The Dutch-American biologist Jan van Deursen, who used to be a bigwig of cancer and ageing research until his forced resignation at the Mayo Clinic over accusations of bullying and discrimination, has sued me in a German court. The hearing was on 1 September, this is the contested article, the verdict was delivered to me on 21 September, I am to bear 2/3 of the costs. In between, van Deursen’s German lawyers of Hoecker tried to achieve a settlement with me, which small print would forbid me under a threat of a fine to ever mention van Deursen, or to write anything about his bullying, research reliability, forced resignation or lawsuits even indirectly again, I would be even explicitly forbidden from even quoting any publicly available sources. The settlement proposal, in all its versions, contained so many dangerous booby traps I still keep discovering them. Luckily, I declined, and received the court verdict just when this article went online. If you wish, you can donate here.
The Mayo Clinic in Rochester, USA, quickly deleted van Deursen’s profile pages without a trace right as he officially left on 24 July 2020. After his lawyer threatened me to never say his client would still pretend to be professor, I warned the company Unity Biotechnology, which van Deursen co-founded. Their founder’s page there swiftly changed.
It is this company’s drug pipeline which this article is about. Drugs, which were co-developed in a lab led by a bullying bigot and a choleric tyrant, denounced as such by several of his lab members. Drugs, to market which Unity Biotech once raised gigantic sums and is now, after a spectacularly failed phase 2 clinical trial, is mass-dismissing personnel for, to stay afloat having lost 60% of stock value.
Bullying and Harassment
The nature of the lawsuit against me is not that van Deursen is not guilty of bullying and harassment. The court verdict achieved forbidding me some quote from first-hand sources about how exactly the bullying happened, and who its targets were profiled. This is also why van Deursen’s lawyer admitted in court that the following Mayo Clinic memo, circulated to students and faculty in February 2020, does indeed describe his client, the court verdict now certified it In The Name of German People.
Here excerpt from the Mayo memo, full document below for download:
“Mayo Clinic recently received reports about the behavior of a long-standing researcher who also supervised students and others. We conducted an investigation which determined that the behavior violated several Mayo Clinic policies, including our policies regarding Mutual Respect, Harassment, and Unacceptable Conduct. Mayo Clinic also concluded that the researcher’s behavior was inconsistent with the Mayo Model of Professionalism and Mayo Clinic’s core values. A recommendation for termination of the researcher’s relationship with Mayo Clinic was made, and a decision was made to close the laboratory involved. The researcher chose to retire and did not challenge the recommendation through termination proceedings. We are thankful to those who shared their concerns and exposed the unacceptable environment that existed.
Mayo Clinic is actively supporting those impacted by these decisions and is in the process of transitioning affected individuals into other opportunities. A coordinated effort is in place to ensure student protection while completing ongoing research projects. Importantly, the researcher will not be permitted to return to the laboratory and is not allowed to have unsupervised communication with any student who wants to coordinate the completion of research. Mayo Clinic has also met its obligation to report this situation to the National Institutes of Health. The combination of these actions, including eliminating the unacceptable environment, and assisting those affected, reflects Mayo Clinic’s commitment to its values, policies, staff, and students.“
One major point for van Deursen’s German lawyers was to forbid me to ever quote anyone criticising his research or even saying it might be anything but 100% reproducible. They failed there at least. The lawyer simultaneously first informed the court that van Deursen retired as pensioner, but then declared that his 57 year old client is actually still applying for jobs. In this regard, the proposed agreement would also forbid me to send tweets like this, or to notify other universities of the bullying charges.
As I was informed, the University of Texas San Antonio took my tweet seriously, and contacted the Mayo Clinic about my article. Maybe van Deursen disapproved of such mistrust, in any case he is not going to UT San Antonio anymore.
But now, let’s see how van Deursen’s iron-fisted way of managing the lab and motivating his pipetting squad has translated into clinical trials. From bullying at the bench to pharma cash at bedside, so to say.
The company Unity Biotechnology was founded in 2011 by van Deursen, another senescence researcher Judith Campisi of the Buck Institute for Research on Aging, together with the oncologist Daohong Zhu of University of Florida and the biotech entrepreneur Nathaniel David, their biotech start-up seeks to market the so-called “senolytics” drugs. The founding story goes:
“The idea for Unity arrived in David’s email inbox in 2011, from multiple senders at the same time. It was a Nature paper from the Mayo Clinic laboratory of Jan M. van Deursen [Baker et al 2011]. Van Deursen had genetically engineered mice so that many types of senescent cells would die. […] Van Deursen introduced David to Judith Campisi, at San Francisco’s Buck Institute, who had helped establish the senescent-cell field. […] [David] founded Unity in 2011, with Van Deursen and Campisi as cofounders. For five years the company didn’t even have offices; all the work was done at the scientists’ labs.”
These senolytic drugs would remove ageing (senescent) cells from the body and lead to tissue rejuvenation and healing. Or so the theory goes. As every educated person knows, the industry of anti-aging is always based on solid peer reviewed science (cough), which explains why it attracts such immense investments (wow), in fact Mayo Clinic itself was listed with 6.9% be one of key investors at Unity Biotech (oops). As local media reported:
“Its work in part builds on scientific advances made by Mayo researcher and Unity scientific co-founder Jan van Deursen, who first demonstrated in 2011 that the elimination of “senescent” cells in mice blunted multiple aspects of the aging process. Senescent cells are living cells which have ceased to reproduce – the theory is that humans age because “toxic” senescent cells are unable to participate in tissue repair. […]
For instance, Unity co-owns exclusive patents with Mayo, the Buck Institute for Research on Aging and Johns Hopkins University in the field of senescence. These include two issued U.S. patents involving the use of UBX0101 for the treatment of osteoarthritis, with others covering dosage and a method of treatment.
Moreover, in October 2016 the company revealed it issued 200,000 shares of its common stock to Mayo as a license fee payment.”
Fundraising-wise, Unity Biotech did very well, at least in 2018:
“The company, based out of Brisbane, California, has received more than $300 million in funding, including from $85 million raised after going public this past May. Amazon founder Jeff Bezos and PayPal co-founder Peter Thiel are also investors. today the company’s market cap is $700 million.“
One such product was, as mentioned above, UBX0101, a p53/MDM2 interaction inhibitor, which is purported to induce apoptosis in those cells which express the senescence marker gene p16. The drug was co-developed by van Deursen’s lab at the Mayo Clinic, van Deursen is also one of the patent holders:
“Unity’s first promising candidate came from Campisi’s lab, where researchers discovered that a small-molecule inhibitor of MDM2 called nutlin-3a had senolytic activity. (A form of that compound eventually became UBX0101.)“
Nutlins have been proposed as cancer therapy drugs by many enterprising researchers, but apparently that led nowhere. Obviously neither Unity nor its founder van Deursen could patent the molecule Nutlin-3a, which other people (Vassilev et al 2004) have years before discovered to be a MDM2 antagonist. But what they could patent, was the use of Nutlin-3a against specific diseases, and indeed this is where van Deursen holds several patents, most recently this patent has been filed to treat neurodegenerative diseases with Nutlin-3a (aka UBX0101).
UBX0101 failed to meet 12-week primary endpoint
“There was no statistically significant difference between any arm of UBX0101 and placebo at the 12-week endpoint for change from baseline in WOMAC-A, an established measurement of pain in OA. Given these results, UNITY does not anticipate progressing UBX0101 into pivotal studies and will narrow the company’s near-term focus to its ongoing ophthalmologic and neurologic disease programs. […]
There were no treatment-related serious AEs and only one patient discontinued because of an AE (for an unrelated cardiovascular event). The most common treatment emergent AE was procedural pain in the study knee (n = 10/183 (5.5%)). […]
Anirvan Ghosh, Ph.D., chief executive officer of UNITY. “While these are not the results we had hoped for, the evidence that senescent cells contribute to diseases of aging remains compelling, and we are excited to advance UBX1325 for retinal diseases, which inhibits Bcl-xL, a distinct senolytic target.”
But it all looked so promising! Couldn’t Unity Biotech just ask their founder van Deursen to have another look at the clinical trial numbers? After all, as one of his lab members said:
“He would also go back and forth on “statistically significant data” versus what we called “trending,” where the average might be different for one group but the standard deviation rendered them equal.“
The failed clinical trial with UBX0101 is based on a very successful preclinical Nature paper. One Unity Biotech investor, Robert Nelsen, was four years ago so impressed by this van Deursen’s study Baker et al Nature 2016 (which claimed to extend mouse life span by 25% using transgenic senolytics approach) that he was quoted by MIT Review:
“Nelsen, who also backed Elixir before it failed, says the science “wasn’t ready” 10 years ago but that seeing van Deursen’s new data was a “holy crap” moment, suggesting an entirely new way to treat disease. “It looks too good to be true, which is always why you take these things forward in a scientific manner,”
“A newly launched company called Unity Biotechnology, which counts Campisi and van Deursen among its co-founders, is working to move the team’s senescence-clearing discoveries to the clinic. “We have spent the last four years identifying a series of Achilles heels that are unique to senescent cells,” says Unity CEO Nathaniel David. “We have molecules that are 300 times more poisonous to these cells than to non-senescent ones.”
It may very well turn out that these same molecules will prove poisonous to Unity Biotech.
Sabotaged by mice and men
These rodent lifespans are a tricky thing sometimes. A former van Deursen lab member experienced themselves first-hand the following:
“I couldn’t reproduce the lifespan curve of one of our mouse models where the experimental group had a different lifespan. I had colonies of WT mice and the experimental mice – and there was absolutely no difference between the two. Jan was incensed. The word ‘retraction’ escaped his lips, but we shifted focus to a different aspect of the model, and I forgot how we explained it to ourselves. Probably that lifespan was but a small part of the larger picture.“
Uh-uh, let’s hope this lifespan paper from van Deursen lab had nothing to do with senolytics, or it will make Unity Biotech even unhappier than they already are.
Yet a Nature paper, as I myself learned as postdoc in a senescence research lab, is always 100% reliable science gospel, in any case it is definetely a gigantic cash machine. From there on, the idea von van Deursen and his enterprising colleagues was to develop senolytic drugs which would mimic the life-extending transgene and kill the p16-expressing cells, which van Deursen’s previous research clearly fingered as culprits for the age-related diseases and the ageing itself.
Yeon et al Nature Medicine 2017 was a collaborative work of van Deursen’s with Campisi and Jennifer Elisseeff of Johns Hopkins University, which investigated UBX0101 in a mouse model for knee osteoarthritis disease. The paper declared:
“To selectively clear SnCs [senescent cells] using a pharmacologic approach, we tested a senolytic (UBX0101) that was recently found to selectively eliminate SnCs […] Together, these results indicate that UBX0101 can clear SnCs from articular cartilage to reduce OA symptoms and modify the disease by creating a pro-regenerative environment even in later-stage disease. […] Removal of SnCs from aged p16-3MR animals using the standard regimen of UBX0101 (Fig. 2a) reduced OA-induced pain, similar to what was observed in young mice […] These findings suggest that UBX0101 can clear SnCs from aged articular cartilage, but the age-related decline in the proliferative and synthetic capacities of articular chondrocytes may reduce subsequent tissue regeneration […] These data suggest that transient UBX0101 treatment may cause a reversible cessation of cell growth (quiescence) in normal cells, which resume proliferation after removal of UBX0101. […] UBX0101 decreased p16INK4a and MMP13 protein levels and increased the levels of COL2A1, proteoglycan and sulfated glycosaminoglycans (sGAGs), confirming new cartilage growth ”
In a review paper from his lab [Postdoc Y et al Nature Reviews Drug Discovery 2017], van Deursen wrote, referencing the Yeon et al 2017 study:
“the proprietary agent UBX0101, has been shown to clear SNCs in a mouse model of osteoarthritis, which significantly attenuates both disease progression and pain. […] Clearance of SNCs through a transgenic system or intra-articular injection of the senolytic molecule UBX0101 (see below) reduces pain and promotes the repair of damaged cartilage8 […] UBX0101 also improves functional measures (increases in aggrecan and collagen II levels, and weight-bearing ability) in a mouse model of osteoarthritis, which indicates that this molecule is a promising candidate for future advancement into clinical trials“
While the phase 1 safety trial with UBX0101 on healthy volunteers was nearing completion, with the already energing result that “the drug failed to statistically outperform placebo in the second part of the study“, van Deursen published another review (van Deursen Science 2019), again referencing the Yeon et al 2017 paper:
“Treatment of a murine osteoarthritis model with the drug UBX0101, which interferes with this regulatory mechanism, triggers apoptosis of SNCs that accumulate in articular cartilage and synovium—cells that are causally implicated in the development of osteoarthritis (9) […] The first clinical trial is testing UBX0101 for the treatment of osteoarthritis of the knee. Another drug, UBX1967, a BCL-2 family inhibitor specifically tailored for diseases of the aging eye, is also advancing to human testing.“
The preclinical science was solid, on the authority of Mayo Clinic professor van Deursen. It seems, where the mice complied unquestioningly, the osteoarthritis patients failed van Deursen’s science, maybe because the patients and trial investigators were not conditioned by shouting, intimidation and gaslighting? Will at least the retinal disease patients prove more cooperative and science-friendly in the next clinical trial?
Business as unusual
The clinical trial with the drug UBX1967 (named after the birth year of the Unity president Ned David, and licenced from the Chinese company Ascentage Pharma and the University of Michigan for $38 million and 133,333 stock shares up front) was supposed to start in 2019. Only that it did not, and also the phase 1 clinical trial with a related drug UBX1325 (which seems to be co-patented by van Deursen) has not started yet (it was first registered on 3.09.2020).
Worse, Unity seems to be financially struggling, as San Francisco Business Times reported on 15 September 2020:
“Unity Biotechnology Inc., whose clinical trial in osteoarthritis of the knee failed last month in clearing away dead cells thought to play a role in inflammation, will cut 30% of its workforce to focus its remaining cash on eye and brain diseases.
One of the first wave of so-called aging drug companies — concentrating on therapies to tackle aging-associated diseases — the South San Francisco company (NASDAQ: UBX) said Tuesday it plans to end the year with about 75 full-time employees.
The move will help to stretch Unity’s available cash through mid-2022, funding it through the readout of a clinical trial of UBX-1325, an experimental drug to treat diabetic macular edema, an eye disease that causes blurred or distorted vision. A Phase I study of the drug is expected to dose its first patient later this year.
Saying it will concentrate on ophthalmology and neurology, the company also will prioritize a preclinical drug that is molecularly different from UBX-1325, called UBX-1967, that could be sent into clinical trials. It also is working preclinically on multiple mechanisms in the neurodegenerative and cognitive disorders space.
Unity had cash, equivalents and securities as of June 30 totaling $112 million, according to a Securities and Exchange Commission filing.”
From $700 million to $112 million company value in 2 years, with shares down 60% “from around $12 apiece in early August to less than $4 today“, as it was reported on 16.09.2020, what a resounding success for this senolytics business. The Unity Biotech pipeline is becoming a toilet drain, despite van Deursen’s oh-so-reproducible and impactful preclinical research.
Now, bullying and harassment is not just fun and games for the ambitious principal investigator (PI), it very well might happen to end in bad science (like here and here), as I also blogged about in a different case. It’s not like van Deursen’s lab never published photoshopped data. Look at this:
X Wang, JR Babu, JM. Harden, SA. Jablonski, MH. Gazi, WL. Lingle, PC. De Groen, TJ. Yen, JMA. Van Deursen The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins Journal of Biological Chemistry (2001) doi: 10.1074/jbc.m101083200
It is not just heavy lane splicing in every single panel. The fragments look suspiciously copy-pasted (highlighted with colour boxes).
To the bully PI, it might appear that their lab personnel are all highly motivated and working hard, having been subjected to constant shouting, humiliation, racial or misogynous harassment, or just plain threats and extortion, but one should not confuse the success of publishing in high-impact papers with the actual scientific quality and reproducibility of the research. People might do crazy things when they are afraid, desperate or willing to please at all cost, especially when a PI has an attitude like this:
“Jan would come to a conclusion in his mind, and then insist that it had to be the correct answer” or “He can’t see beyond what he thinks the result should be, and won’t accept the answer if it doesn’t match with what he’s made up in his mind”, as two lab members have reported on my site. Then, accidents like these happen:
Cynthia J. Sieben, Karthik B. Jeganathan, Grace G. Nelson, Ines Sturmlechner, Cheng Zhang, Willemijn H. Van Deursen, Bjorn Bakker, Floris Foijer, Hu Li , Darren J. Baker, Jan M. Van Deursen BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome The Journal of clinical investigation (2019) doi: 10.1172/jci126863
“Red boxes: The BubR1 +/L1002P and BubRR1+/- panels appear to show an overlap.“
van Deursen declared in German court that there never was any problems with his research, and nobody outside his lab was supposed to be repeating it anyway (he also declared himself to still be professor at Mayo Clinic, in the English original, as opposed to German translation).
But it is not exactly the case that van Deursen’s results were uniformly confirmed by other labs, as he declares under oath, while demanding a court verdict forbidding all criticism of his research. Here a Pubpeer comment regarding a Nature paper from van Deursen’s lab, Bussian et al 2018.
“P16(INK2A) (aka Cdkn2a) is their major marker of senescence here, but I don’t see any functional proof of senescence. How well is it established that P16(INK2A) is even a reliable marker of microglial/astrocyte senescence (if indeed this occurs at all).
A paper on macrophages suggests that their two major markers, P16(INK2A), and ‘senescence-associated beta galactosidase’ are induced as part of a physiological response to pro-inflammatory stimulation, and (unlike senescent cells) in a p53-null background. To quote the paper below “These observations suggest that the antiaging effects following eradication of p16Ink4a-positive cells may not be solely attributed to SCs but also to non-senescent p16Ink4a/SAβG-positive macrophages” https://www.ncbi.nlm.nih.gov/pubmed/28768895
So are the authors really clearing the brain of senescent microglia, or are they actually clearing the brain of non senescent pro-inflammatory microglia?“
So basically, van Deursen’s p16-targeting p53-dependent senolytics approach may be utterly misguided and at best pointless at least for neurodegenerative diseases. Yet this is exactly what was trialled with UBX0101 for osteoarthritis, and failed spectacularly in phase 2 clinical trial.
How can it be van Deursen’s research does not always match what his peers find in their own studies? Maybe the work environment in the van Deursen Mayo Clinic lab is a clue? As a former member narrated:
“He would routinely shout at lab members, including cursing, and slam his hands on his desk, and otherwise intimidate members in his office and in lab meetings. He was proficient in gaslighting.“
Blackmail, threats and coercion also happened, as this and another witness revealed:
“When the mouse tech decided to leave the lab, he yelled at her telling her she was a shitty person and if she went to HR he would give bad recommendations to her boyfriend (graduate student in the lab).“
At some point, even the Mayo Clinic had enough, its officials barred van Deursen from entering his own lab and eventually got rid of him completely, despite Mayo’s own financial investment into Unity Biotech. van Deursen may call it voluntary retirement (ten years too early!), but the only alternative, spelled out clearly by the Mayo memo, was for him to be FIRED for bullying and harassment.
The journalist Jeff Kiger reported in the local media:
“Insiders say it was van Deursen’s treatment of a graduate student who was a new mother that led to him being banned from his lab and his eventual departure. In the days before giving birth, people in the lab say van Deursen attempted to have the student sign a document saying she would not take the entire maternity leave time allowed to her. She declined. After she returned from maternity leave, van Deursen became angry about her missing one of their daily meetings.
He and the student met with a graduate school representative. Early in the meeting, van Deursen reportedly complained that the student did not work during her maternity leave. The school representative responded that he couldn’t hold that against the student, because she shouldn’t have worked during her leave. From that moment, people familiar with the meeting say van Deursen started “very aggressively” screaming. The tirade went on for at least an hour.
Following that public display, people close to the situation say someone other than the new mother reported his behavior to Mayo Clinic’s human resources department. “They started asking other people about his behavior. I think they realized he was screaming and yelling at everybody,” according to a person inside the lab.”
It was not the first time van Deursen tried to coerce a pregnant woman to return to the lab, and this is why the court did not forbid me to cite that source. In this regard, Robin Ricke narrates her own account here on my site, and also on LinkedIn. She described her former boss as a “petulant toddler” and was also quoted by Kiger:
“Jan is 100% an extreme example. Even with the lack of professionalism in academia, Jan was unique,” Robin Ricke said. “Anything could set him off.”
On my site, Ricke wrote in a guest post about van Deursen’s rule of terror:
“I can think of at least four individuals who I specifically considered suicide threats at various times. Three of these individuals were on immigrant visas that requires current employment to stay in the US. One was sending money to a child who remained in their home country. One was concerned about what others would think if they left as culturally, quitting was not an option. Everything in their life was connected to being successful in that job. Walking away was not an option. The pressure was immense. Besides these specific people, I witnessed many other members of Jan’s lab who were bullied.“
Is this really an appropriate environment for reliable scientific research? Let’s see how the German court sees it.
Darren J. Baker, Meelad M. Dawlaty, Tobias Wijshake, Karthik B. Jeganathan, Liviu Malureanu, Janine H. Van Ree, Ruben Crespo-Diaz, Santiago Reyes, Lauren Seaburg, Virginia Shapiro, Atta Behfar, Andre Terzic, Bart Van De Sluis, Jan M. Van Deursen Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan Nature cell biology (2013) doi: 10.1038/ncb2643
“Figure 1D: All bars have the same mean and error. This is highly unexpected.“ Baker then shared the original numbers on Pubpeer and wrote: “The authors regret the errors“.
The journalist Kiger brings an example how van Deursen motivated his newly arrived lab members:
“Another person who worked in the lab for more than four years agreed, asking to protect their identity to prevent reprisals. They say van Deursen was charming … at first. After a few months of working together, his former staffer says it was like van Deursen “flipped a switch.”
“It became a nightmare. He started insulting me … being verbally abusive,” they recalled. “It was hard to say what would set him off. He was a powder keg … Every day, I’d have this horrible dread … It continued for years.”
There are many more examples of van Deursen’s inappropriate behaviour, please read this account by Robin Ricke and another colleague, as well as the initial article which first-hand witness quotes are soon to be ruled upon by the German court. As usual, I reject all responsibility for all 3rd party internet content on any internet archive platforms.
Only today my lawyer shared with me the court verdict delivered on 15 September 2020. Strangely, this Vancouver-based commenter below knew of the verdict long before me. The article was edited accordingly, since I won only 1/3 of the van Deursen case, your donations will be most welcome.
On 18 December 2019 Mayo Clinic’s Research Operations Administrator Michael Lee sent a round email announcing van Deursen being placed on administrative leave and banned from direct communication with his lab members:
If you are interested to support my work, you can leave here a small tip of $5. Or several of small tips, just increase the amount as you like (2x=€10; 5x=€25). The legal costs are quite serious.