The Kathrin Maedler Dynasty

German academic jargon has a peculiar expression: Doktorvater. It means “doctoral father”, a fatherly figure who takes his helpless PhD student progeny by the hand and guides and teaches the offspring of his academic loins the wisdom of science, up to the graduation. Nowadays with the system being less patriarchal, one can instead have the figure of a Doktormutter, doctoral mother. Which obviously doesn’t bring same gravitas or inspires same respect and awe, and is therefore hardly ever used.

The German diabetologist and Professor at University of Bremen Kathrin Maedler is a central figure of an academic dynasty. Using Photoshop simulations (read here), she discovered a cure for diabetes via inhibition of the inflammatory cytokine interleukin-1-beta (IL-1β), which was then confirmed as a definite cure for diabetes in clinical trials led by her own Swiss Doktorvater Marc Donath, then professor at University of Zürich, now in Basel. Over 15 years later, the Maedler-Donath cure was proven as utterly ineffective against hypoglycaemia and diabetes by same Donath, in another clinical trial. Because of her Photoshop creativity with discovering diabetes cures and ensuing retractions, Donath’s past PhD student Maedler was asked by the German Research Council DFG to surrender her prestigious Heisenberg professorship, while the German Diabetes Society (DDG) revoked her Ferdinand Bertram Prize from 2011 (read here). Since 2017, her PhD thesis is again under investigation of University of Zürich.

That diabetes research was also what made the career of Maedler’s own PhD student, Amin Ardestani, presently junior research group leader at the University of Bremen. His thesis received an award from the local Rotary Club, of course also Ardestani got a prize from DDG, which he also saw revoked for engaging into same activities as his Doktormutter. Still, he is still receiving awards, including from Elsevier. I will present below some data irregularities and unacknowledged textual reuse from Ardestani’s 2013 PhD thesis, which was supervised by Maedler.

Grandfather Donath

Marc Donath was the Doktorvater of Maedler, when she did her PhD at University of Zürich in Switzerland 2000-2003. With their common paper in Journal of Clinical Investigation (JCI), Maedler et al 2002, Maedler and Donath postulated the role for IL-1β in causing Type 2 Diabetes Mellitus. High glucose levels in blood make pancreatic islet cells produce that cytokine, which in turns kills them via apoptotic molecular pathway of the nuclear factor-kappaB (NF-kappaB). All you have to do to cure diabetes Type 2 is to treat patients with an inhibitor of IL-1β signalling pathway.

A clinical trial followed, sponsored by pharma company Novo Nordisk and with Donath as principal investigator, and published in elite journal NEJM as Larsen et al 2007, “Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus”. That study on 70 patients used an IL-1β antagonist Anakinra (which is a non-functional form of IL-1β) and found:

“In summary, our study suggests that antagonism of interleukin-1 has possible therapeutic potential in the treatment of type 2 diabetes. Further studies are needed to test higher doses of anakinra, to evaluate its long-term use, and to test interleukin-1 antagonists that have a prolonged half-life, with the aim of preventing beta-cell destruction and promoting beta-cell regeneration in type 2 diabetes”.

This was the conflict of interest declaration:

“Dr. Donath is listed as the inventor on a patent (WO6709) filed in 2003 for the use of an interleukin-1–receptor antagonist for the treatment of or prophylaxis against type 2 diabetes. The patent is owned by the University of Zurich, and Dr. Donath has no financial interest in the patent”.

The discovery was indeed patented to the University of Zürich, yet it is not entirely true that Donath has no financial interest in it. As the journal PNAS, where Donath published a preclinical study Ehses et al 2009 on diabetic rats using IL-1 receptor antagonist (“kindly donated by Amgen”), explained after contacting Donath:

“He says that the patent family is owned by the University of Zurich and not by the author personally. As an inventor he receives from the University of Zurich an adaptation of his salary based on licensing and other scientific achievements. Otherwise he said he does not receive financial compensation on this invention”.

Adaptation of his salary means Donath’s salary as professor in Zürich was expected to rise proportionally to the revenue his invention generated. This was however Donath’s COI declaration in PNAS:

“M.Y.D. is a consultant for Amgen, XOMA, Novartis, Merck, Solianis, and Nycomed. M.Y.D is listed as the inventor on a patent (WO6709) filed in 2003 for the use of an interleukin-1 receptor antagonist for the treatment of or prophylaxis against type 2 diabetes. The patent is owned by the University of Zurich, and M.Y.D. has no financial interest in the patent”.

Fantastic talk from Marc Donath on the duel role of IL-1 in metabolism & metabolic disease at #isi2017 #IrishImmunology #sciencerising pic.twitter.com/dAilZBwtta

— O'Shea & Hogan Lab (@OSheaHoganLab) September 17, 2017

After the phase 1 trial in NEJM, Donath partnered with the biotech company XOMA, which announced in 2007 two clinical trials to test its product XOMA 052, which is a monoclonal antibody against IL-1β. The phase1/2 trial in US recruited 68 participants and completed in February 2010. The European phase 1 clinical trial for XOMA 052 was run in Zürich by Donath himself, involved 38 participants and concluded at the same time. No results were posted for any of those two trials on the ClinicalTrials.gov website.

Whatever Donath foudn out an dis not telling, a huge clinical trial named Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) with over 10,000 patients and using an anti-IL-1β antibody Canakinumab was initiated in 2011 by the pharma giant Novartis Pharmaceuticals in the United States. Its data is still being evaluated, with last results expected by 2020. The main focus is obviously not finding a cure for diabetes, but to see if IL-1β inhibition can “prevent recurrent cardiovascular events”.  The substudy 2 of CANTOS specifically recruited well-controlled Type 2 Diabetes patients and measured their the glycaemic index in response to Canakinumab. Results of a related earlier phase 1 clinical trial with 556 participants, published in 2012 in the journal Circulation, Ridker et al 2012, suggested what effect was to be expected for diabetes therapy, namely exactly none:

“Similarly, among these individuals with relatively well-controlled diabetes mellitus at baseline, there were no statistically significant effects of canakinumab on the change in plasma glucose, fasting insulin, or in calculated values for the change in homeostatic model of assessment of insulin resistance at 4 months”

Now, to analyse the results of the huge phase 3 clinical trial CANTOS, the authors of Ridker et al 2012 teamed up with the discoverer of the IL-1β-based diabetes cure himself, Marc Donath. The great man assured the peer community in May 2017 via Retraction Watch that Maedler et al JCI 2002 paper was scientifically solid and the postulated IL-1β role in Type 2 diabetes a scientific fact:

“the main findings of this publication have been reproduced by around 50 independent follow up publications. I am aware that 2-3 groups claimed that they cannot reproduce it [e.g, Cnop et al 2005,-LS], but the technical issues underlying these differences can be easily addressed and have been partly published…. Last but not least, more than 12 clinical studies have confirmed the findings”

Not even a year later, Donath and CANTOS investigators published a common paper in March 2018 in Journal of the American College of Cardiology, Everett et al 2018. The findings of CANTOS, featuring over 4000 diabetes patients and almost 5000 pre-diabetic participants:

“In spite of these significant, dose dependent reductions in inflammation with canakinumab, IL-1 β inhibition did not reduce rates of new onset diabetes, a major pre-specified secondary endpoint of CANTOS. […] The use of physician reported diabetes as an endpoint yielded similar neutral results (Table 1 and Online Figure 1). We repeated these analyses in the subgroup of patients with normal glucose at study entry (Online Table 6) and saw no benefit of canakinumab on rates of new onset diabetes. We also found no evidence that compared to placebo, canakinumab reduced the risk of new onset diabetes. […] contrary to our protocol pre-specified hypothesis, IL-1 β inhibition over a 5-year period did not limit the development of new onset diabetes. […]

IL-1 β inhibition did not reduce the risk of new onset diabetes in spite of significant reductions in hsCRP and IL-6, a transient improvement of HbA1c, nor did it have long-lasting effects on glycemia among those with diabetes”.

Marc Donath in Trinity College Dublin describing the success of CANTOS /anti-IL1beta trial in many diseases pic.twitter.com/zV7ou6BDJ8

— Luke O'Neill (@laoneill111) September 15, 2017

There goes Maedler’s and Donath’s great discovery, out of the window. Donath basically very quietly distanced himself from his photoshopping doctoral progeny Maedler and everything he used to claim about their common discovery for over 15 years. One now also understands why Maedler saw the need to adjust the results of her seminal Maedler et al JCI 2002 paper in this way:

An internal investigation by the University of Zürich in 2015 officially found no misconduct on the part of Donath or Maedler (read here). Yet strangely, when the same year Donath was perfectly certain in becoming the next director of the university hospital’s Clinic for Endocrinology, Diabetology and clinical Nutrition, he was not even nominated (see this NZZ report). 15 Zürich professors, joined by 11 more Swiss clinical academics, wrote an angry open letter to the rector Michael Hengartner, protesting the “shocking” and “libellous” injustice done to such eminent a colleague who basically cured diabetes. To no avail.

Doktormutter Maedler

Donath then went to University of Basel, where he leads the clinic of Endocrinology, Diabetology and Metabolism. His past employer University of Zürich now began to investigate the PhD thesis of Kathrin Maedler which he supervised. Kurt Bodenmüller, responsible for Media relationship, wrote to me:

“Following a renewed accusation of scientific misconduct, an internal investigation regarding Kathrin Mädler at the University of Zurich was commenced at the end of 2017. At the moment, the allegations are being examined and it is not yet clear when the investigations will be completed”.

Uni-Professorin Kathrin Mädler erhält Paul Ehrlich- und Ludwig Darmstaedter-Nachwuchspreis 2012 http://t.co/9MMStolC pic.twitter.com/Cc3SaqC7

— Universität Bremen (@UniBremen) December 21, 2011

The University of Bremen made utter fools of themselves trying to defend obvious data manipulators in Maedler’s papers, as I described before. Maybe they really are convinced that Maedler is a misunderstood genius, and not a zombie scientist, whose husband Lutz Maedler is incidentally also professor at the same University of Bremen. Herr Maedler is head of the Institute for Material Science and endowed with enormous external funding (last year with €2.5 Million Leibniz Prize) which he in principle could easily take anywhere with him, for example should his family feel unwelcome at the University of Bremen. When humbly asked by his university what he might be missing there, Lutz Maedler said:

“I wish that the great tolerance in our department would involve the whole university: we are not all the same.”

Tried as they have (despite the scandal and zombie-status, Maedler only has two retractions, Shu et al, Diabetes, 2014 and Ardestani et al, JBC, 2011), University of Bremen could not make every Maedler equally happy. As I reported before, Kathrin Maedler’s Heisenberg professorship from DFG and even her 2011 Diabetes Award from DDG are now revoked. Anke Semrau, manager of the university’s rectorate, needed almost a whole month to assemble this reply to me:

“The University of Bremen is not involved into awarding of Prizes of German Diabetes Society (DDG). Hence we cannot provide any statement on the issues you reported”.

At least the university removed most of their outdated press releases, like those celebrating Maedler’s DDG award. Most, but not all: some are still stored here.

Maedler lab in Bremen currently lists quite a number of alumni, but not a single current PhD student or postdoc. The former star of German diabetes research seems left with one technician, supervised by her former PhD student and now junior group leader Ardestani.

Amin Ardestani @UniBremen on mTORC2 activity and signaling impairement in diabetic β cells. JMB Career Advancement Initiative #jmbCAI https://t.co/jr8HMX6aqR pic.twitter.com/SHDqXUAVIz

— J. Molecular Biology (@JMolBiol) March 12, 2018

Ardestani, the Junior

Amin Ardestani received his PhD, supervised by his Doktormutter Maedler, in 2013. The year after, he became junior group leader in her lab (his research is funded by the DFG till 2018). Of course also Ardestani took a hit from the Maedler affair. His paper in Journal of Biological chemistry (JBC), Ardestani et al 2011, was retracted for image reuse (that journal is not to be messed with).

Like his Doktormutter in 2011, Ardestani received in 2014 a career advancement award from the German Diabetes Society (DDG), sponsored by Sanofi-Aventis with €10,000 in cash.  The DDG press speaker Anne-Katrin Döbler now told me:

“Amin Ardestani was also stripped of the prize for the same reasons. The DDG has, however, refrained from reclaiming the prize money, as it was earmarked for research”.

Yet some scientists abroad trust Ardestani’s research with Maedler more than their envious ill-wishing peers in Germany. Just in 2017, this junior group leader received a cash award from the Endocrine Society, and in 2018 he was given JMB Career Advancement Initiative award by an Elsevier-published journal.

Being third-generation genius scientist (Doctoral son of Maedler, Doctoral grandson of Donath) and having have learned the skills, Ardestani obviously published in top journals also. His paper in Nature Medicine, Ardestani et al 2014, discovered another culprit for beta-cell demise in diabetes, namely the kinase enzyme MST-1. Just 2 months after that paper was published in Nature Medicine, Ardestani and Maedler patented Mst-1 inhibition as method to cure diabetes. Guess what competing financial interests the Ardestani et al 2014 paper declares?

“The authors declare no competing financial interests”

I informed the journal in December 2016 that they have been had, but apparently the Nature Publishing Group didn’t mind.

Ardestani’s doctoral thesis contains figures which also appear in his Nature Medicine paper and his patent with Maedler. Which, in itself, is perfectly normal. Not normal is that the experimental data appears having been re-used for obviously different experiments. This is new evidence I obtained just this week:

There is even more of this kind regarding this PhD thesis and the Ardestani et al Nature Medicine 2014 paper on PubPeer.

While Ardestani apparently incidentally rotated, cropped, contrast-adjusted and duplicated fragments of western blots in his publications, his PhD thesis also contains (certainly unintentional) text re-use from other sources which he did not co-author, here from Bremer et al 2006.

One can say, Ardestani was well taught by Maedler, Maedler was well taught by Donath, and this little entire academic dynasty deservingly became award-winning stars of diabetes research. So much for University of Bremen to be proud of.

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Update 18.02.2020

In January 2020, Maedler and Donath lost two more papers, Maedler et al 2006 and Maedler et al 2006 in the journal Diabetes by American Diabetes Association (ADA). From the retraction notices:

“In September 2018, ADA’s Panel on Ethical Scientific Programs (ESP) contacted the University of Zurich, the lead and corresponding authors’ institution at the time the research was conducted, to request an institutional investigation of concerns related to image manipulation and duplication in the article cited above. The University’s review is ongoing. 

The ESP has since coordinated an independent review of the anomalies cited in the expression of concern. On the basis of its review, the ESP has determined that the following instances of potential image duplication compromise the overall reliability of the study.”

Despite or maybe exactly because of these 2 new retractions, Marc Donath has been appointed Vice-Dean for Research, in this position he is now in charge of research integrity at the Medical Faculty of the University of Basel.

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