Jan and Ricky, two blind mouse ophthalmologists

Yet another case of bad science in Australia. This time, the forged ophthalmology papers served to bring the money to the authors’ company and run clinical trials on patients, while the authors insist to have no financial conflicts of interests whatsoever. Director of research Riccardo Natoli hides behind his mentor and former dean Jan Provis, who is now fighting to save his career and their papers.

Jan Provis is Emeritas Professor of Anatomy and former Associate Dean for Research at the School of Medicine and Psychology of the Australian national University (ANU). She is (or used to be) also Chair of Retina Australia’s Grants Assessment Committee and member of the Scientific Advisory of the Ophthalmic Research Institute of Australia. For years now Provis chairs the board of a biotech named EYE CO Retinal Therapeutics, which celebrates her achievements:

“Her research team at the ANU pioneered the rodent light-induced model of photo-oxidative retinal damage, which is proving to be a very useful model for investigating therapeutic approaches for the management of dry AMD. She has a track record in leadership, mentoring of early career scientists and research consultancy.”

One of her extremely successful mentees is Riccardo Natoli, who made it to associate professor and Associate Director for Research at ANU’s School of Medicine and Psychology, and since earlier this year member of EYE CO’s scientific advisory board. Natoli’s institutional website at ANU informs:

“My work using miRNA and EV to understand and treat this disease is funded by competitive funding agencies (including multiple NHMRC Ideas and Project Grants), industry partnerships, philanthropic funding and a prestigious ANU Translational Fellowship. […]
In 2019 I received a Tall Poppy Award in recognition of my scientific excellence and achievements in the fields of vision sciences.

Provis’s pioneering research and Natoli’s scientific excellence and achievements are indeed unmatched:

Riccardo Natoli , Matt Rutar , Yen-Zhen Lu , Joshua A. Chu-Tan , Yuwei Chen , Kartik Saxena , Michele Madigan , Krisztina Valter , Jan M. Provis The Role of Pyruvate in Protecting 661W Photoreceptor-Like Cells Against Light-Induced Cell Death Current Eye Research (2016) doi: 10.3109/02713683.2016.1139725 

The ophthalmologist Provis complained of poor eyesight:

“This appears to be a simple human error made during selection of panels for the plate. There is no advantage to be gained deliberately duplicating the image. The quantitative data indicate there should be about 50% fewer apoptotic figures in the control E, compared to light damage J. Not so easy to see these things when preparing figures. The error doesn’t change the findings of the study.”

Provis’s strategy is to quickly publish corrections to have the issue legally closed. As she currently tries here, because obviously millions of dollars are invested into her ophthalmology research for no other reason but the sole entertainment of one person playing the editor at some commercial journal:

Joshua A Chu-Tan , Nilisha Fernando , Riemke Aggio-Bruce , Adrian V Cioanca , Krisztina Valter , Nektaria Andronikou , Xavier DeMollerat Du Jeu , Matt Rutar , Jan Provis , Riccardo Natoli A method for gene knockdown in the retina using a lipid-based carrier Molecular vision (2020) 26:48-62

In September 2024, Provis warned on PubPeer:

“An erratum process is underway as of Sept 26“

It hasn’t materialised yet. Provis did succeed here:

Tanja Racic , Andrew Chang , Nilisha Fernando , Alice Brandli , Riccardo Natoli , Philip Penfold , Jan M. Provis , Matt Rutar Anti-inflammatory and neuroprotective properties of the corticosteroid fludrocortisone in retinal degeneration Experimental Eye Research (2021) doi: 10.1016/j.exer.2021.108765 

What also might need a correction is that Provis, Penfold and Natoli lied about their conflicts of interests in this paper. And it seems, this happened in other appers, certainly in most if not all preclinical ones! For example, the Racic et al 2021 study declares:

“Declaration of competing interest No conflicting relationship exists for any author.”

As I mentioned, Provis is since at least 2019 Chairman of the Board of Directors of EYE CO Retinal Therapeutics (EYECO PTY LTD). The biotech’s main product is fludrocortisone (what the Racic et al 2021 advertises for), it just passed phase 1 safety clinical trial (Hong et al 2022), a phase 2 multicentre clinical trial received an ethics approval in September 2024. EYE Co was founded in 2006 by Provis’ close associate Philip Penfold, who is Director and Chief Scientist, and also coauthor of Racic et al 2021. Still, both Penfold and Provis declare to have “No conflicting relationship“!

Also Natoli has nothing to declare, indeed he only became EYE CO’s Scientific Advisory Board member in May 2024. But this is not the whole truth: Natoli was funded by EYE CO since at least 2019 , and Provis since at least 2013.

On the following study where EYECO-funded Natoli and his coauthors “declare that they have no competing interests“, Provis is not even coauthor. Yet she made sure that Natoli’s paper wasn’t retracted, but swiftly corrected instead:

Riemke Aggio-Bruce, Joshua A Chu-Tan, Yvette Wooff, Adrian V Cioanca , Ulrike Schumann, Riccardo Natoli Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration Molecular Neurobiology (2021) doi: 10.1007/s12035-020-02158-z 

The Correction from 20 September 2024 explained:

“The original version of this article unfortunately contained an error, specifically in Fig. 1, 3 and Supplementary Fig. 2.

The authors recently noticed that some incorrect representative images (Fig. 1d and 1e) appeared in the published article. These errors occurred due to incorrect image files being linked to the Figure files during manuscript finalisation following the review process and transfer from Molecular Neurodegeneration.

The representative images were correct in our original submission (Fig. 3d and 3e in the original submission) to Molecular Neurodegeneration (MOND-D-20–00326).”

On PubPeer, Provis blamed the journal editors for faking her pristine data behind her honest back:

“During revisions some Adobe Illustrator images, which had been adjusted for dissemination in an outreach brochure, were automatically linked and reinserted into the manuscript files undetected. There was no attempt to mislead although we acknowledge that more care should have been taken. The journal editors have confirmed that the original manuscript did not include these errors.“

As reminder, Provis is not a co-author of this study. Noteworthy, the Editor-in-Chief who allowed this bizarre correction is Benedict Albensi, who defends fraudsters by crying “targeted harassment!” on social media and who published dodgy science of his own. Read September 2022 Shorts and here:

Here, same experimental dataset was reused in 3 papers:

• Matt Rutar , Riccardo Natoli , Krisztina Valter , Jan M. Provis Early Focal Expression of the Chemokine Ccl2 by Müller Cells during Exposure to Damage-Inducing Bright Continuous Light Investigative Opthalmology & Visual Science (2011) doi: 10.1167/iovs.10-6010 (published April 2011)
• Matt Rutar , Riccardo Natoli , Peter Kozulin , Krisztina Valter , Paul Gatenby , Jan M. Provis Analysis of Complement Expression in Light-Induced Retinal Degeneration: Synthesis and Deposition of C3 by Microglia/Macrophages Is Associated with Focal Photoreceptor Degeneration Investigative Opthalmology & Visual Science (2011) doi: 10.1167/iovs.10-7119  (published July 2011)
• Matt Rutar , Riccardo Natoli , Jan Provis , Krisztina Valter Complement Activation in Retinal Degeneration Advances in Experimental Medicine and Biology (2012) doi: 10.1007/978-1-4614-0631-0_5 

Provis’s postdoc and corresponding author Matt Rutar recently made it to associate professor at University of Canberra and Honorary Senior Fellow of University of Melbourne. Krisztina Valter-Kocsi is associate professor at ANU.

The April 2011 paper in Investigative Opthalmology & Visual Science also shares image data with other papers by Provis, Natoli, Rutar and Valter:

• Riccardo Natoli , Nilisha Fernando , Michele Madigan , Joshua A. Chu-Tan , Krisztina Valter , Jan Provis , Matt Rutar Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration Molecular Neurodegeneration (2017) doi: 10.1186/s13024-017-0175-y 
• Matt Rutar , Riccardo Natoli , RX Chia , Krisztina Valter , Jan M Provis Chemokine-mediated inflammation in the degenerating retina is coordinated by Müller cells, activated microglia, and retinal pigment epithelium Journal of Neuroinflammation (2015) doi: 10.1186/s12974-014-0224-1 

In September 2024, Provis attested her critics to be some kind of idiots:

“The 2011 (ref [13])and the 2015 (ref [28]) studies are each referred to in the manuscript text in relation to identification of the cells that express Ccl2 and Cxcl1 (page 3), although they are not referred to in the Legend to Figure 3 in the 2017 study. A revised Figure legend has been submitted to the journal editors for their consideration. This is obvious if you READ the paper“

There were other issues in the 2015 paper:

What followed, was completely insane, because while ANU’s Associate Director for Research Natoli remained silent as a dead mouse, his patron Provis appointed herself as the “authorised spokesperson ” of the investigation. This Natoli paper incidentally also omitted his EYE Co funding (“The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.“):

Rakshanya Sekar , Yvette Wooff , Adrian V. Cioanca , Melan Kurera , Chinh Ngo , Si Ming Man , Riccardo Natoli Impairing Gasdermin D-mediated pyroptosis is protective against retinal degeneration Journal of Neuroinflammation (2023) doi: 10.1186/s12974-023-02927-2 

On 7 November 2024, Provis proclaimed on PubPeer:

“Clarification: I am the authorised spokesperson on this matter“

She did the same on other Natoli papers where she wasn’t not coauthor. The comments were however soon all deleted after I notified ANU.

This Natoli paper (“The authors declare no competing interests“) was flagged in June 2024 and corrected soon after by the “authorised spokesperson“:

Yvette Wooff , Nilisha Fernando , Josephine H C Wong , Catherine Dietrich , Riemke Aggio-Bruce , Joshua A Chu-Tan , Avril A B Robertson , Sarah L Doyle , Si Ming Man , Riccardo Natoli Caspase-1-dependent inflammasomes mediate photoreceptor cell death in photo-oxidative damage-induced retinal degeneration Scientific Reports (2020) doi: 10.1038/s41598-020-58849-z 

In October 2024, Provis triumphantly announced that an Author Correction has been published (on 16 September 2024):

“This Article contains a repeated error in the group of wildtype mice. The same group of wildtype mice was utilized as a comparison to multiple knockout models and presented the data across several figures. The baseline control images for these wildtype mice in healthy (referred to as dim-reared; DR) and diseased conditions (referred to as photo-oxidative damage (PD)), were used as a comparison to knockout models.”

The figure legends were changed. Also on this Natoli-authored preprint, published without declaring Natoli previous ascendance to Eye Co’s Scientific Advisory Board, Provis installed herself as “ the authorised spokesperson“:

Rakshanya Sekar , Adrian V. Cioanca , Yilei (Evelyn) Yang , Karthik Shantharam Kamath , Luke Carroll , Riccardo Natoli , Yvette Wooff Therapeutic potential of red blood cell-derived extracellular vesicles in reducing neuroinflammation and protecting against retinal degeneration bioRxiv (2024) doi: 10.1101/2024.08.06.606930 

Before announcing “I am the authorised spokesperson on this matter“, Provis resolved the matter by posting a revised manuscript version on bioRxiv with “Updated Supplementary Figure 3 with updated western blot 3E“.

Here, Provis forgot to step in and take over:

Chieh-Lin Stanley Wu , Adrian V. Cioanca , Maria C. Gelmi , Li Wen , Nick Di Girolamo , Ling Zhu , Riccardo Natoli , R Max Conway , Constantinos Petsoglou , Martine J. Jager , Peter J. McCluskey , Michele C. Madigan The multifunctional human ocular melanocortin system Progress in Retinal and Eye Research (2023) doi: 10.1016/j.preteyeres.2023.101187 

Same data published in three papers, Provis’s former postdoc Rutar in charge again:

• Riccardo Natoli , Elizabeth Mason , Haihan Jiao , Aaron Chuah , Hardip Patel , Nilisha Fernando , Krisztina Valter , Christine A. Wells , Jan Provis , Matt Rutar Dynamic Interplay of Innate and Adaptive Immunity During Sterile Retinal Inflammation: Insights From the Transcriptome Frontiers in Immunology (2018) doi: 10.3389/fimmu.2018.01666 
• Haihan Jiao , Matt Rutar , Nilisha Fernando , Ted Yednock , Sethu Sankaranarayanan , Riemke Aggio-Bruce , Jan Provis , Riccardo Natoli Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration Molecular Neurodegeneration (2018) doi: 10.1186/s13024-018-0278-0 
• Haihan Jiao , Jan M Provis , Riccardo Natoli , Matt Rutar Ablation of C3 modulates macrophage reactivity in the outer retina during photo-oxidative damage Molecular vision (2020) 26:679-690
• Riccardo Natoli , Haihan Jiao , Nigel L. Barnett , Nilisha Fernando , Krisztina Valter , Jan M. Provis , Matt Rutar A model of progressive photo-oxidative degeneration and inflammation in the pigmented C57BL/6J mouse retina Experimental Eye Research (2016) doi: 10.1016/j.exer.2016.04.015 

Provis again lamented her poor eyesight:

“Re-use of the Control and 1d images from 2016 is not ideal; the lead / senior authors would have had great difficulty spotting this without the assistance of AI, because the images show an absence of specific labelling. The lab has since introduced improved image management processes. There is no intention to mislead, and the matter is currently with the relevant journals. This mistake has no bearing on the findings of the studies.“

Once again, not just the images were accidentally reused, but also the quantifications of entire experiments:

Provis then explained that those TUNEL data merely “serves to illustrate“. Someone else commented, namely the Australian National University:

“The Australian National University (ANU) is aware of this matter and is investigating. The University does not comment on the details of individual investigations. ANU has robust policies governing research integrity. All research at ANU is governed by the Australian Code for the Responsible Conduct of Research. Further information on ANU processes can be found on our Research Integrity website.“

I received a similar reply from Ann Evans, ANU’s Acting Deputy Vice Chancellor Research and Innovation:

“Dear Leonid
The University does not comment on the details of individual investigations. If the University is made aware of any possible breaches of research integrity, they are taken seriously and appropriately investigated.”

Is Natoli really in trouble? Not likely, given that ANU’s Vice Chancellor Genevieve Bell adores him? Look at the X posts on the right, she just gave this beautiful young genius a “Vice-Chancellor’s Award” for his dashing excellence!

I asked Evans and Bell about the hidden financial conflicts of interests regarding EYE CO in all those ophthalmology papers by Provis and Natoli. Will this self-enriching malpractice be investigated? And what about Provis being former ANU dean of medicine and Natoli being Director of Research of the ANU medical school, and thus with all the right contacts and opportunities to interfere into a possible investigation of their papers? And Rutar, who is a professor at a different University now? Who will investigate his role?

Silence.

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