Lopez-Otin and Daley retract Nature Cell Biology paper

Boom, the 2015 Nature Cell Biology paper by the famous, award-winning and now fugitive Spanish cancer and ageing researcher Carlos Lopez-Otin and his US partner George Q Daley, stem cell titan and dean of Harvard Medical School, is retracted. That happens because correct original data was unavailable, prompted by a prolonged debate on PubPeer (which in turn followed my reporting on Lopez-Otin’s data integrity practices), which established that the figures do not match what the authors deposited as supplement.

The paper Soria-Valles et al 2015 established the role of the transcription factor protein NF-kB in cellular senescence and cell reprogramming, while offering a potential cure to child patients suffering from the deadly premature ageing syndrome, such as Néstor–Guillermo or Hutchinson–Gilford progeria. Under this premise, the impactful Nature-themed paper earned Lopez-Otin in 2017 an ERC grant of €2.5 million, for a project named “Deconstructing Ageing: from molecular mechanisms to intervention strategies“. Earlier this year however, Lopez-Otin abandoned his ERC funded lab at University of Oviedo and escaped to Paris, to stay with his Photoshop expert friend Guido Kroemer. If past behaviour is anything to go by, ERC will now probably again play three monkeys and pretend that Lopez-Otin is still in Spain and his grant-deciding Nature Cell Biology paper was never retracted.

Another Soria-Valles et al paper from Daley lab, which proposed a way to produce haematopoietic stem cells via iPS technology and save people with leukaemia, was meant to be already published, but it is not even submitted and might never be. This and the retracted study’s first author Clara Soria-Valles was a former PhD student of Lopez-Otin, funded by EMBO postdoctoral fellowship and delegated to the Harvard labs of Daley and his junior partner Thorsten Schlaeger, to learn cellular reprogramming technique. Daley and Schlaeger are reported to be all but ready to apply the blood cell making technique in the clinic, at Boston Children’s Hospital, but now nobody knows if Soria-Valles’ preclinical data is anywhere near reproducible.

It is indeed difficult to find out what results still might be reliable. Soria-Valles disappeared already in April 2018 on a medical leave, though Daley still pays her (neither Daley nor Harvard normally pays any medical leaves for other sick lab members). Nobody else on that manuscript is available, because the Schlaeger lab people involved also left since. Money to try and reproduce it is not an issue though: the research project was funded from Daley’s biggest grant, the NHLBI Progenitor Cell Translational Consortium (NIH U01), which is worth almost $50 million.

As I was informed, that Soria-Valles paper on haematopoietic reprogramming was meant to be originally submitted to the elite Cell family journal Cell Stem Cell (this is how the circulated draft was labelled in April 2018). Later on, roughly in August 2018, when my article appeared, the chosen target journal was Stem Cell Reports (published by International Society for Stem Cell Research, ISSCR). For someone like Daley this is a huge status reduction of journal venue. The results were presented earlier by Soria-Valles at the ISSCR annual meeting in 2017:

INTEGRATION-FREE SYSTEM FOR GENERATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS FROM HUMAN PLURIPOTENT STEM CELLS
Soria-Valles, Clara 1 , Sugimura, Ryohichi 1 , Kumar Jha, Deepak 1 , Lummertz da Rocha, Edroaldo 1 and Daley, George 2
1 Boston Children’s Hospital, Boston, MA, USA, 2 Stem Cell Program, Boston Children´s Hospital, Boston, MA, USA
The generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (PSCs) constitutes a valuable tool with promising applications for research and therapy. However, derivation of HSCs with in vivo long-term engraftment and multi-lineage potential remains elusive. We have described a combinatorial approach, based on the directed differentiation of hemogenic endothelium (HE) and transduction with five transcription factors (TF) (RUNX1, ERG, LCOR, HOXA5 and HOXA9) expressed in lentiviral vectors that allowed the conversion of human PSCs into hematopoietic stem
and progenitor cells (HSPCs). The resulted cells exhibited long-term and multi-lineage hematopoietic capabilities when injected into irradiated immune-deficient mice.
Despite this proof of principle, the engineered cells have a limited self-renewal capacity due to the integration of the transgenes and are still molecularly distinct from bona fide HSCs. Thus, in an attempt to achieve bona fide HSCs and make them safer for future therapeutic interventions, we have established integration-free systems that have shown comparable efficiency to the previously developed lentiviral strategy through in vitro and in vivo experiments. Therefore, this new method may overcome some limitations of the lentiviral approach and hold the key for future regenerative medicine advances in blood diseases.

Soria-Valles however was not present at the 2018 ISSCR meeting (a conference which I incidentally wrote about here, in a story about another dishonest stem cell researcher, who was set to be ISSCR 2018 keynote speaker). Nobody knows how much of Soria-Valles’ claim to make haematopoietic stem cells via iPS technology is still valid. Sources were quoted with estimates of too low a yield or even not sure of producing any haematopoietic stem cells at all. Yet just this September 2018, Daley spoke at a lecture at Dana-Farber-Institute of his future Stem Cell Reports paper and even of his plans to apply the method to treat paediatric patients with congenital bone marrow deficiencies, in particular Shwachman Diamond Syndrome and Diamond Blackfan Anemia.

But now back to the main subject, the Nature Cell Biology retraction. The journal warned readers on 4 October 2018 with an editorial note that “that the reliability of data presented in this manuscript has been the subject of criticisms“. 4 December 2018 was the deadline imposed by the publisher to submit signatures from co-authors for a retraction. Lopez-Otin’s Oviedo colleague Jose Maria Perez Freije collected the signatures of all authors, including the elusive Soria-Valles, and submitted them to the publisher Nature.

This is the retraction notice:

“We, the authors, are retracting this Article due to issues that have come to our attention regarding data availability, data description and figure assembly. Specifically, original numerical data are not available for the majority of the graphs presented in the paper. Although original data were available for most EMSA and immunoblot experiments, those corresponding to the published EMSA data of Supplementary Fig. 8a, the independent replicate immunoblots of Fig. 8b and Supplementary Fig. 1e, and the independent replicate EMSA data of Supplementary Figs 6e, 8b, 8c and 8d, are unavailable. Mistakes were detected in the presentation of Figs 3c, 4i and Supplementary Figs 6a, 8a, 8d, 9, and in some cases the β-actin immunoblots were erroneously described in the figure legends as loading controls, rather than as sample processing controls that were run on separate gels. Although we, the authors, believe that the key findings of the paper are still valid, given the issues with data availability we have concluded that the most appropriate course of action is to retract the Article. We deeply regret these errors and apologize to the scientific community for any confusion this publication may have caused. All authors agree with the retraction.”

This slide show illustrates the data issues mentioned in the retraction notice. 

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And this slide show illustrates the issues the retraction notice chose not to address at all. 

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In Daley’s lab, more things do not work as expected. His most famous Nature paper, Park et al 2008 , meant to compete with Shinya Yamanaka for induced pluripotency (iPS) fame and the Nobel Prize, is being plucked apart on PubPeer, accused of not having delivered any pluripotency as such. The exogenously delivered reprogramming transgenes remained namely active, while they were supposed to become silenced as cells’ own pluripotency genes become active. Also, Daley’s method of using Large T Antigen and telomerase TERT in addition to Yamanaka’s four iPS reprogramming factors proved rather counterproductive.

For someone like Daley, all of this is not the end of the world. There are always new windows of opportunity. Just as Chinese scientist Jiankui He caused a worldwide scandal with his unethical human experiments with CRISPR-modified babies, Daley (and his Harvard colleague George Church) offered a more enthusiastic view: America cannot afford a CRISPR gap to China. Daley suggested that Harvard should take the lead and apply CRISPR eugenics to ensure the survival of the human race:

“There have even been discussions that we as a species need to maintain the flexibility in the face of future threats to take the control of our own heredity.”

Harvard’s CRISPR experiments on human germ line editing are already starting. An Alzheimer’s associated gene is to be edited in human sperm, while Daley announced big plans to design the children of the future to be resistant to various diseases. Ethics is something this Harvard dean is apparently less interested in.

Harvard recently received a $200 million donation to set up a new institute, the money came from a controversial tycoon Leonard Blavatnik with Russian origins, whose lawyers made The Guardian apologise for erroneously calling him a “Putin pal” and an oligarch. 

It is Daley’s Spanish collaborator, the fugitive Lopez-Otin, who is in deep trouble with that retraction now. Lopez-Otin did manage to bring himself into news recently with his new paper (in a Nature -themed journal!) where his Oviedo lab analysed the genome of Lonesome George, the last member of his giant tortoise species who died in 2012. The press release omitted to say whether he spoke from Oviedo or Paris, Lopez-Otin the turtle geriatrics researcher was quoted with:

“We had previously described nine hallmarks of aging, and after studying 500 genes on the basis of this classification, we found interesting variants potentially affecting six of those hallmarks in giant tortoises, opening new lines for aging research” 

Nature now probably deeply regrets having awarded him with a 2017 Mentoring Award. Maybe they can give next one to Daley? Maybe Daley can get Soria-Valles to CRISPR some of those turtle genes to create a new long-lived human race of Homo harvardiensis crispri?

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Update 21.12.2018. My article was apparently well received in Harvard, according to this information I was privy to:

“Daley was complaining intensely at lab meeting in front of entire lab and his junior faculty labs (Trista North and Thorsten Schlaeger) about potential lab members who might have leaked Soria-Valles information to the German blogger. It was intense”

I also learned that the now retracted Soria-Valles Nature Cell Biology 2015 paper was originally submitted to Science, were it was rejected due to some statistics issues.

Update 5.01.19. I was recently alerted by a source:

“George [Daley, -LS] has scared the lab members and provoked Stockholm syndrome among members. The Daley lab is trying to figure out who the leaks are now. Some of the members are trying to crash the German website by sending Hakenkreuz images.”

This was exactly what happened. Commenters used several fake identities to post highly defamatory comments about Daley on my site, equalling his research to Macchiarini’s trachea transplants and, indeed, using Nazi Swastika armband photoshopped on a photo of Daley. Exactly same picture was shared by Daley lab members in preparation of the campaign, it was confirmed to me. I deleted all those comments, but made backup, also of IP addresses.

Specifically, those IP addresses were located in US to Connecticut, 06902 Stamford, and New York State, 10022 New York. My source suggested I contact these Daley lab alumni: In-Hyun Park at Yale, CT, and Kitai Kim at MSKCC in NY, as well as the person allegedly orchestrating the campaign, the current Daley postdoc Deepak Jha. None of them replied, but Jha immediately blocked me on Twitter. This is how some grown men behave to please their mighty (ex-)boss. Maybe they should rather relax and read the book by Daley’s wife, Amy C. Edmondson, “The Fearless Organization: Creating Psychological Safety in the Workplace for Learning, Innovation, and Growth“.

Daley will be opening the Blavantik institute in ceremony on February 5th, at 5:30 PM. Come to talk about plans of CRISPR babies!

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