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Mr. ACE2 Josef Penninger, Greatest Scientist of Our Time

By July 22, 2020No Comments

Josef Penninger is a polymath scientist with many genius ideas but only two labs, on different continents. He is the biggest science star Austria has today, or maybe of all times. Almost 20 years before the COVID-19 pandemic, the magazine Esquire brought this prescient portrait of the young Wunderkind and his scientific genius:

The Greatest Scientist of Our Time

“Josef Penninger is thirty-six. He’s the son of Austrian farmers. He’s saved the world once. He’s on the verge of saving it again. And his greatest discovery is just around the corner. He’s going to save you.”

Little did they know back in 2001 that the now 55-year-old Josef Penninger will save the entire humanity from the coronavirus. And other diseases: cancer, obesity, heart attack, stroke. Everything.

Dr Penninger used to be director of the Institute of Molecular Biotechnology (IMBA) in Vienna, Austria,until the University of British Columbia in Vancouver, Canada made him a better offer. He does all of the biomedicine: virology, microbiology, immunology, genetics, cancer and cardiovascular research, neuroscience and brain diseases, regenerative medicine and stem cells, osteoporosis, diabetes and obesity, you name it, he solved it and published in Nature or Cell.

Much of Penninger’s research in the last decades was about the angiotensin converting enzyme 2 (ACE2), which was eventually discovered to be the target of the SARS virus, and then of course of SARS-CoV2, the COVID-19 pandemic causing coronavirus. Penninger is credited with discovering the ACE2 receptor in 1990ies. He explains about the SARS-CoV2:

Many, including myself, realized that the new virus is a very close sibling of the first SARS coronavirus. It was very clear to me that the receptor for this new virus would be ACE2, which I discovered as a young investigator in the 1990s, was a receptor for the first SARS coronavirus. For about a decade after the first SARS breakout, I was known as Mr. ACE2!

APN01, COVID-19 crusher

It seems, Professor Penninger has now found the cure for SARS-CoV2, published as Monteil et al Cell 2020. A soluble version of the ACE2 receptor, called APN01, was deployed on monkey Vero-6 kidney epithelial cells, and also on embryonic-stem cell derived clumps of vascular epithelium cells, or “mini-organs”, as Nature called them, and dramatically reduced the infection rate of the coronavirus. Penninger was quoted:

We are hopeful our results have implications for the development of a novel drug for the treatment of this unprecedented pandemic […] Our previous work has helped to rapidly identify ACE2 as the entry gate for SARS-CoV-2, which explains a lot about the disease. Now we know that a soluble form of ACE2 that catches the virus away, could be indeed a very rational therapy that specifically targets the gate the virus must take to infect us. There is hope for this horrible pandemic.

Clinical trials with the APN01 drug, patented by Penninger and marketed by his Vienna-based company Apeiron Biologicsstarted immediately in Austria (and another one in China). In Austrian media, Penninger said that this discovery finally brings him close to the long-deserved Nobel Prize.

A new promising drug, hurray, I hear you exclaim? Well, almost new. Second-hand, or pre-used drug, if you like. In 2010, same company Apeiron licenced same APN01 as therapy for acute lung failure to the pharma giant GlaxoSmithKline (GSK) for €239 Million, with €12.7 million paid upfront. Prior to that, a safety and tolerability trial for this drug was completed in Austria in 2009, but no results were posted so far. After APN01 was exclusively licenced to GSK, it became GSK2586881, for that there are 3 trials listed on One, done in Germany for “Acute Hypoxia and Exercise”, was terminated, not a good sign. Another refers to the two-part phase II trial by GSK in ten intensive care units in USA and Canada, and there is a relevant paper about that trial, Khan et al Critical Care 2017. It aimed to prevent lung injury in patients with acute respiratory distress syndrome (ARDS) and concluded:

GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.


GSK2586881 infusions did not result in improvement in physiological or clinical measures of ARDS“.

Obviously, GSK investigators were disappointed with the drug’s performance, because “continued recruitment was not justified, and the trial was terminated early“. As adverse effects were observed “hypernatremia; pneumonia; dysphagia; and, in particular, rash“.

That does not sound promising for COVID-19 therapy. Not really. I mean, knowing these results, is it really reasonable or responsible to continue treating COVID-19 patients, whose typical symptom and cause of death is ARDS, with APN01?

Yes it is. APN01 is being trialled once again, in phase 2 clinical trial on 200 COVID-19 patients in Austria (the Chinese trial’s permission was withdrawn, and no new one is registered). This time the trial’s sponsor is not GSK but Penninger’s Apeiron Biologics, a company with 20 employees. The reader may be confused here, since I wrote that 10 years ago Apeiron sold the “exclusive licence” on APN01 to GSK. How can Apeiron run trials with a drug they no longer own? Well, GSK gave the licence back in 2019, and it stopped being GSK2586881 and became Penninger’s drug APN01 again. They didn’t even bother to follow up on the data from their third trial with 23 patients, for pulmonary arterial hypertension, which results were posted in April 2020, long after GSK gave Penninger the APN01 licence back.

The Austrian visionary, eager to test APN01 for COVID-19, announced clinical trials in Germany and Denmark, in addition to Austria. He also spoke of his Monteil et al Cell 2020 paper:

The team’s findings hold promise of an early vaccine for COVID-19

In German media, the Genius has been quoted:

We know the drug is active and it is relatively safe, so you can use it. Now we have to test it on Covid 19 patients

Relatively safe”? Is this why the 2009 trial results were never released? What about adverse effects and lack of clinical efficiency which GSK reported? Does APN01 only work when its inventor himself applies it? Why did GSK give the licence back, having paid so many millions? Is it a conspiracy of Big Pharma against the Genius? I think it must be, what other explanations might you have, dear reader?

Colon cancer gene and heart-eating bacteria

People call me and say, ‘I’m dying of cancer, can you give me that percent of this stuff comes through, that’s, enough. It gives them hope, and It should.

Dr Josef Penninger (2001)

Groundbreaking medical discoveries is what Dr Penninger does almost daily. Twenty years ago, Penninger discovered the cause and thus the potential therapy approach for colon cancer, namely the p110γ catalytic subunit of the phosphoinositide-3-OH kinase (PI(3)K). It was published in Nature, as Sasaki et al 2000. But in August 2003, a correction was published:

However, after backcrossing these mice onto a C57BL/6 background, we now find that the tumour phenotype has disappeared. Also, when we retargeted the allele in different ES cells using the same targeting construct, no tumours developed.

Which, dear failed scientists and layman readers, means in Nature-publishing academic circles that the main conclusions of this study are not affected. The German newspaper Zeit wrote in 2015:

“Penninger announced a sensation 15 years ago: he had found the gene that blocks colon cancer. Mice in which it was switched off fell ill. However, other laboratories were unable to reproduce the discovery, and other data were also criticized. Did he dribble too much? A commission cleared his team of all allegations. Penninger wept with relief, but the soil in Canada was poisoned.”

As it turned out, the investigation was performed not by a university, but by the pharma giant Amgen, which used to own the research institute Penninger and his then-boss Tak Mak worked in. The investigation happened after Mak accused Penninger of “cheating” who kept insisting that “Our mice got colon cancer. That we know. End of story“, as narrated in this article by MACLEANS magazine. Three scientists whose labs failed to reproduce Penninger’s colon cancer results submitted evidence in writing, but the Amgen commission refused to interview them. The records of the internal Amgen investigation are secret, but:

“The unanimous conclusion, announced to the University of Toronto medical community in June 2002: total exoneration. Penninger’s lab displayed “scientific rigour and good laboratory practices” and “allegations to the contrary were unfounded.”

For some reason, some months before that announcement Amgen completely severed its financial support for the Toronto research institute, while insisting that had nothing to do with Penninger affair.

It wasn’t just about the colon cancer in Nature. There was also heart disease in ScienceBachmaier et al 1999. According to MACLEANS:

Mak flew to Stockholm for a conference. Immunologists there were saying they couldn’t duplicate several Penninger discoveries. Then Hans Wigzell, head of Sweden’s Karolinska Institute, which hands out the Nobel Prize for medicine and physiology, challenged one of the discoveries that had made headlines. In 1999, Penninger said he had found the first biological proof that the bacterium chlamydia could cause heart disease. It was big news because scientists had long suspected a connection, but hadn’t been able to prove it.

But Wigzell was puzzled. His group had injected mice with chlamydia and hadn’t noticed any heart disease. Later Wigzell would retrace Penninger’s exact steps, even using a tiny bit of protein from Penninger’s lab. “We saw nothing,” he says. In Toronto, alarm bells were sounding. Why were so many scientists saying they couldn’t duplicate Penninger’s work?

Another Penninger discovery was that Helicobacter pylori, the bacterium which cause ulcers and cancer in the stomach, was also the cause of colon cancer, or so Penninger claimed, speaking of “a vaccination against colon cancer!”. The scientific community remained unconvinced, thus Penninger lost interest also and refused to publish on the topic ever again.

But mediocre losers, haters and failed scientists kept pestering the Genius. Penninger was quoted by MACLEANS with “People in other hospitals were emailing my [researchers]: ‘Oh, I hear you’re retracting your papers.’“. Luckily, science is self-correcting, and this is why no papers of Penninger’s were ever retracted. The chlamydia paper in Bachmaier et al Science 1999 was never even corrected, because there was no need.

Back then, Penninger was academically affiliated with the University Health network (UHN) and the University of Toronto , which he decided to punish by leaving in summer 2002, just when the Amgen investigation fully exonerated him and more than a year before the peculiar correction to his Sasaki et al Nature 2000 paper was published. The Canadian newspaper Globe and Mail reported:

But he told no one beyond a small circle of friends that he was prodded to go by what he felt was an assault on his reputation against which neither the UHN nor the University of Toronto faculty of medicine was defending him. He is an associate professor in the university’s department of medical biophysics.

Colleagues said he is also upset by a toxic relationship he had with his boss and former mentor, Tak Mak, 55, director of the Amgen Research Institute, which operated in UHN.

Conspiracies is what geniuses often suffer from their scheming detractors, and Canada’s loss became Austria’s gain. Penninger returned to Vienna to become the founding director of the newly established Institute of Molecular Biotechnology (IMBA). Maybe the pond was too small for such a big fish after all, because Zeit mentions that in 2015 Penninger was negotiating with the Max-Delbrück-Centrum in Berlin, to become the scientific director of that German institute. Unfortunately, the old cheating allegations from Canada were brought up again, which Penninger described as “unfair”. In 2018, Penninger returned to Canada, this time to University of British Columbia, under the elite Canada 150 Research Chair Programme, which recruits the best of the best in science. Professor Penninger now runs both labs, in Vancouver and in Vienna, very productively so.

We are now back in 2020. Just weeks after his COVID-19 breakthrough which of course will save the humanity, Penninger published another Cell paper, Orthofer et al 2020, which solved another plague of human civilisation: obesity. The Austrian polymath found the gene for thinness, ALK. This time, it will definitely be 100% reliable, unlike with the colon cancer gene or the heart-eating chlamydia. The solution to the obesity epidemic is nigh, Penninger already patented it: “The agent may be, for example, a ALK antagonist or inhibitor, or the agent may decrease the level of ALK in a cell“.

Guido and Josef, friends forever?

I myself, just as the next man on the street, sincerely hope that Professor Penninger’s discoveries, in particular APN01, are all correct and that all his envious haters will be proven wrong, put to shame and subjected to their due punishment, as severe as humanely possible. I mean, everyone says he is a genius, right? But then again, we are what our friends are.

One friend and scientific collaborator of many years is Guido Kroemer, German-born and France-based scientist and a star of cancer and ageing research. Together, the two friends planned already in 1998 to rid the world of cancer, heart and brain and all other diseases, by targeting the apoptosis gene AIF they together have cloned. It could have worked, maybe if enough Photoshop power was deployed.

Like Penninger, Kroemer was long considered a genius, but his reputation has been tarnished in later years what with the currently SIXTY papers flagged on PubPeer for data irregularities. Several of these papers were co-authored by Penninger, three of these were presented in this article, more follow below. The two friends are both members of the German Academy of Sciences, Leopoldina, and in 2008 they simultaneously received the prestigious Carus Prize from the Academy.

Right to left: Carus-Prize awardees Josef Penninger and Guido Kroemer, with Schweinfurt mayor Gudrun Grieser and Leopoldina President Volker ter Meulen. Original photo source: Mainpost.

I wrote about Kroemer before, in particular about his other best friends, the Spanish ageing scientist and martyr Carlos Lopez-Otin, and Didier Raoult, the French genius microbiologist who is presently also saving the world from COVID-19, but with chloroquine instead of ALN01. On 2 March 2020, Raoult and Kroemer proclaimed in an editorial:

Yet unconfirmed reports indicated that inhibitors of SARS-CoV-2 replication includ-ing chloroquine are clinical efficient against declared SARS-CoV-2 infection

The rest, as you know, is history happening before out very eyes.

In his own way, Guido Kroemer is the centre of the world. Which is why I will finally show you some papers Kroemer and Penninger co-authored.

Miramar DM, P Costantini, L Ravagnan, LM. Saraiva, De Haouzi, G Brothers, JM. Penninger, ML Peleato, G Kroemer , SA. Susin NADH oxidase activity of mitochondrial apoptosis-inducing factor Journal of Biological Chemistry (2001) doi: 10.1074/jbc.m010498200

Copy-pasted bands (see boxes and arrows), twice in one figure. Granted, it is a collaborative paper with Kroemer’s institute colleague in Paris, Santos Susin. There are four more Susin & Kromer joint papers which can be used as teaching material on what should justify an immediate retraction. The next paper has Penninger as last author:

Pospisilik JA, C Knauf, N Joza, P Benit, M Orthofer, PD. Cani , I Ebersberger, T Nakashima, R Sarao, G Neely, H Esterbauer, A Kozlov, C.R Kahn, G Kroemer, P Rustin, R Burcelin, JM. Penninger Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes Cell (2007) doi: 10.1016/j.cell.2007.08.047

Even if the gel was vertically compressed before accidental duplication which made it look different, Professor Penninger should still consider a correction. But then again, it’s just loading control, who cares, right? Not in Austria for sure. Same problem:

Perfettini JL, T Roumier, M Castedo, N Larochette, P Boya, B Raynal, V Lazar, F Ciccosanti, R Nardacci, J Penninger, M Piacentini , G Kroemer NF-kappaB and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope The Journal of Experimental Medicine (2004) doi: 10.1084/jem.20031216

And other accidental gel duplication:

Vahsen N, C Candé, JJ Brière, P Bénit, N Joza, N Larochette, PG Mastroberardino, M O Pequignot, N Casares, V Lazar, O Feraud, N Debili, S Wissing, S Engelhardt, F Madeo, M Piacentini , JM Penninger, H Schägger, P Rustin, G Kroemer AIF deficiency compromises oxidative phosphorylation The EMBO Journal (2004) doi: 10.1038/sj.emboj.7600461

Three more Kroemer & Penninger papers, with rather unpleasant gel band duplications, were discussed in my previous article. But now I would like to show you some papers without Kroemer, but with Penninger.

The first one, in PNAS, proved something cool. Penninger, whose genius led him to discover simple causes for cancer, heart failure, or obesity has discovered that male aggression is controlled by just one gene: RGS2. The claim is bold, this is why it needed to be published without independent peer review, but “Communicated by Alfred G. Gilman“, where this member of National Academy of Sciences and two other friends he and Dr Penninger invited, gave thumbs-up.

Oliveira-dos-Santos AJ, G. Matsumoto, B.E. Snow, D. Bai, F.P. Houston, I.Q. Whishaw, S. Mariathasan, T. Sasaki, A. Wakeham, P. S. Ohashi, J. C. Roder, C. A. Barnes, D. P. Siderovski, J. M. Penninger Regulation of T cell activation, anxiety, and male aggression by RGS2 Proceedings of the National Academy of Sciences (2000) doi: 10.1073/pnas.220414397

Sure, this duplicated flow cytometry plot can be an accident. But why are the quantifications different, on the same file? More flaw cytometry:

Wada T, N Joza, HM. Cheng, T Sasaki, I Kozieradzki, K Bachmaier, T Katada, M Schreiber, EF. Wagner, H Nishina, JM. Penninger MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence Nature Cell Biology (2004) doi: 10.1038/ncb1098

Once again, why are the numbers different if the file was accidentally reused? Should not have happened if same setting were applied for all samples of the experiment. But then again, Nature journals are not that harsh in this regard.

Speaking of Nature. Gel splicing must be declared now, and in many old papers it is forgiven as historical. But in the following paper, the hidden splicing would make the entire result rather worthless. Except it doesn’t because the last author is Penninger, whose Nature papers from that era cannot be doubted (see above the Amgen announcement from 2002)

Bachmaier K, C Krawczyk, I Kozieradzki, YY Kong, T Sasaki, A Oliveira-dos-Santos, S Mariathasan, D Bouchard, A Wakeham, A Itie, J Le, PS. Ohashi, I Sarosi, H Nishina, S Lipkowitz, JM. Penninger Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b Nature (2000) doi: 10.1038/35003228

What is the point of the Spleen panel in Figure 1c, if all gels were done separately, and then spliced together? Same for Figure 5c, how much was really loaded of which sample and where? Why even presenting experimental data like this, instead of just drawing it with a felt-tip marker?

To conclude, a paper which was previously corrected, feel free to illustrate if for yourself.

Qi Y, X Tian, J Liu, Y Han, AM. Graham, MC Simon, JM. Penninger, P Carmeliet, S Li Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis The Journal of Cell Biology (2012) doi: 10.1083/jcb.201111063

2013 correction has been published:

“The actin panel in the original version of Fig. 5 B was flipped horizontally, and the Fig. 5 B and Fig. 6 C legends did not indicate the intentional duplication of the 3 and 4 d actin data. In addition, the HIF-2? panel in the original version of Fig. 7 C was a duplicate of the HIF-2? panel in Fig. 6 F. The authors have indicated that these issues were due to clerical errors during figure and manuscript preparation.”