Investigating Fraud At The Heart Of Alzheimer’s Research

FLORA LICHTMAN: This is Science Friday. I’m Flora Lichtman. Every year, billions of dollars are funneled into Alzheimer’s research. And yet, so far, there’s no treatment that’s been able to reverse the disease or even meaningfully slow the cognitive decline of patients. Part of the reason is that the disease is complex. Brain disorders are notoriously difficult to understand.

But in a new book, an investigative science reporter makes the case that there’s another reason Alzheimer’s treatments have stalled, and that is scientific fraud. Charles Piller is an investigative journalist at Science magazine and author of the new book Doctored Fraud, Arrogance and Tragedy in the Quest to Cure Alzheimer’s. He’s based in Oakland, California. Charles, welcome to Science Friday.

CHARLES PILLER: Thank you so much for having me, Flora.

FLORA LICHTMAN: Your book starts with the story of the drug simufilam, which was in phase III clinical trials to treat Alzheimer’s. Ultimately, it was found ineffective. But even before that, while it was still in trials, a neuroscientist whistleblower uncovered some red flags in the science underpinning the drug. Tell me about it.

CHARLES PILLER: Sure. So this drug was made by a company called Cassava Sciences, and the drug was haunted by concerns associated with a few different aspects of its development. The first was the basic science behind its development as a compound that could possibly be an effective drug.

And this testing, this scientific research, was found by a particular image sleuth, a guy by the name of Matthew Schrag at Vanderbilt University, to be riddled with suspect scientific images. And ultimately, there were lots of concerns that were raised about both the company and the drug, both clinically and in the basic science behind it. And some of these are stories that I broke in the pages of Science, including a finding of egregious misconduct by one of the key scientists behind the drug.

Additionally, there was a admission by the company itself that it had cherry-picked data to make it look better in clinical trials than it actually looked. So that’s a lot of problems, a lot of problems with this drug.

FLORA LICHTMAN: For this drug, was the FDA aware of this misconduct and the doctored images that Matthew Schrag found? And did they still let the trials go on even though they had this awareness?

CHARLES PILLER: In a word, yes. The FDA was aware of every element of the concerns about the company, the concerns that even in one case, their own inspectors learned of and reported to the FDA chain of command.

FLORA LICHTMAN: Did you speak to anyone from the FDA? Did they have an explanation?

CHARLES PILLER: The FDA would not give any interviews to me on this, even though I requested many times. And in fact, by and large, they are pretty close mouthed about all these matters. And that’s very problematic because it leaves the public wondering what’s going on and why.

FLORA LICHTMAN: I want to talk about this whistleblower, Matthew Schrag. So he uncovered this apparent image doctoring in the case of this drug. But then he took it much further.

FLORA LICHTMAN: So basically what happened is that after that episode, he became increasingly interested in trying to learn whether this was more or less a one off, or if there was reason to be concerned that other important research in the field might be affected by apparent misconduct. And in the process, he ran across a study that was published in 2006, in the very important scholarly journal, Nature, and this study was a seminal study in the history of Alzheimer’s research. And what Matthew Schrag found in looking at it, stunned him.

And I was actually on the phone with him just very shortly after he started to look at this. And the two of us were a little bit gobsmacked by it, because here you have a situation where one of the most influential studies in the last couple of decades seemed to have been based on doctored images.

FLORA LICHTMAN: Doctored images. What should I be picturing? How are they doctored?

CHARLES PILLER: I think the way to think about these doctored images is two key examples that are very prevalent in Alzheimer’s research. One is something called micrographs, which are highly magnified images of tissue– usually brain tissue in this case, could be animal or human brain tissue. And the other is something called Western blots. Western blots are a technique for displaying different proteins, and you can show both the amount of a particular protein and the types of proteins that are within a tissue sample.

This is very important because proteins are thought to be key to understanding Alzheimer’s disease, and so alterations can be made in each of these kinds of images. Things can be moved around. They can be copied and pasted. They can be erased to sort of suggest that an experiment was successful, when there are reasons to doubt that it actually was proven.

FLORA LICHTMAN: So the image is actually the data. I mean, it’s essentially falsifying the data.

CHARLES PILLER: Exactly right. And just to provide a little bit of context, as part of the research for my book, I worked with a number of forensic image analysts who are experts in trying to identify possibly doctored images. And we looked at 46 scientists in the field, many of them leading figures in Alzheimer’s research, and found there were many hundreds of studies that appeared to be based on doctored images.

FLORA LICHTMAN: Many hundreds of studies.

CHARLES PILLER: Many hundreds, yes, that had been cited about 80,000 times in the scientific literature.

FLORA LICHTMAN: OK. Many hundreds of studies that have been cited 80,000 times had doctored images.

CHARLES PILLER: That’s exactly right. Yeah. It’s sobering, a degree of concern associated with apparent misconduct or error or both in the field.

FLORA LICHTMAN: Talk to us about the amyloid hypothesis. You know, what is it and how does it fit into this?

CHARLES PILLER: So let me go back, if I may, very briefly, more than 100 years to the way in which Alzheimer’s disease was discovered and named by the German scientist Alzheimer, who was the guy behind all this. So he was a pathologist, meaning that he did autopsies, and also a clinician for people with dementia. And he had a patient who had very serious dementia. After she died, he did an autopsy of her brain.

And what he found there were a couple of different kinds of classic Alzheimer’s-related proteins. Now, one is amyloid beta plaques. These are the sticky plaques that people hear about related to Alzheimer’s disease. And the amyloid hypothesis holds that the presence of these amyloid proteins leads to a series of biochemical changes in the brain that ultimately kills brain cells and causes dementia. So there was a lot of logic and a lot of really clear evidence to suggest that amyloid proteins were at the heart of this problem.

But for decades and decades and decades, there wasn’t that much money and that much time spent on research associated with the disease because of a simple demographic reason, not enough people were living to late old age when Alzheimer’s normally becomes a problem. And so consequently, as medical developments started extending our lifespans, suddenly the population of people experiencing Alzheimer’s dramatically grew and the government started to say, this is a big problem. We’ve got to spend a lot of money on it. And it was during that period, actually in the ’80s and then early ’90s, where this amyloid hypothesis developed and became the central focus of research for a very long time.

FLORA LICHTMAN: So a lot of fields have dominant hypotheses, right? What goes wrong, in your view, with the amyloid hypothesis?

CHARLES PILLER: What has gone wrong, in my view, is that there has been– I don’t know, you could probably call it something like a scientific monoculture that developed around this hypothesis. And there’s a way in which the domination of one set of ideas that are characterized by this amyloid hypothesis had taken hold in the field that tended to crowd out other ideas and kind of lead to a groupthink and a lack of creativity that was getting funded and well supported by the scientific community.

FLORA LICHTMAN: What I’m asking is, so there’s this dominant hypothesis, and I totally understand how that might lead to people pursuing fewer alternate lines of research. Right? Because the funding dollars are all going to flow through this dominant hypothesis. But how does that lead to misconduct?

CHARLES PILLER: Yeah. Well, it doesn’t inherently lead to misconduct. By no means does it do that. But the way the amyloid hypothesis ties into this issue is as follows. When an idea is so dominant in the field, it creates incentives for people to go after that idea. And this is in terms of funding and to get credit for important work. If you move with the conventional wisdom, you often have greater success.

But there’s also another side to it, which is that if people are dishonest, it’s clear that being dishonest or doctoring images in a way that fits in with the conventional wisdom makes it easier for them to get through the gatekeepers of science, the institutional authorities whose job it is to ensure that the science behind these studies is true and correct.

If you’re meeting their expectations with yet another permutation or finding associated with the amyloid hypothesis, then people are thinking to themselves, oh yes, of course, we expect this. It must be right. And that is the problem.

FLORA LICHTMAN: Confirmation bias.

CHARLES PILLER: Exactly right.

FLORA LICHTMAN: You know, of course there’s wrongdoing and cheating and fraud in every industry, as you say. You know, people are people. But I think what’s so shocking about your book is that science is supposed to be self-correcting. Like, there are mechanisms in place, like independent peer review and replication of experiments and double blind studies that are supposed to guard against all this, but it seems like they’ve failed in this case.

CHARLES PILLER: Well, I totally agree that science is self-correcting, but it may take a very, very long time. As Matthew Scheraga said, you can’t cheat to cure a disease. So in the long run, science is going to grind on and people are going to figure this out. They’re already figuring it out, and then new ideas will take their place.

FLORA LICHTMAN: You know, we’re in a moment of high scientific skepticism. What do you make of people who point to this story and say, look, the scientific process is a fraud?

CHARLES PILLER: Yeah, thanks for asking that question, Flora. It’s something that I ponder and think about all the time, in part because there are people who dishonestly try to point to these kinds of investigations and say, it proves that all science is unreliable. This is nonsense. You know, even though this is a book that describes a lot of misconduct in the field, I would say that, on the whole, the vast, vast majority of scientists who are doing this work are honest, well-intended, and do this research with great integrity.

And I think the fundamental problem is that the scientific institutions that are charged with ensuring the integrity of the system– the funders like NIH, the regulators like FDA, universities and the scholarly journals– many of them have been very complacent. They haven’t taken the concerns associated with image doctoring and other forms of misconduct seriously enough. And as a result, their processes for detecting, correcting, and at times policing the scientific record have been inadequate.

And so what I think my book is is an opportunity for those institutions to take a good, hard look in the mirror and say, what has gone wrong in our important areas of research that we need to address much more deliberately and with greater responsibility and with greater speed? If they do not, I’m afraid that anti-science forces, including some within the current administration in Washington, they will do the job themselves, and it will not be pretty. So I’m asking the scientific institutions to think about it and to do better.

FLORA LICHTMAN: If you could wave your magic wand, how would you change scientific institutions?

CHARLES PILLER: People need to understand that the investigations of allegations of misconduct usually are managed by the home institution of the investigator. So if it’s a professor at a university, it’s that university that looks into the problem and tries to find out whether there’s any truth to the claims of misconduct.

That is probably the least efficient and worst way to do it, because that institution is very conflicted. They have the most to lose and the least to gain by doing a swift and penetrating and publicly accessible examination of the issues. So we need to have independent agencies that would handle those sorts of investigations. That’s step one.

Step two is that scholarly journals, which are the gatekeepers of scientific knowledge, they definitely need to up their game in examining and correcting doctored images that come through in papers that are submitted to them for publication. Step number three, I think, is that FDA and NIH need to be vetting candidates for jobs and drug development candidates for possibly doctored images in applications. They’re not doing that well enough.

And so what you have is drugs, like the drug from Cassava Sciences that have suspect research behind it, that instead of being stopped in midstream to be re-examined, it just sails through the FDA approval process and then fails of its own weight. In the meantime, patients who were involved in those clinical trials were, in effect, being exploited for no good.

FLORA LICHTMAN: You’ve been reporting this story for years from all of those conversations that you had. What’s your takeaway on the root cause of these problems?

CHARLES PILLER: Sure. I think the root problem is, first of all, this is a disease that is so difficult to solve. The brain is so complex. There’s so much we don’t know about what might cause the disease and how it progresses. And consequently, there’s an enormous amount of frustration in the field. More frustration, I would say, than in other diseases like heart disease or cancer, where there have been solutions found to many of the elements of those diseases. So one part is frustration, which leads to people cutting corners.

But what I’m saying is that people who benefit from these studies that have been inappropriately altered have a responsibility to redouble their scrutiny of science. Science is a team sport. It’s very difficult in today’s very complex, experimental world for one person to do one of these kind of experiments. And so it means checking, double checking, verifying information, and trying to validate that the findings really are what they seem.

FLORA LICHTMAN: Charles, thanks so much for talking with us today.

CHARLES PILLER: It’s been my pleasure, Flora. Thanks for your interest.

FLORA LICHTMAN: Charles Pillar is an investigative reporter at science magazine and author of the new book, Doctored Fraud, Arrogance and Tragedy in the Quest to Cure Alzheimer’s. He’s based in Oakland, California. If you want to read an excerpt of the book, go to sciencefriday.com/doctored. That’s sciencefriday.com/doctored.

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