Who killed Margarita Lorenzo’s reputation?

On 7 April 2010, the Spanish cancer researcher Margarita Lorenzo, professor of biochemistry at the Complutense University in Madrid, died of metastatic melanoma, aged 51. Some years after her death, her scientific legacy became tainted by massive research fraud found in her publications, while her former colleagues, mentees and regular co-authors not only deny having anything to do with the data forgeries, they even seem to be discretely pointing fingers at someone who cannot defend herself anymore.

I wrote about this affair already in 2018.

Three of these Lorenzo papers I wrote about, all originally published in the journal Diabetes, have been later retracted by the American Diabetes Association (ADA).

The retraction notice from September 2020 for Nieto-Vazquez et al 2007 went:

“After learning that certain representative immunoblot images in the above-cited paper may have been duplicated, authors Iria Nieto-Vázquez, Sonia Fernández-Veledo, Cristina M. Rondinone, and Ángela M. Valverde have decided to voluntarily retract the article. […]

Because the laboratory of the senior author, the late Dr. Margarita Lorenzo, was dismantled and closed immediately after her death in 2010, many of the original source files could not be found; therefore, it is not possible to fully assess the above-cited anomalies. As such, Drs. Nieto-Vázquez, Fernández-Veledo, Rondinone, and Valverde have decided that the best course of action is to retract this article. Dr. de Alvaro could not be reached to provide her input. The submitting authors of this statement regret this situation and apologize to the scientific community for any inconvenience this may have caused.”

The simultaneously issued retraction notices for Nieto-Vazquez et al 2008 and Garcia-Guerra et al 2010 sounded very similar, all referring to absence of raw data due to Lorenzo’s death.

The affair is somewhat similar to that of the deceased Israeli diabetologist and immunologist Ofer Lider, who also died from cancer, and whose papers were also tainted by falsified data. Some of these papers were even published after Lider’s death, and two were retracted. It seems that Lider’s lab members and his own PhD mentor Irun Cohen may have played a role in the research misconduct, because big money with a bullshit diabetes drug had to be earned.

But the Lider retractions never dared to point fingers at the deceased. Unlike the retractions for Lorenzo papers, which all insisted that the Lorenzo’s authors were nothing but innocent and clueless outsiders: “after her death in 2010, many of the original source files could not be found; therefore, it is not possible to fully assess the above-cited anomalies“.

Are they blaming their deceased mentor here? This is at least how I understand the retraction notices. For sure, Valverde wants nothing to do with the forgeries, as she told me via email (typos hers):

“I did not falsify the data on Dr Lorenzo´s paper. I participated in this study providing the mice and with advice. Nothing more. My possition is this paper was at the end. I totally promise this. I did touch any experiment in this paper.”

The Lilly Foundation in Spain, together with the Sociedad Española de Bioquímica y Biología Molecular (SEBBM), now issues a Margarita Lorenzo Award to early career biomedical researchers. There is exactly zero interest in Spain to do anything about the tainted papers. Certainly not from Lorenzo’s co-authors.

The main character of this farce, next to the deceased Lorenzo, is her PhD mentor, the Universidad Complutense professor Manuel Benito (who never replied to emails), and their former joint PhD mentee Angela Valverde, group leader at Instituto de Investigaciones Biomédicas “Alberto Sols”, also in Madrid. But to be fair, there are so many guilty parties that it is a lost case trying to figure out who faked what. It is certainly quite convenient to frame the deceased.

Benito is a God-like figure in Spanish diabetes research. His creative approach to biomedicine allowed him to invent a Type 3 diabetes, which he connected to Alzheimer’s disease, because grant money. In his own words: “the human amylin plaques generated in pancreatic beta cells are sent to the brain via exosomes, and there they aggravate brain neurodegeneration.” You might laugh, but Benito received the Alberto Sols Award 2019 from the Spanish Diabetes Society for just that.

Valverde is a much smaller fish than Benito, but still: she was elected as member to the Royal Academy of Pharmacy in 2021. In an interview some years ago, she said:

“Science does not stop, it works 24 hours a day, 365 days a year. Today, its techniques and technology are increasingly complex. The processes move faster and faster, and it is not easy to keep up. Also, things don’t always turn out, you don’t always have brilliant ideas.“

Oh yes, they always had brilliant ideas, and they always knew how to put the technology to good use.

Let’s start with an ancient classic.

Teresa TERUEL , Angela M VALVERDE, Manuel BENITO , Margarita LORENZO Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures Biochemical Journal (1996) – doi: 10.1042/bj3190627 

Why was the gel reused in a different context? This message from Valverde can probably describe what happened:

“I have noy any intention to falsify any data in all my life.”

Here another vintage classic.

Another gel reused to show utterly unrelated samples and experiments. But it’s just the loading control! Those were always allowed to be falsified, no? Another strange case:

Paloma Navarro , Angela M. Valverde, Jennifer L. Rohn, Manuel Benito , Margarita Lorenzo Akt mediates insulin rescue from apoptosis in brown adipocytes: effect of ceramide Growth Hormone & IGF Research (2000) doi: 10.1054/ghir.2000.0165

Jennifer Rohn, now professor at UCL London, replied:

“Thanks so much for flagging this up. I was a minor co-author on this paper. While working in my first postdoc, I was added as an author for helpful advice on the constructs they were using and detailed discussion about the methods of experimentation, although I was not involved in the experiments which took place in another country. The images you show above clearly look problematic. A quick search shows that the senior author is deceased, and I lost touch with the first author soon after the paper was published back in 2000 and can’t easily find her details. Hopefully the other authors, who were more associated with the senior author’s lab, will see this and reply, but if not I will take action.“

Dear Dr Rohn, a spoiler: your co-authors Angela M. Valverde and Manuel Benito most obviously DO NOT CARE. Because this is SPAIN. The perpetrators are always the first to play the real victims and decry being persecuted, if needed by racists, terrorists and inquisitors.

At least since the Carlos Lopez-Otin travesty circus, we know how miserably rotten the attitude to research ethics in Spain is. The national science elites not just failed, they proved to be the central enabling and performing part of the research fraud problem.

We saw how it worked in the Susana Gonzalez lab (also in Madrid). When her lab members left en mass and reported her for research misconduct, Gonzalez lost her research grants and was kicked out of science (she sued to retain her public service employment), as her former lab members were telling Spanish newspapers how Gonzalez used to teach them to fake data.

And the same story keeps happening in many Spanish labs. Young PhD students, naive and clueless, get trained by their dishonest professors in research misconduct. They fake data because their principal investigators tell them to do it and even show them how. Those who have a problem with this kind of education, can only quietly leave the lab and try again elsewhere. Like in this story:

Now, let me show you who we are dealing with in this sad Lorenzo affair. The following papers are all by Benito and Valverde, but without Lorenzo. I am sure the authors, when needed, will find a creative way to explain the manipulation and absence of raw data with Lorenzo’s death. If they even understand the concept of image data integrity, they are not the only Spanish biomedical researchers struggling with it.

For example, whose lab can be blamed for this fake gel? Certainly not Lorenzo’s.

Oscar Escribano, Mónica Arribas , Angela M. Valverde, Manuel Benito IRS-3 mediates insulin-induced glucose uptake in differentiated IRS-2−/− brown adipocytes Molecular and Cellular Endocrinology (2007) doi: 10.1016/j.mce.2006.12.039

Or this gel? Sure, it’s just the loading control.

C. Guillen, P. Navarro , M. Robledo , A. M. Valverde, M. Benito Differential mitogenic signaling in insulin receptor-deficient fetal pancreatic beta-cells Endocrinology (2006) doi: 10.1210/en.2005-0831 

Three authors here, one student and two principal investigators.

Carmen Nevado , Angela M. Valverde , Manuel Benito Role of insulin receptor in the regulation of glucose uptake in neonatal hepatocytes Endocrinology (2006) doi: 10.1210/en.2005-1663 

Same three authors, different fake paper.

Carmen Nevado , Manuel Benito, Angela M. Valverde Role of insulin receptor and balance in insulin receptor isoforms A and B in regulation of apoptosis in simian virus 40-immortalized neonatal hepatocytes Molecular Biology of the Cell (2008) doi: 10.1091/mbc.e07-05-0473

What shall we call that, innocent mistakes which don’t affect the conclusions? Is this the kind of science Benito used to discover Type 3 diabetes?

Angela M. Valverde , Cecilia Mur , Michael Brownlee , Manuel Benito Susceptibility to apoptosis in insulin-like growth factor-I receptor-deficient brown adipocytes Molecular Biology of the Cell (2004) doi: 10.1091/mbc.e03-11-0853 

Regarding the last two papers, Valverde explained:

“Leonid, the student [Carmen Nevado] was supervised by Dr Benito and me. The other student Cecilia Mur was also astudent supervised by both. Dr Benito and Dr Lorenzo were my mentors. I have never have intention to falsify. Please, believe me”

Oh I see, the students did it! Well, maybe they did, but they sure didn’t do it behind their supervisors’ noble backs. What if someone taught them to do science like this?

Agueda Gonzalez-Rodriguez , Jill E. Clampit , Oscar Escribano, Manuel Benito, Cristina M. Rondinone, Angela M. Valverde Developmental switch from prolonged insulin action to increased insulin sensitivity in protein tyrosine phosphatase 1B-deficient hepatocytes Endocrinology (2007) doi: 10.1210/en.2006-0644

There is more in that train wreck of a paper, for example:

More from Valverde, Benito et al.

Angela M Valverde, Deborah J Burks , Isabel Fabregat , Tracey L Fisher , José Carretero , Morris F White, Manuel Benito Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes Diabetes (2003) doi: 10.2337/diabetes.52.9.2239 

Another one, similar team of authors:

Mónica Arribas , Angela M Valverde , Deborah Burks , Johannes Klein , Robert V Farese , Morris F White, Manuel Benito Essential role of protein kinase C zeta in the impairment of insulin-induced glucose transport in IRS-2-deficient brown adipocytes FEBS Letters (2003) doi: 10.1016/s0014-5793(03)00049-8 

But then again, their US collaborator and Harvard professor Morris White has other issues on PubPeer, not just with Benito.

And here are our Spanish friends with the US titan of diabetes research, Carl Ronald Kahn. Kahn has a huge PubPeer record (over 50 papers), 3 retractions, and yet the scientific community is still on its knees kissing his bum, hoping for grant crumbles falling off Kahn’s table, and for Kahn to cure diabetes one day with his creativity.

Angela M. Valverde , Monica Arribas , Cecilia Mur , Paloma Navarro , Sebastián Pons , Anne-Marie Cassard-Doulcier, C. Ronald Kahn, Manuel Benito Insulin-induced up-regulated uncoupling protein-1 expression is mediated by insulin receptor substrate 1 through the phosphatidylinositol 3-kinase/Akt signaling pathway in fetal brown adipocytes Journal of Biological Chemistry (2003) doi: 10.1074/jbc.m209363200 

More fun with Kahn. This is the paper sharing blots with Valverde et al 2003, its first author Cecilia Mur (you met her before) is for 18 years already at Eli Lilly, researching drugs:

Cecilia Mur , Angela M. Valverde , C. Ronald Kahn, Manuel Benito Increased insulin sensitivity in IGF-I receptor–deficient brown adipocytes Diabetes (2002) doi: 10.2337/diabetes.51.3.743

Kahn, Kahn, give us more Kahn, I hear you cry? Here, knock yourself out, with Mur, Valverde, Benito and even Morris White from before:

Angela M. Valverde , Cecilia Mur , Sebastián Pons , Alberto M. Alvarez , Morris F. White, C. Ronald Kahn , Manuel Benito Association of insulin receptor substrate 1 (IRS-1) y895 with Grb-2 mediates the insulin signaling involved in IRS-1-deficient brown adipocyte mitogenesis Molecular and Cellular Biology (2001) doi: 10.1128/mcb.21.7.2269-2280.2001

More Kahn, you say? Can’t get enough?

Carmen Guerra , Paloma Navarro , Angela M. Valverde , Monica Arribas , Jens Brüning , Leslie P. Kozak , C. Ronald Kahn, Manuel Benito Brown adipose tissue–specific insulin receptor knockout shows diabetic phenotype without insulin resistance Journal of Clinical Investigation (2001) doi: 10.1172/jci13103

The German co-author Jens Brüning, director of a Max Planck Institute in Cologne, announced in August 2018 to me to have had no contact with Benito for over 15 years and promised to take care of this affair. In January 2019, this Expression of Concern was issued:

“A reader recently contacted the Editors regarding possible duplication of portions of the images presented in Figure 3, A–C, and Figure 4, A and B, that were used to represent distinct samples. The Editors have requested that the corresponding author provide the original data supporting these figures; however, these data are no longer available. As we are unable to evaluate the integrity of these figures, we are publishing this notice to alert readers to the concern.”

I was that reader, who informed the journal’s chief editor and research integrity expert Arturo Casadevall in July 2018. And I think that paper should have been retracted, but…. C Ronald Kahn is on it, so it won’t be retracted, get over it everyone. But then again, a year later I also suggested Casadevall corrects or even retracts his own papers, and he got very angry at me.

Whatever Valverde learned as Benito’s (and Lorenzo’s) PhD student, it sure advanced here career as independent group leader.

Águeda González-Rodríguez , Jose A. Más-Gutierrez , Mercedes Mirasierra , Antonio Fernandez-Pérez , Yong J. Lee , Hwi J. Ko , Jason K. Kim , Eduardo Romanos , Jose M. Carrascosa , Manuel Ros , Mario Vallejo , Cristina M. Rondinone , Ángela M. Valverde Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging Aging Cell (2012) doi: 10.1111/j.1474-9726.2011.00786.x

But, as Valverde told me:

“I promise that I did noy falsify the data.”

Not, of course not. She is busy training the next generation of Spanish biomedical elites.

Soledad Miranda , Águeda González-Rodríguez , Jesús Revuelta-Cervantes , Cristina M. Rondinone , Ángela M. Valverde Beneficial effects of PTP1B deficiency on brown adipocyte differentiation and protection against apoptosis induced by pro- and anti-inflammatory stimuli Cellular Signalling (2010) doi: 10.1016/j.cellsig.2009.11.019

Maybe this statement by Valverde can be used to explain what is going on (typos hers):

“I do not who is doing this, who is behind this. Papers were not manipulated, please believe me. Someone must want my scientific death. This is scaring Believe me please. I am a modest scientist.”

I raise no protest.

Jesús Revuelta-Cervantes , Rafael Mayoral , Soledad Miranda , Águeda González-Rodríguez , Margarita Fernández , Paloma Martín-Sanz, Ángela M. Valverde Protein Tyrosine Phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice American Journal Of Pathology (2011) doi: 10.1016/j.ajpath.2010.12.020

Same names, again and again. Valverde however is innocent:

“Please, believe me that there was any intention to falsify or fraud. Not at all”

She then corrected herself: “Sorry, I am very confused. I wanted to write that there was not any intention of fraud“. But I liked the first version more, to be honest.

Another joint study of Photoshop effect on liver physiology with Valverde’s institutional colleague Paloma Martin-Sanz:

Carmelo García-Monzón , Oreste Lo Iacono , Rafael Mayoral , Águeda González-Rodríguez , María E. Miquilena-Colina , Tamara Lozano-Rodríguez , Leonor García-Pozo , Javier Vargas-Castrillón , Marta Casado , Lisardo Boscá, Ángela M. Valverde , Paloma Martín-Sanz Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C Journal of Hepatology (2011) doi: 10.1016/j.jhep.2010.06.021

Finally, these two papers, and there is more from Valverde’s lab on PubPeer.

Valverede’s last message to me was:

“If necessary I will get legal advice.”

Benito never replied to emails. And it’s not like he needed Valverde to get the results he needed:

Alberto Bartolomé , Carlos Guillén , Manuel Benito Role of the TSC1-TSC2 complex in the integration of insulin and glucose signaling involved in pancreatic beta-cell proliferation Endocrinology (2010) doi: 10.1210/en.2010-0048 

Sure, an innocent duplication, an honest mistake. Give Benito another award.

Amparo Valladares , Cesar Roncero , Manuel Benito , Almudena Porras TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK FEBS Letters (2001) doi: 10.1016/s0014-5793(01)02264-5 

Or here, with same Almudena Porras, now department head at Universidad Complutense:

Álvaro Gutiérrez-Uzquiza , María Arechederra , Isabel Molina , Rocío Baños , Vera Maia , Manuel Benito, Carmen Guerrero , Almudena Porras C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death Cellular Signalling (2010) doi: 10.1016/j.cellsig.2009.11.008 

Again, Porras, plus Angel Nebrada from IRB Barcelona, a not really angelic character with currently quantitatively still modest, but qualitatively quite scary PubPeer record.

Almudena Porras, Susana Zuluaga , Emma Black , Amparo Valladares , Alberto M. Alvarez , Concetta Ambrosino , Manuel Benito , Angel R. Nebreda P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli Molecular Biology of the Cell (2004) doi: 10.1091/mbc.e03-08-0592

It is a mess. I kind of agree a misconduct investigation is pointless, too many are involved and it goes to the very top. Guess the others will blame Lorenzo here also, if pressed?

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