When taxpayer dollars fund fraudulent research

Another prominent neuroscientist with tens of millions of NIH-funding has been placed on leave due to allegations of research misconduct and fraud.

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Following in the growing trend of shoddy neuroscience research a prominent University of Southern California (USC) researcher Berislav Zlokovic has been placed on leave after a year-long investigation into possible research misconduct.

This comes after one of the most pivotal papers in Alzheimer’s pathology was retracted due to questionable figures and research, and also comes after another prominent neuroscientist’s research regarding alpha-synuclein proteins came under scrutiny for fraud.

And yet, as many of the foundational hypotheses and figures that form the bedrock of neuroscience research come under fire we have yet to see any sort of acknowledgement that the field is not in a good state.

Consider that billions upon billions of dollars have been used to fund research that never amounted to anything, or have resulted in researchers looking at the wrong protein or hypothesis, or worse resulted in scientists who have manipulated their own works to gain prominence in the field and receive large federal grants.

And while this malfeasance has resulted in some scientists questioning the validity of neuroscience research we are still seeing fast-tracked approval of Alzheimer’s therapies with questionable efficacy and concerning safety, all being pushed onto a public who may be none the wiser to the degree of retractions and misconduct that is occurring.

In the case of Zlokovic his research includes decades of publications focused on the blood-brain barrier, Alzheimer’s, and strokes, resulting in him heading USC’s Zilkha Neurogenetic Institute and its Department of Physiology & Neuroscience prior to his leave.

Like with several other neuroscientists mentioned Zlokovic is considered one of the most widely cited and seminal researchers in the field of neuroscience:

From Science

In particular, Zlokovic’s team was interested in a class of proteins known as Protein C.

Protein C is a plasma protein zymogen (enzyme precursor) which exhibits anticoagulant properties. When activated, protein C acts as a proteolytic enzyme and helps to inactivate proteins involved with coagulation and clot formation such as Factor V_a and Factor VIII_a.¹

From Griffin, et al. Several of APC’s properties are shown above, including their ability to act as an anticoagulant by inactivating clot-related proteins. Of greater interest has been research which suggests that APCs may provide cytoprotective effects to cells, and may be involved with cellular and neuronal repair. The latter mechanisms have resulted in great interest in APCs as possible therapeutic agents.

Those with Protein C deficiency are at increased risk of pulmonary embolisms and thrombosis, and in infants with genetically inherited Protein C deficiencies purpura fulminans can develop and can often be fatal.

However, not only is Protein C an anticoagulant, but evidence seems to suggest that Protein C is cytoprotective, and may be involved with maintaining endothelial cellular integrity and aid in repair of cell damage through anti-inflammatory and anti-apoptotic mechanisms.

Thus, this multifaceted protein has garnered a great deal of attention amongst researchers who wanted to see if activated Protein C (APC) could be utilized within a therapeutic context, such as in cases of stroke victims or those predisposed to blood clotting.

This is where Zlokovic’s questionable research comes into play.

You see, although APC is multifaceted in its mechanistic qualities, it is also paradoxical. That is, APC has the capacity to both cause endothelial leakage while also maintaining endothelial integrity. In short, this paradox stems from the type of receptors that APC activates, as well as the type of proteins it targets.

This created several concerns when it came to testing APCs as some clinical studies involving people with severe sepsis suggested that wildtype-APC increased the risk of excessive bleeding.² This concern of possible excessive brain bleeding also became a huge roadblock in stroke-related research given that years of research have attempted to find means of helping to protect and repair the brain’s environment following a stroke to little avail.

Thus, if APCs were able to be modified to reduce their anticoagulating properties while maintaining their cellular signaling properties these modified APCs could hypothetically be used to treat those with strokes and other serious diseases without risk of serious harm.

In the case of Zlokovic’s team this resulted in the eventual creation of a modified APC known as 3K3A-APC, in which 3 consecutive lysine residues (residues 191-194) of APC were replaced with alanine residues.

Zlokovic’s team argued that such a modification greatly attenuated the anticoagulant effects of APC while maintaining the critical repair and protective properties of the protein, resulting in a slew of research from Zlokovic’s team emphasizing the benefits of this modified APC such as the following paper published in Nature³:

These findings, and a need for a stroke-related therapeutic, resulted in NIH providing nearly 30 million in funding towards a Phase 3 clinical trial utilizing 3K3A-APC within the context of ischemic stroke victims, while also being provided fast-tracked status by the FDA with possible accelerated approval given the study showed efficacious evidence of 3K3A-APC.

Now, there’s much to the story of Zlokovic which has been heavily truncated here. Like with many of the prior articles note that a far more detailed look into Zlokovic’s history and the eventual allegations of fraud can be found in a Science article published in 2023:

In essence, at the time that Zlokovic’s team were readying for Phase 3 clinical trials with their modified APC Science was provided a nearly 113-page raising doubts regarding the validity of Zlokovic’s work, including the fact that an analysis of the team’s Phase 2 clinical trial seemed to suggest that treatment with their modified APC resulted in higher rates of death and debilitation among the treatment group relative to the placebo group:

The dossier, which they submitted to NIH, highlights evidence from the phase 2 trial that the experimental remedy might have actually increased deaths in the first week after treatment: Six of the 66 stroke patients who received 3K3A-APC died within this period, compared with one among 44 in the placebo group, although the death rate evened out after a month. Patients who received the drug also trended toward greater disability and dependency at the end of the trial, 90 days after treatment.

And like with prior stories of research fraud there appeared to be evidence of possible image manipulation in many of the papers that listed Zlokovic as a consistent coauthor, including one image which seems to have appeared in two separate publications. In this case, the image tampering seems to have removed several stained cells resulting in the possibly false interpretation that APC is neuroprotective:

From Science

More strikingly, testimonials from former lab members suggested that evidence contrary to the team’s hypothesis would intentionally be removed:

Several former lab members provided details of experimental data from Zlokovic’s lab that they say were falsified. These included experiments referenced in the whistleblower dossier. In some cases, they said, data points that would have invalidated the desired results were removed. “It was not real science. He already knew what he wanted to say” before the experiment was completed, one says. “I started hating science. … It made me sick.”

The article goes on to further state that junior members of his team were allegedly prevented from speaking up in meetings lest they be humiliated or dismissed for providing any insight. They were also were castigated if they did not capture the results that Zlokovic wanted, suggesting that they had to always find result that fit his hypothesis.

Again, please consider reading the 2023 Science article for greater context and details on the matter.

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Unfortunately, there continues to be mounting evidence that much of the work, and many of the leaders of neuroscience may be involved with highly questionable work.

It’s this questionable work that forms the bedrock of much of the research that is being conducted in this and many other fields. It’s this research that much of our tax dollars are put towards in the name of science, even if this work is predominately unscientific.

In the case of Zlokovic his decades of work has garnered him a celebrity status among his fellow scientists. He’s seen as one of the most influential players in the field, and is considered to have played a major role in obtaining tens of millions in NIH-funding for USC:

Under Zlokovic’s leadership, the USC institute has expanded to more than 30 labs and grown its annual funding more than 10-fold, exceeding $39 million in 2022. NIH grants to Zlokovic have totaled about $93 million. A prodigious fundraiser, in the past decade alone he has added at least $28 million from private sources, according to USC.

Not only that, but it’s possible that the very same work now coming under question may have directed hundreds of millions of NIH funding towards research on the blood-brain barrier and neurological diseases, again pointing to the deep impact that scientific fraud can have on funding.

Questions remain whether revelation of deeply-rooted fraud may result in a reckoning of neuroscience research, although so far prior controversies don’t seem to have helped move the needle much in that direction.

So far, in lieu of the mounting controversies the Phase 3 clinical trial for 3K3A-APC was halted by the NIH. The study was sponsored by ZZ Biotech, a company which Zlokovic helped to co-found and has partial stake in. ZZ Biotech would go on to withdraw its trial, and as of now it appears that the NIH is demanding nearly $1.9 million from USC for funding of the clinical trial according to a recent Science article.

We are at a pivotal point in society where trust in science has never been lower, and while many scientist continue to blame this lack of trust on “misinformation”, there continues to be clear evidence of malfeasance and fraud happening behind the scenes that either goes unquestioned or swept under the rug.

Rather than spending time fact-checking people on social media scientists should put their effort towards fact-checking the researchers and publications to ensure that no misconduct is occurring. Scientists can’t regain trust while simultaneously being complacent to bad science.

The public, and a public that predominately helps to fund much of this research, is right to lose trust if this is how their money is being spent.

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Photo by Milad Fakurian on Unsplash

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1. John H. Griffin, Berislav V. Zlokovic, Laurent O. Mosnier; Activated protein C: biased for translation. Blood 2015; 125 (19): 2898–2907. doi: https://doi.org/10.1182/blood-2015-02-355974

2. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., Steingrub, J. S., Garber, G. E., Helterbrand, J. D., Ely, E. W., Fisher, C. J., Jr, & Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. The New England journal of medicine, 344(10), 699–709. https://doi.org/10.1056/NEJM200103083441001

3. Wang, Y., Zhao, Z., Rege, S. et al. 3K3A–activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice. Nat Med 22, 1050–1055 (2016). https://doi.org/10.1038/nm.4154