Internal review found ‘falsified data’ in Stanford President’s Alzheimer’s research, colleagues allege

Feb. 17, 2023, 12:17 a.m.

In 2009, Marc Tessier-Lavigne, then a top executive at the biotechnology company Genentech, was the primary author of a scientific paper published in the prestigious journal Nature that claimed to have found the potential cause for brain degeneration in Alzheimer’s patients. “Because of this research,” read Genentech’s annual letter to shareholders, “we are working to develop both antibodies and small molecules that may attack Alzheimer’s from a novel entry point and help the millions of people who currently suffer from this devastating disease.”

But after several unsuccessful attempts to reproduce the research, the paper became the subject of an internal review by Genentech’s Research Review Committee (RRC), according to four high-level Genentech employees at the time; two were senior scientists and two were scientists who also served as executives. Three spoke on the condition of anonymity because of the sensitivity of the allegations and non-disclosure agreements. The scientists, one of whom was an executive who sat on the review committee and all of whom were informed of the review’s findings at the time due to their stature at the company, said that the inquiry discovered falsification of data in the research, and that Tessier-Lavigne kept the finding from becoming public.

Tessier-Lavigne denies both allegations. Genentech said in a statement that “as part of our diligence related to these allegations, we reviewed the records from that November 2011 RRC meeting and saw no allegations of fraud or wrongdoing.” The company acknowledged that “given that these events happened many years ago … our current records may not be complete.”

After the review, which began in 2011, Genentech canceled research based on the paper’s findings. Till Maurer, a senior scientist at the company from 2009-2018 who said he was assigned to develop drugs based on the 2009 paper, told The Daily that his superior informed him that, in Maurer’s words, “the project is being canceled and it’s because they found falsified data.”

Tessier-Lavigne, who became Stanford’s president in 2016, has been under investigation by the Stanford Board of Trustees since late November, after The Daily revealed concerns that several other papers he had co-authored contained altered imagery. But these latest allegations, about a different paper, are more serious because they involve what was once considered a promising treatment target for Alzheimer’s disease — and because people involved in the review allege that Tessier-Lavigne tried to keep its findings hidden.

Tessier-Lavigne declined multiple requests for interviews over email as well as in person. Stephen Neal, chairman emeritus of Cooley, a prominent law firm representing the president, responded in writing to questions sent to Tessier-Lavigne.

“Dr. Tessier-Lavigne is not aware of any internal investigation of the Paper,” wrote Neal. “Given that there was no investigation of the Paper, Dr. Tessier-Lavigne categorically disputes any allegation by unnamed scientists that he ‘covered up’ any findings regarding such investigation or was opposed to allowing such (non-existent) findings to become public.”

Genentech, in a written statement to The Daily, confirmed that an internal review took place in 2011, a fact that was not previously public. The company characterized the review as “routine.” When asked whether this was accurate, the scientist whom The Daily confirmed belonged to the research review committee said, “no no no no no no.”

“There have not been any formal investigations, allegations, claims or complaints regarding scientific fraud or misrepresentation involving the Nature 2009 paper,” wrote Susan Willson, a Genentech spokesperson. “The project received a regular review by Genentech’s Research Review Committee (RRC), as is routinely done for Genentech’s drug discovery projects.”

She wrote that “neither the RRC meeting nor the decision to conduct follow-up experiments was due to any concern about fraud in the Nature 2009 paper.” Willson would not answer multiple questions about whether any issues were ever discovered in the paper.

The research review committee authorized subsequent experiments to further analyze the paper’s conclusions, Willson wrote, and “based on the results of the genetic experiments at Genentech, the RRC terminated the Genentech research project in 2012.” She would not answer repeated questions about whether there were ever attempts to replicate the experiments in the 2009 paper and if the research was found to be reproducible.

Matthew Schrag, an Alzheimer’s expert with no relation to Genentech or Tessier-Lavigne who reviewed the scientific literature surrounding the paper at the request of The Daily, concluded that parts of the paper implicating a specific pathway in Alzheimer’s “were found in later studies to be inaccurate.” Schrag, who did not have knowledge of the internal review and based his analysis on published information, made clear that “this is not, by itself, evidence of misconduct.”

According to the four senior scientists, including the scientist who served as a member of the research review committee, the committee found that the fundamental science underpinning the 2009 study’s conclusion was fabricated. In the face of a finding of fabrication, retraction of the paper would have been the expected outcome, according to Nature’s policies. The Committee of Publication Ethics, a nonprofit that supports journal editors around the world, recommends retraction in the case of “clear evidence that the findings are unreliable, either as a result of major error (eg, miscalculation or experimental error), or as a result of fabrication (eg, of data) or falsification (eg, image manipulation).” But Tessier-Lavigne “was unwilling to clean up the mess,” said the scientist and former Genentech executive who participated in a series of 2011 meetings about the paper.

Neal, Tessier-Lavigne’s lawyer, asserted the conclusions of the 2009 paper that did not hold up, revolving around caspase 3 and caspase 6, beta secretase, N-APP binding to DR6 and DR6 playing a role in Alzheimer’s disease, were the result of “the normal march of science.” He continued, “no one involved in the experiments described in the Paper forged gels, falsified assays or fabricated experiments.” He did not answer a question about whether any concerns had been raised over the paper or if he believed there were any “issues with the paper.”

A “miracle result” that didn’t pan out

Each of the four senior Genentech scientists was contacted individually by The Daily and was unaware of the others’ accounts. Their independent accounts, given over several hours of interviews, were highly consistent with each other, and also consistent with publicly available information about the research.

Two days after the 2009 paper came out, Genentech’s letter to shareholders called it “groundbreaking basic research about an entirely new way of looking at the cause of Alzheimer’s disease.” At the time, Paul Greengard, a Nobel Laureate, called it “a very exciting paper,” saying “it’s going to have a major impact on the Alzheimer’s field.” And the news wing of Nature published an article entitled “Alzheimer’s theory makes a splash.”

People within the company were similarly excited, at first. One of the senior scientists recalled that Tessier-Lavigne’s initial presentation of the research left the room stunned. “This came out of nowhere,” said the scientist. Another senior executive in the room said, “We all thought: holy shit. This is Nobel Prize stuff…It was the miracle result.”

The study was co-authored with a Genentech postdoctoral student, Anatoly Nikolaev, as well as two Salk Institute scientists who provided expertise on certain experiments and were supported by a government grant. After publication of the paper, Nikolaev was hired by Genentech as a scientist and Tessier-Lavigne, who was then executive vice president of research drug discovery, was promoted to chief scientific officer, in charge of more than 1,400 scientists.

The paper received 1,245 citations in a field where most scarcely get 10. Soon after it was released, Tessier-Lavigne and Nikolaev submitted a 187-page patent to the World Intellectual Property Organization with the title “method for inhibiting neurodegeneration.” On the same day they also filed applications for patents in the United States, Brazil, Taiwan, Israel, Canada and Australia, in the hopes of leveraging their research to develop life-saving drugs.

But the research has not turned into an Alzheimer’s treatment. And several of the patent applications, including the US patent application, were abandoned after the internal review.

By 2011, Alzheimer’s experts had raised suspicions over the paper, both inside the company and outside, said the scientists. (Genentech declined to say whether any concerns had been raised about the paper, though the company denied “any formal … complaints regarding scientific fraud or misrepresentation”).

According to independent experts who did not have knowledge of the internal review and analyzed the published works, several aspects of the original paper raised eyebrows. For example, the study did not include a robust statistical analysis of its findings, included a low number of samples and, according to Schrag the Alzheimer’s expert, “the degree of variation [between experiments] is extremely low.”

None of these issues inherently connote wrongdoing, said Schrag.

Genentech’s research review committee, to which Tessier-Lavigne belonged until his departure from the company, decided to conduct an internal inquiry into the underlying experiments of the paper, according to the scientist who belonged to the review committee. The member characterized the review as “a deliberate attempt by some experienced biologists to reproduce the key findings in the paper” and “a reexamination of the paper’s key findings.” Genentech, in its written statement, called the inquiry a “normal review process.”

Till Maurer, the senior scientist who was tasked with drug discovery based on the research, recalled that following the publication of the paper, he was “invited to a meeting with the new rising star scientist at Genentech, which was Anatoly.” Maurer said he was told by his superior that Nikolaev had found “the involvement of a very specific protein in Alzheimer’s disease,” and “the company immediately initiated a drug discovery program around that protein.” But the team assembled to target the protein was later abruptly re-assigned, said Maurer.

The review committee found that “lab data had been falsified,” Maurer recalled being told, in a communication using those exact words. He was unable to provide the document to The Daily because he had to relinquish all company emails when he departed Genentech for another biotechnology company. But he said he was certain that the word “falsification” was used to describe the errors in the paper.

The Daily has not located a written document detailing the committee’s findings, but the four scientists, who were all familiar with the conclusions of the review, described the findings, and their accounts were consistent. Genentech did not provide documents detailing the conclusions of the review.

The specific issues with the paper had to do with its central conclusions, according to all four scientists. The paper included several experiments claiming to show that the amino-terminal fragment of the amyloid precursor protein (N-APP) binds to death receptor six (DR6) and that this bind causes neurodegeneration. But later-published studies by Tessier-Lavigne’s lab and other research groups show this conclusion was inaccurate. A crystal structure — a type of labor intensive experiment that determines the exact arrangement of atoms — published in 2015 proved that APP, the complete protein, binds to DR6 at the E2 site. The N-APP fragment used in the 2009 research did not include the E2 site, meaning that DR6 could not have bound to the fragment and caused the results described in the paper.

“It was a shock,” said Maurer of the alleged findings. “It was a shock to every scientist.”

Genentech, in its written statement to The Daily, said “no claims or complaints of scientific fraud or misrepresentation involving the Nature 2009 paper were ever made by or to the RRC.”

Nikolaev, responding to questions by email, first said that “nothing in our paper is ‘false’ or ‘falsified’ — I can assure you that.” In a subsequent interview, he said, “I can only speak for myself…and say I did not do anything wrong when I was at Genentech.” He demurred from speaking more specifically about the paper, citing a confidentiality agreement.

Neal, Tessier-Lavigne’s lawyer, wrote that “the Paper’s original results were accurately reported.” In response to questions from The Daily about whether, even aside from the concerns raised by scientists that the results of experiments had been falsified, four panels of the paper appeared to contain visible duplications and whether this constituted inaccurate reporting, Neal wrote: “Dr. Tessier-Lavigne first saw reference to those allegations yesterday, when he saw the new post in PubPeer,” an online site where scientists identify issues in published papers. “Dr. Tessier-Lavigne is looking into those issues.” (Schrag, in reviewing the 2009 paper, noted several panels that were supposed to represent different experiments but appeared to contain the same result. He posted his concerns on PubPeer. Elisabeth Bik, a prominent research misconduct investigator, independently identified the same alleged duplications when she reviewed the paper at the request of The Daily).

According to the executive who was part of the committee that reviewed the paper, the inquiry was thorough and left little room for doubt. Laboratory technicians and assistants were interviewed while scientists independent of the lab attempted to verify the findings of the study. “None of [the research review committee members] believed that these data were true by the time people had attempted to reproduce it,” the executive said. He said that the understanding of the research committee was that the paper’s supposed finding of N-APP’s role in Alzheimer’s had been “faked,” and used “made up” figures as evidence.

The executive and other independent scientists with whom The Daily consulted warned that the complexity of biology makes it difficult to ascertain exactly how incorrect results are obtained. But the executive said that based on the results of the review he was “100% confident that [the incorrect conclusions in the paper] weren’t innocent.”

Tessier-Lavigne, who wrote a response to several followup questions The Daily sent after the initial letter from his lawyer, wrote that “I understand that Genentech has also communicated to you that [the review] did not raise issues.” Genentech did not say that the review raised no issues and declined several times to answer questions about whether the review had uncovered any issues.

According to the 2009 paper, Nikolaev performed all of the experiments that provided conclusions revised in subsequent research and “M.T.-L. supervised or co-supervised all experiments, and co-wrote the paper.”

The internal review’s aftermath

Fabrication constitutes the most troubling form of manipulation in the scientific world. According to a report about research malpractice also released in 2009 by the National Academy of Sciences, to which Tessier-Lavigne belongs, this type of misconduct goes against “fundamental research standards and basic societal values. These actions are seen as the worst violations of scientific standards because they undermine the trust on which science is based.”

It was “all really bad,” said one of the senior scientists, referring to the findings of the review committee.

Tessier-Lavigne, who had just departed Genentech to become president of Rockefeller University in New York when the review was instigated in 2011, flew back to California to “clean it up,” said one of the senior scientists.

A sketch of President Marc Tessier-Lavigne
Stanford’s President Marc Tessier-Lavigne

Faced with such a finding, leadership at Genentech urged Tessier-Lavigne to retract the paper and its apparently unsound conclusions, according to the senior executive who participated in the review committee and whom other scientists named as a key decision maker in the aftermath of the review. “Our interest is really in Genentech’s credibility,” said the executive, “and if that meant that we had to go retract papers publicly, so be it. Marc’s interest was — is — to try to keep it quiet.”

Neither a correction nor a retraction was issued, and the paper stands to this day. The scientists said the journal had not been informed of any potential issues. Nature’s editor in chief, Magdalena Skipper, said in a statement to The Daily that “whilst we do not usually comment on details of individual cases for confidentiality reasons, we can confirm that we have not received a report relating to an internal investigation of this paper.”

Nikolaev received a Columbia Ph.D. in 2005 and published one of the most cited Alzheimer’s papers of the decade. Social media posts and Nikolaev’s LinkedIn show that he departed Genentech in 2011 and spent the year after he left the company taking pre-med classes at Washtenaw Community College in Michigan, before enrolling in Florida Atlantic University’s medical school. He now works in Weston, Fla. as a radiation oncologist.

In a phone interview in late January, Nikolaev denied that a review had occurred and said he “left on very good terms” and is “on very good terms with the senior author” — Tessier-Lavigne — “and we speak often.” Nikolaev, explaining his exit, said medicine was his “lifelong dream” and cited Genentech’s 2009 merger with Roche. He then emailed hours after the initial interview to recant one of his statements, writing that “I have not spoke [sic] with Marc since after he left Genentech in 2011.” In another interview, he again amended his statement, saying that Tessier-Lavigne had invited him to a lab reunion, which he did not attend, but that he had otherwise had no interaction with the Stanford president since leaving Genentech in 2011. Genentech would not comment on several questions about the circumstances of Nikolaev’s exit.

Nikolaev also told The Daily that “the [2009] paper doesn’t talk about Alzheimer’s disease” and said Alzheimer’s was not “even mentioned in the paper.” But the word “Alzheimer’s” appears in the paper 31 times, including in the abstract. Alzheimer’s was also routinely referenced in comments by Tessier-Lavigne and Genentech upon release of the research, and in their responses to Daily questions regarding this article.

Those with knowledge of the review were sworn to secrecy, according to the scientists, several of whom cited their own confidentiality agreements.

“I don’t think anyone at Genentech would be interested in this becoming public,” said Maurer, adding that “it’s a dent in the reputation.” Another senior scientist said that withdrawing the paper would have been viewed as “sullying Marc’s/Genentech’s reputation.” The senior executive who participated in the review committee put it more bluntly: “Instead of stopping it and saying, ‘Okay, hold it here. We got something, we’ve got to look into it,’ what [Tessier-Lavigne] did was walk around behind Anatoly with a broom and sweep up the footprints in the dirt.”

No retraction was issued, but Tessier-Lavigne walked back the research in several subsequent publications, according to the scientists. Tessier-Lavigne’s lawyer wrote that the “revisions to the conclusions” were not “nefarious” and asserted “this is how science works.”

Specific conclusions in the original paper were first revised by a 2012 Journal of Neuroscience paper that included all co-authors of the original 2009 study except Nikolaev (and for which Tessier-Lavigne served as senior author). In a seemingly direct rebuke to the Alzheimer’s hypothesis in the 2009 paper, the title of a 2014 paper also published in the Journal of Neuroscience by all of the original authors except Nikolaev says the molecule DR6 identified in the 2009 paper “Does Not Contribute to Alzheimer’s Disease-Related Pathophysiology in Murine Models.”

Schrag, the Alzheimer’s researcher without knowledge of the internal review, told The Daily that “to his credit, Dr. Tessier-Lavigne authored several of the later studies which revised the findings of his 2009 paper.” The Genentech scientists interpreted the subsequent papers differently, with one saying that the original “absolutely should’ve been retracted” based on what had been proven inaccurate.

Neal, Tessier-Lavigne’s lawyer, wrote that subsequent research “fully validated the involvement of these three factors,” referring to APP, DR6 and an enzyme called caspase 6. Subsequent research found that N-APP, the fragment used in the 2009 paper, does not bind to DR6 as described in the study, caspase 6 is not actually required for axonal degeneration as claimed in the 2009 paper, caspase 3, which was ruled out by the 2009 paper, is required for apoptosis (cellular suicide), beta secretase is not actually required in the functions of DR6 and DR6 does not play a role in Alzheimer’s.

The top Genentech executive who sat on the review committee explained what he saw as the issue: “If everything were true in the original paper, [Tessier-Lavigne] would have won the Nobel.”

Genentech said the revision of aspects of the first paper was “exactly what one would expect in a complex area of science, especially one as confounding and challenging as neuroscience and Alzheimer’s Disease.”

Genentech’s research “started with biochemical and cellular studies, and later progressed onto more sophisticated genetic studies in animal models,” Willson, the company spokesperson, said in her written statement. “The results of those studies were published in well-regarded, peer-reviewed journals. Scientists in the field discussed, debated, and learned from those studies.” She continued, “based on the animal model results that DR6 did not have a role in AD, Genentech terminated our DR6 program.”

At the time of the 2014 study undermining the role of DR6 in Alzheimer’s, Tessier-Lavigne told Alzforum, a widely read online hub for the field, “We were intrigued to see if this pathway underlies pathophysiology in mouse models of [Alzheimer’s disease]. It appears it does not.” Tessier-Lavigne acknowledged in a February 15 letter to The Daily that “since it is important to have preclinical models to test therapeutic candidates, the failure to see protection in this [mouse] model effectively made further progress on a therapeutic program targeting DR6 very difficult.”

“Genentech reacted by instituting a program within the company to address these problems” identified by the research review committee, said Maurer, and Tessier-Lavigne “sort of managed to duck out of the way.” According to the scientists, the pharmaceutical corporation brought in Davo Vaux, a prominent Australian misconduct investigator, to lead several sessions with researchers about, in the words of one executive, “why not to falsify data” and “how to identify falsified research.”

Vaux confirmed that he had been brought in several times, beginning in May 2012. “My hosts at Genentech did not tell me why they asked me, but of course I had my suspicions,” wrote Vaux in an email. “I did not ask them directly. They also made attendance universal and compulsory, and asked me to give the talk several times, because no auditorium was big enough to hold all their staff at once.”

A well known molecular biologist and member of the Center for Scientific Integrity, Vaux wrote that he had given versions of the talk at several institutions but that one aspect of his presentation was modified. “Genentech also asked me to include one slide of theirs, which was an external phone number, so that anyone with concerns could speak up anonymously,” wrote Vaux.

Genentech conducts ongoing training “on the importance of rigor and integrity in scientific research,” wrote Willson. “These trainings are done as a matter of good practice and are wholly unrelated to the research project and publications at issue in this inquiry.”

Despite the discontinuation of the research and training within the company, frustration remained that the issues the review allegedly raised had not been disclosed publicly, said the scientists.

“It’s extremely important that things like this actually hit the public domain,” said Maurer. The other scientists agreed. Each of them cited a commitment to the scientific record in deciding to respond to interview requests by The Daily.

Vishva Dixit, vice president of discovery research at Genentech, who was on the committee that reviewed the DR6 research — and was thanked in the acknowledgments of the 2009 paper — referred The Daily to Genentech’s press office when asked about the study. “Oh gosh, I really can’t say anything about that,” he said.

The research review committee comprised roughly 10 members. The Daily reached out to each who participated in the 2011 meetings; two declined to comment and seven did not respond to repeated requests for comment. None gave an account that contradicted the descriptions of the four scientists.

Genentech said in its statement that “our company is founded on the principles of scientific integrity, and we have remained committed to this throughout our 45+ year history through to today. We would never stand for fraud in our papers.”

Aidan Ryan, a spokesperson for the special committee of the Stanford Board of Trustees charged with investigating Tessier-Lavigne’s research, would not answer questions about whether the committee was aware of these allegations and whether the board had been informed of any such concerns when originally considering Tessier-Lavigne for the presidency.

“The committee expects and has authorized Kirkland & Ellis and the panel to apply their expertise and impartial judgment to evaluate any information or questions that may arise in the course of their work,” wrote Ryan. “As a reminder, those who wish to share their perspectives with the Special Committee may contact [email protected].”

Theo Baker is the Vol. 263 Spotlight Investigations Editor. A frosh from Washington, D.C., he is the youngest ever recipient of a George Polk Award. Contact [email protected] for encrypted email. Find him on Twitter @tab_delete.

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