Exciting news in Big Pharma, only from last year: in April 2018 the French multinational Sanofi recruited the former Roche executive John Reed as their new Head of Research & Development. As media reported, Reed previously left the Swiss pharma giant Roche “for personal reasons” in March 2018. The stint at Roche in Basel was relatively short, as Reed only switched there in 2013, having left his position as CEO of Sanford-Burnham Medical Research Institute in La Jolla, California. Prior to that, Reed had a career as academic, at University of California at San Diego (UCSD), he is also member of American Association for the Advancement of Science (AAAS).
Recently the data integrity sleuth Clare Francis pointed me towards some research papers on PubPeer, most of which are from Burnham Institute and signed by Reed as corresponding last author. I personally think Sanofi should distribute these Reed papers in all their research facilities worldwide to teach their employees how to science properly. Maybe complemented by the papers of Reed’s past collaborators Paul B Fisher and Paul Dent of Virginia Commonwealth University.
Reed’s scientific expertise lies in discovering new pharmacological targets for cancer research, a huge market in pharma business, and the following representative papers show how highly efficient cancer cures can be designed with the most minimal of technological investments. Quite some of them appeared at the Journal of Biological Chemistry (JBC) which is known to be needlessly mean to successful scientists (e.g., here and here). Let’s see how it works out for Dr Reed, Head of R&D at Sanofi, whose annual salary is probably higher that the entire budget of JBC‘s academic publisher, the American Society for Biochemistry and Molecular Biology.
Let’s start with an over 20 year old classic from Burnham.
Ryosuke Takahashi, Quinn Deveraux, Ingo Tamm, Kate Welsh, Nuria Assa-Munt, Guy S. Salvesen, John C. Reed A single BIR domain of XIAP sufficient for inhibiting caspases The Journal of biological chemistry (1998) doi: 10.1074/jbc.273.14.7787
Here Reed and colleagues identified a novel caspase inhibitory domain which can become pharmacologically relevant when a cancerously-transformed gel lane divides while acquiring a metastatic invasive propensity in a gel-figure transgression assay.
Meral Guzey, Shinichi Takayama, John C. Reed BAG1L enhances trans-activation function of the vitamin D receptor The Journal of biological chemistry (2000) doi: 10.1074/jbc.m004977200
The authors uncovered a mechanism with which Vitamin D receptor ligand BAG1L prevents proliferation of cancer cells by mirroring the metastatic invasion activity of dividing loading control bands:
More from exactly same authors, where another Vitamin D receptor ligand, D3, proved itself as potent apoptosis inducer in cancer cells by inducing a rotational tetramer formation of the loading control:
Meral Guzey , Shinichi Kitada, John C Reed Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer Molecular cancer therapeutics (2002) Jul;1(9):667-77.
Ning Ke, Adam Godzik, John C. Reed Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak The Journal of biological chemistry (2001) doi: 10.1074/jbc.c000871200
Here the authors discovered yet another novel protein, Bcl-B which proved a potent apoptosis suppressor, likely used by cancer cells undergoing clonal expansion due to oncogene-overexpressing gel bands.
Loredana Fiorentino, Christian Stehlik, Vasco Oliveira, Maria Eugenia Ariza, Adam Godzik, John C. Reed A novel PAAD-containing protein that modulates NF-kappa B induction by cytokines tumor necrosis factor-alpha and interleukin-1beta The Journal of biological chemistry (2002) doi: 10.1074/jbc.m200446200
Here, a novel protein termed PAN2 was discovered which mediates inflammation by promoting high-rate mitotic division activity of bands and other usually non-dividing gel elements.
Christian Stehlik, Hideki Hayashi, Frederick Pio, Adam Godzik, John C. Reed CARD6 is a modulator of NF-kappa B activation by Nod1- and Cardiak-mediated pathways The Journal of biological chemistry (2003) doi: 10.1074/jbc.m300009200
Here, another immunomodulatory protein was discovered, CARD6. Its proliferative effects on gel bands are even more impressive, the signalling happens following the splice-event induced tertamerisation of Cardiak protein from two identical heterodimeric gel band subunits.
Han-Jung Chae, Hyung-Ryong Kim, Chunyan Xu, Beatrice Bailly-Maitre, Maryla Krajewska, Stan Krajewski, Steven Banares, Janice Cui, Murat Digicaylioglu, Ning Ke, Shinichi Kitada, Edward Monosov, Michael Thomas, Christina L Kress, Jeremy R Babendure, Roger Y Tsien, Stuart A Lipton, John C Reed BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress Molecular cell (2004) doi: 10.1016/j.molcel.2004.06.038
Here, an inhibitor of the apoptotic protein Bax was studied, the authors discovered that BI-1 protein can prevent cell death by stimulating gel band mitotic activity in a research-integrity-refractory Molecular Cell.
Yunfei Wen, Vladislav S. Golubkov, Alex Y. Strongin, Wei Jiang, John C. Reed Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation The Journal of biological chemistry (2008) doi: 10.1074/jbc.m708419200
Here Dr Reed probably decided to follow-up in the mysterious mitotic activities of gel bands in his previous papers and found that these were caused by a chronic Hepatitis B infection of the western blot apparatus. The virus apparently can even cause band bleaching during oncogenic band-self-replication.
Obviously Burnham institute was tremendously successful in its drug discoveries under Reed’s leadership. This is a more recent paper it published, with the director as penultimate author:
Yoshito Nagano, Toru Fukushima, Kazuo Okemoto, Keiichiro Tanaka, David D.L. Bowtell, Ze’ev Ronai, John C. Reed, Shu-ichi Matsuzawa Siah1/SIP regulates p27(kip1) stability and cell migration under metabolic stress Cell cycle (2011) doi: 10.4161/cc.10.15.16912
The authors studied here the effect of glucose starvation on research integrity, and found that the effect is devastating, while mediated by an abnormally formed Siah1-homodimer.
In 2015, Dr Reed was already in charge of an oncology branch at Roche. His Burnham lab published this, while Dr Reed provided his new Roche affiliation:
Zhifen Yang, Rachel P. Wilkie-Grantham, Teruki Yanagi, Chih-Wen Shu, Shu-Ichi Matsuzawa, John C. Reed ATG4B (Autophagin-1) phosphorylation modulates autophagy The Journal of biological chemistry (2015) doi: 10.1074/jbc.m115.658088
Here it turned out that phosphorylation of the autophagy-relevant protein ATG4B somehow leads to one loading control being eaten. It is then replaced by a de-novo synthesised clonal actin element undergoing lightness-induced rotational cropping activity.
The following 17-year-old collaborative study of Reed’s Burnham Institute with the University of Chicago provided some mechanistic insights into the gel image complex formation process induced by rigorous drug discovery research.
Alexander H. Stegh, Bryan C. Barnhart, Jorg Volkland, Alicia Algeciras-Schimnich, Ning Ke, John C. Reed, Marcus E. Peter Inactivation of caspase-8 on mitochondria of Bcl-xL-expressing MCF7-Fas cells: role for the bifunctional apoptosis regulator protein The Journal of biological chemistry (2002) doi: 10.1074/jbc.m108947200
The journal JBC namely saves images in pdf as they were submitted, so if an image is a composite one, it can be disassembled into the individual images it was made of. Some gels proved to consist of several malfunctional subunits, assembled by a hitherto unknown novel mechanism. Reed’s Burnham Institute apparently decided more research was needed, see above and here on PubPeer, a total of 40 papers from between 1998 and 2015.
I think Sanofi made a genius choice with Dr Reed as their Head of R&D, every patient should flip from excitement and at least double or even four quadruplicate their trust into Sanofi’s research and novel therapies now. And as the high achiever Reed himself teaches, successful pharma research depends on sacking people who do not perform:
Over two years have passed, and guess how many of these reed papers were retracted? Zero. Apparently, not even a single correction. With some more recent finds, Reed’s PubPeer record now stands at whooping 46 papers, and nobody dares to touch them.
But a reader told me something interesting about Reed’s past. He once had to issue a correction to declare his conflicts of interests:
“In “Authorship” on page 3327, the conflict-of-interest disclosure should have included the following: “Dr Reed is a consultant to and shareholder in Apoptos, Inc, Coronado Biosciences, Inc, and ISIS Pharmaceuticals, Inc, as well as the sole inventor of Genasense™ (oblimersen sodium).“
Reed invented Genasense while mentored by none other but Carlo Croce, and licenced the drug to the company Genta, on whose board Reed used to sit and into which his current employer Sanofi invested almost $500, all of which went up in smoke. There was an article about this Genasense scam, published by Jim Silverman in 2012 on now defunct The Street, but here a backup. It kind of lets one wonder if Sanofi’s long-term plan is to destroy their company from inside. I quote the article in full:
BOSTON (TheStreet) — On August 2, Genta (GNTAQ) filed for Chapter 7 bankruptcy liquidation, thereby ending 24 years of repeated clinical failures, multiple FDA rejections, countless toxic financings and epically piggish executive behavior.
Before the Genta corpse rots into distant memory, I thought it might be helpful to document the company’s colorful and painful history. The Genta story is a warning to biotech investors showing how chronic clinical failure can lead to soul-crushing shareholder dilution. [Cell Therapeutics (CTIC) shareholders — pay special attention.]
Old-timers may recall that Genta was founded with the mission to develop generic versions of hard-to-manufacture drugs. The company’s first target in the late 1990s was the calcium channel blocker Procardia XL, which at the time was among the world’s biggest selling branded drugs. Generic drug makers were keen to develop their own versions of Procardia. Genta was in the hunt too, and thought it had an advantage because of a proprietary drug delivery technology licensed from a European company called Jagotec. Unfortunately, Genta’s efforts flopped and other generic drug makers copied Procardia first. None of Genta’s generic drug projects ever made it to market and the entire program was eventually scrapped.
Enter Genasense, an “antisense” drug designed to block a key protein involved in various cancers, including certain leukemias and skin cancers. In the early 2000s, antisense was big news, the “flavor of the day” biotech technology, much the way RNA interference rose to prominence more recently. Genta promoted Genasense relentlessly despite murky evidence of efficacy. All that hype paid off in 2002 when Aventis (now Sanofi (SNY)) agreed to partner with Genta on Genasense’s development.
It’s hard to believe now, but Genta traded on the Nasdaq back then and was considered a real biotech company — albeit one steeped in controversy. The Aventis deal — $480 million in up-front cash payments and development milestones — was a high water mark for Genta and Genasense. It went downhill from there for the company and its shareholders.
This where the Genta story becomes more familiar. Genasense’s phase III study in melanoma failed, although Genta claimed the data were positive. The company sought FDA approval but the drug was rejected. Genta tried for FDA approval again, this time with lackluster data from a leukemia clinical trial. Again, FDA kicked Genasense to the curb. Genta decided to give melanoma another shot but a do-over clinical trial failed. Finally, in 2011, Genasense was scrapped.
It costs a lot of money to run a drug development program with this level of ineptitude. Of course, all this money was essentially thrown away, leaving shareholders holding stock diluted into oblivion through an endless series of financing and reverse stock splits. This is where the Genta story boggles the mind.
Take a look at Genta’s catalog of reverse stock splits:
1997: 1 for 10
2007: 1 for 6
2009: 1 for 50
2010: 1 for 100
2011: 1 for 50
2011/2012: FINRA denied multiple Genta requests for yet another reverse split, evidently saying enough is enough.
July 2012: Genta shareholders approve a “reincorporation” of the company from Delaware to California, merging Genta Delaware into Genta California, effectively trying to game the system so they could institute an up to 1-for 25,000 share split.
Multiplied together, Genta pushed through an astounding 1-for-15 million reverse stock split, beginning with their initial split in 1997 and ending in 2011.
A 1-for-15 million reverse stock split is hard to grasp but think about this way. If you had owned 15 million shares of Genta in 1997 and never sold a single share, today you would own 1 Genta share.
In 1997, Genta had slightly more than 40 million shares outstanding so that means there are just two of these Genta common shares remaining. Their value today: $0.0006.
Okay, here’s where Genta gets downright freaky. Let’s assume Genta never instituted any reverse stock splits. How many outstanding shares would the company have on its balance sheet today?
The answer: Approximately 100 quadrillion shares outstanding!
This is what 100 quadrillion looks like numerically:
Mind you, 100 quadrillion shares only represents Genta’s common stock (15 million in splits multiplied by roughly 6-7 billion shares currently outstanding.
The fully diluted share count, sans reverse stock splits, would be 1 quintillion!
This is what 1 quintillion looks like numerically:
A history of Genta is not complete without mention of Dr. Ray Warrell, chairman and CEO since 1999. In 13 years, Warrell manned Genta’s helm through all but one of the reverse stock splits, the failed Genasense program, $1 billion in accumulated losses and an almost 100% plunge in the company’s stock price. At Genta’s end, Warrell was still chairman and CEO, surely a record for futility and resilience.
And at his side, through it all, stood Genta’s chief medical officer Loretta Itri, also known as Warrell’s wife. Surely, the Warrell/Itri combo must be near the top of any biotech Power Couple list.
In reward for their ignominious track record — and to “incentivize and retain” the duo — Genta’s board of directors, just six weeks prior the filing bankruptcy, awarded Warrell and Itri a combined 1.45 billion shares of Genta restricted stock.
Alas, as they say, all good things must come to and end. On August 2, biotech flags around the world were lowered to half-staff to recognize Genta’s filing of Chapter 7 bankruptcy liquidation.
That Genta was able to survive for 24 years, burn through $1.2 billion dollars of investors money, finance themselves through deeply discounted converts for over two decades, with a single CEO for its final 13 years, even after losing 100% of shareholder value, is truly a remarkable, perhaps never-to-be-replicated story.
Silverman has no position in Genta — thankfully.
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