An Expression Of Concern

On 12/17, J. Neurosci followed up an erratum published 10/11 with an Expression of Concern.

The first thing to point out is that the editor of the journal has been subjected to constant harassment by the Twitterati, some of whom have influential positions. Nevertheless according to COPE guidelines, accommodations must be made and in this case the expression of concern defers the legitimacy of the blots to the City University of New York (CUNY).  We note here that the J.Nsc has also updated the original paper to include the Erratum on 12/15, 2 days before issuing the Expression of Concern

This strengthens our view that the Expression of Concern is tied to the ongoing investigation. We fully expect that CUNY will be able to adjudicate this issue with the diligence it deserves. While hard evidence may be lacking to counter all accusations, Dr. Wang’s authorship of multiple papers with many different researchers, faculty and students over many decades provides a unique window into his actions, and an opportunity to determine wrongdoing. CUNY will no doubt be able to interview some of these people and weigh their opinion before making a decision.  Below are some thoughts on the blots in question:

Figure 6A & 6B: original pubpeer report

The erratum addresses these concerns, and there has been no issues raised so far on the original blots submitted for this figure.

Figure 9A: original pubpeer report from Dr. Bik

The original in the erratum was then analyzed by Dr. Bik, and the following crop signature was flagged:

[Updated] What is likely going on with the darker background seen in the figure is that a small unexposed film was taped to the surface of a larger exposed film to run through the developer. This is done because you don’t need a full 8 x 11” or 5 x 7” film to expose a small WB, so they are usually cut into smaller pieces. The small film is then taped to a larger film because smaller films inevitably get caught in the rollers of the developer. It’s not fun digging out a stuck film from the developer. Anyways, when this occurs you can sometime see the image of the larger exposed film under the smaller taped film, which I think is what is happening here. There could be other explanations as well, including defects with the nitrocellulose membrane, which is usually cut from a large roll. What is interesting about this figure though is that the dark background appears to run through a band, which is completely illogical if the data was manipulated by cutting and pasting. As far as the 2 additional bands at the right, many researchers will run “extra samples” to try to gain more information. There is no rule that you have to report an entire figure in a publication, just provide the whole figure if questions arise of validity of the data. That fact that they actually provided an uncropped original data with the 2 extra lanes, which would undoubtedly raise more suspicion from the doubters, tells me that they are being completely honest with addressing the data manipulation claims.

Cassava critics and blots

As an example of how blots can be questioned, here is a look at an “original” blot from a paper we looked at. See figure 6C  

Setting contrast to 100%, the same figure looks like this: 

Notice the obvious contrast changes, crop signature, identical-looking blots, irregular spacing etc. We highlighted a few spots. Note that this paper is authored by Enea Miloris, one of the PhDs who constantly accuses Cassava of fraud..

We then looked for Western Blots run by Adrian Heilbut, another self-proclaimed expert on blots and a foul-mouthed critic of Dr. Wang and Dr. Burns. We found zero blots in his papers.

Elisabeth Bik already owned up to not having enough experience in the field in one of her tweets.

Put this in perspective. The twitter experts finding flaws don’t have much real-world experience running blots.  So why not look at a critic who has actually run blots over many decades?

Figure 1A Bidirectional Synaptic Plasticity Regulated by Phosphorylation of Stargazin-like TARPs

Figure 1A Blue arrows show vertical splices

Figure 4B Identification of PSD-95 Palmitoylating Enzymes

Yellow arrows show possible splice. Also one can see what looks like a partial fingerprint

The left-most bands in the PS and AD lanes have a rectangular box with a different background appearance as the other lanes.

The last three papers were co-authored by David Bredt, the same expert who found flaws with Dr. Wang’s western blots and filed a Citizen Petition anonymously for monetary benefits.

Source

The petition is also plagued with inaccuracies and we have addressed many of them in earlier posts.

Another look at Dr. Wang’s blots with contrast at 100%

Source: Fig 1: Reducing Amyloid-Related Alzheimer’s Disease Pathogenesis by a Small Molecule Targeting Filamin A
Source: Cassava Sciences phase 2a slide deck

Dr. Wang has run a lot of blots over the years and most have no issues. The phase 2a blots above show ptau levels dropping over the 28 day dosing period. Note that ptau is a crucial biomarker of AD and given that these blots look clean, its a remarkable achievement. An upcoming blog post will dwell into this further.

Our Expression of Concern

We understand that there are concerns around Dr. Wang’s research and scrutiny isn’t always a bad thing. However there are some well known folks who have dedicated themselves to harassing anyone associated with the company to serve their financial goals. These folks are at it all day picking and dicing every little detail, running a maximum pressure campaign aiming to influence investors and regulators. We want to remind folks that Simufilam has been used by Bordey Labs collaborating with Calderwood Labs at Yale School of Medicine. The following excerpt is from the mission statement of Bordey Labs.

Source

Calderwood labs have done research on FLNA and how it can have cryptic binding sites. Below is a screenshot of a slide deck presented by Dr. Bordey in the recent past. 

Dr. Bordey’s lab observed Simufilam/NT-125’s treatment effects in preventing seizures associated with TSC, and in preventing cell enlargement that leads to TSC. They also have reason to believe this may be a similar path for Alzheimer’s treatment.

We question why Dr. Wang would need to fake so much science for a drug that seems to have some effect on TSC. We also question all the antagonism towards Cassava when their drug, if not better, is as promising as the multitude of other drugs undergoing clinical trials for AD – see figure below.

In our view, the short and distort crowd are willing to go to any length including preventing an effective treatment for AD from reaching the market. We ask the FDA, NIH, CUNY and other prominent players to step in and ensure completion of these trials. 

8 Comments

  1. You’re knocked it out of the park, again. Thank you for your time and effort on this. One request please, can you post a link here to the video. I love to keep up on my due diligence and see everything possible on Simufilam. The fight is real and we will win.
    Dale Wayne

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    1. im2bz2p345 says:

      I am not the author, but here is the video link: https://www.youtube.com/watch?v=Ku-4UrVxIls

      Hope that helps,

      ~ im2bz2p345

      Like

  2. Found it, very exciting! So happy it helps these children.

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  3. Matt Nachtrab says:

    Very well done. Thanks for the detailed work on this.

    Like

  4. Tim Jenkins says:

    Excellent work. Was staggered by the pie chart. Guess we haven’t give up on finding AD solutions/cure. Will follow your blog with interest.

    Like

  5. Gary J Milne says:

    Keep up the excellent work. Loved the WB’s of the SAVA critics showing many of the same characteristics that they find suspicious in Dr’s Wang and Burns.

    Like

  6. wiscbirch says:

    What do you mean the bands in 9A don’t look similar ? Simply saying that doesn’t make it true. And what is meant by “reusing” the gel ? Are you saying they ran the last 2 lanes then blotted on the original blot ? And where are the MW marker lanes ?
    Maybe it’s true that some of the CP claims are incorrect but there are examples for all to see on Pubpeer where the (obviously )same blots and IHC samples are claimed to be from 2 different animals. And please explain how in the binding study they got 10000 C14 dpm out of the 1 pM labelled ligan.. If you are really keen on supporting Team Cassava, that would be a good way to start.
    Cheers

    Like

  7. wiscbirch says:

    What do you mean Fig 9 Doesn’t have similar looking bands ? Are you kidding? Also, where is the MW marker lane ?
    And please explain what you mean by “reusing” the gel for the two last lanes. The figure is of a blot to which the protein has been transferred from the gel. Why would you run the last 2 lanes then blot to the old blot ?
    But aside from that, there are other incredibly obvious examples available for all to see on pubpeer wherein the same blots and IHC samples are claimed be from different tissue.
    And you almost certainly know this.

    Like

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