1792, in July 2000. This was repeated 4, 12 and 24 weeks later with no apparent adverse effects. A fifth injection with a reformulated preparation containing polysorbate-80, subsequently used in a multinational phase 2a trial, was given 36 weeks after the first injection. Four weeks after her last injection, her cognitive test results were unchanged (MMSE 23), but at six weeks she suddenly became unwell with dizzy spells, drowsiness, an unstable gait and fever. Two weeks after that, she deteriorated such that an MMSE could not be performed. Neuroimaging (Fig. 1a) showed extensive bilateral alterations in the cerebral white matter and enhancement on the brain surface. There was mild hydrocephalus; an isodense mass was identified above the splenium of the corpus callosum on the right side. The appearances were interpreted as representing either edema, possibly associated with an inflammatory process, or an infiltrating primary brain tumor. Therapy with dexamethasone was started. The patient remained relatively unchanged until she died in February 2002 from a pulmonary embolism 20 months after the first injection and 12 months after the last injection."

Lets' focus on the following sentences from the above paragraph:

"She received her first injection, containing 50 microg of AN-1792, in July 2000. This was repeated 4, 12 and 24 weeks later with no apparent adverse effects. A fifth injection with a reformulated preparation containing polysorbate-80, subsequently used in a multinational phase 2a trial, was given 36 weeks after the first injection. Four weeks after her last injection, her cognitive test results were unchanged (MMSE 23), but at six weeks she suddenly became unwell with dizzy spells, drowsiness, an unstable gait and fever. Two weeks after that, she deteriorated such that an MMSE could not be performed... The patient remained relatively unchanged until she died in February 2002 from a pulmonary embolism 20 months after the first injection and 12 months after the last injection."

Although the article missed specific dates the above allows the following calculation and notes:

(a) This patient was immunized with AN-1792, that was latter used in FDA approved Phase2 clinical trial ("...A fifth injection with a reformulated preparation containing polysorbate-80, subsequently used in a multinational phase 2a trial...")

(b) last immunotherapy injection was at the end of year 2000 (24 weeks after the first injection in July 2000)

(c ) patient remained unchanged during January 2001 ("four weeks after her last injection")

(d) patient became unwell at the beginning of February 2001 ("at six weeks [after her last injection] she suddenly became unwell")

Especially dramatic could be the possibility that this patient deterioration caused preslump shares sale by Elan directors. Quoting Des Crowley's The Sunday Times article:

"Selkoe... sold 20,000 shares for around $1m on February 6, 2001. Other insiders at Elan declared sales of more than $43.5m in the months following Selkoe's disposal. After the American Food and Drug Administration (FDA) refused to endorse the drug in January 2002, the share price fell to a low of $2."

I believe that specific dates in medical record of this patient may add clarity to the above timing match, and therefore warrants your investigation.

Quoting my senior colleague from Australia:

"did you realise that the new Nature Medicine article by Nicholls et al shows that this case of meningoencephalitis occurred 6 months before Elan's Phase 2A [clinical] trials were begun? You may be interested in exploring the implications of this timing."

It is thus possible that Selkoe's Elan failed to report in time this case reaction on a vaccine. If so, should Elan Phase2 Trial be ever launched, yielding many more patients' illness, following the vaccine withdrawal a year latter, [436] further threatening Alzheimer's research community with a rush movement of the not-validated hypothesis to the clinic and making harm to patients, while serving ones' commercial interest. Based on the facts, provided in earlier paragraphs of this written evidence, it is regrettable to realize that major scientific journals are involved in this unfair play.

I am not alone in my belief. Below are voices of my two colleagues, senior professors:

"...Many thanks for all the information... I was going to do an article more than a year ago saying that a clinical trial of A-beta vaccination was too hazardous to try, but never got around to it. Then the disaster that many of us predicted would result came to pass. I thought common sense would then prevail and this whole idea would be abandoned. But as you have pointed out, the dogma is too strong to be dropped, and now it is the application, and not a faulty theory that is being blamed. More AD cases are in danger...".

"I agree whole heartily with your letter to Science concerning Alzheimer's disease and the amyloid beta protein. It is amazing how this field has been led down the "amyloid hypothesis" trail to the exclusion of other viable hypotheses. If you don't go along with the amyloid dogma, you have difficulty publishing and extreme difficulty being funded. The anti-intellectual, anti-science mentality displayed by many in this field has slowed progress to a crawl. This is a shame."

Also, please note that American Academy of Neurology (AAN) Potamkin Prize 2001 (chaired by Elans' D.Selkoe, see paragraph 2.4 above for further details) was awarded to Elan scientist Dr. Dale Schenk. This Prize 2001 apparently was awarded to Dr. Schenk [at AAN Meeting 2001] after the above UK Alzheimer's case was deteriorated and after Selkoe sale of Elan shares in early 2001. [437], [438]

3. CONCLUSION

I do believe that an unfortunate story of an UK Alzheimer's patient subjected to the Selkoe's amyloid-hypothesis-based treatment, became possible due to the editorial and publisher corruption in biomedical publications.

It is therefore my responsibility to bring the above facts to The Committee Attention. The corrupted practicies by biomedical journals is a threat to the public interest and to the public health.

I therefore hope that The Committee will follow my recommendations i) to introduce rules to protect public interest of biomedical publication; ii) to introduce rules on personal responsibility and penalties for those helping to conceal the dishonesty by others in biomedical publications; iii) To introduce rules to safeguard true independence of editors of biomedical publications; and iv) to investigate UK Alzheimer's patient case.

February 2004

345 Dyer O. British Medical Journal Vol. 328: pp. 244-b (2004). Back

346 Nature Med. Vol. 5(7): p. 713, p. 717 (1999). Back

347 Birmingham K, Ready T. Conflict-of-interest problems lead to policy changes. Nature Med. Vol.5(7), 717-8 (1999). Back

348 Waldholz M, King RT, Jr. The Wall Street Journal. (30 Nov 1998). Back

349 Ready T. (29 April 1999). Available at: http://www.bostonphoenix.com/archives/1999/documents/00521742.htm Back

350 Available at: http://bmj.com/cgi/content/full/326/7400/1202. Back

351 Nature. Vol. 416, pp.535-53 (April 4, 1999). Back

352 Koudinov A. Amyloid beta is an essential synaptic protein, NOT neurotoxic junk. See Appendix 1 below. Back

353 Available at: http://www.nature.com/nsu/020402/020402-5.html Back

354 Available at: http://www.nature.com/nsu/020402/020402-5.html Back

355 See my full corr. With Nature at: http://anzwers.org/free/neurology/reports/eletters.html£let2nature Back