Potential fabrication in research threatens the amyloid theory of Alzheimer’s

https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

by panabee • 4 years ago

604 253 4 years ago

tmaly• 4 years ago

Yes, that is a lot of grant money to waste, but I think the biggest loss here is 16 years of research in the wrong direction.

nabla92• 4 years ago

Intentionally diverting resources and skewing research from one of the most biggest growing epidemics of our time seems seems like huge crime against humanity that has not been criminalized yet.

johndhi• 4 years ago

hehe, ironically diverting resources and skewing research and overall making worse the biggest PANDEMIC of our time isn't a crime at all :)

legulere• 4 years ago

Alzheimer isn’t a growing epidemic. The incidence is going down.

upwardbound4• 4 years ago

Agree. The perpetrator should go to prison for some sort of criminal fraud or racketeering or whatever a prosecutor can apply. This is serious crime.

permo-w• 4 years ago

based on the comments from alzforum, the relevant academics do not see this as 16 years of research in the wrong direction. they seem to see it as an invalidation of one branch of the research, while the overarching theory is still intact

the cynic in me suspects that they're saying that to maintain their - presumably funded - status quo, but not being even remotely knowledgeable in the subject, I have no idea whether that is well-founded

snapetom• 4 years ago

Holy hell. Someone please correct me, but the beta-amyloid camp has been under attack, establishment researchers still keep going despite weak evidence, and now the best drug they have might have fabricated data???

resoluteteeth• 4 years ago

Nope. It wasn't evidence for a drug that was fabricated, it was a 2006 study published in Nature that convinced everyone to believe the amyloid hypothesis.

JPLeRouzic3• 4 years ago

* it was a 2006 study published in Nature that convinced everyone to believe the amyloid hypothesis.*

The amyloid hypothesis is one century old.

jamiek88• 4 years ago

Oh my god if true, and it looks to be true this is huge.

The amyloid beta (Aβ) hypothesis has always been fishy but this paper is basically the bedrock of the current investigational trajectory.

The Aβ hypothesis was almost dead in 2006 when this method was invented and results posted and it sent shockwaves through the research world. Since then spending on Aβ research by NIH has gone from $0 to $290 million all it seems based on a lie cited over 2000 times in further papers.

The article is pretty convincing as is the independent verification that not only concurred but found additional evidence.

Sylvain Lesne has some ‘splainin to do.

phkahler• 4 years ago

> it seems based on a lie cited over 2000 times in further papers.

Since papers tend to get published only if they have positive results, what does it mean for thousands of publications all citing a fraudulent paper? This seems really strange. If the first 1000 failed to produce results and were partially based on that original paper it should cast significant doubt on it, but again failures are rarely published.

What does this mean then?

api2• 4 years ago

Citation doesn't mean dependency. It just means the paper was mentioned. What it does mean is that each and everyone of those papers must be re-examined with extra scrutiny to see if they hold up without the cited paper.

BoorishBears• 4 years ago

That's why it was described as a "bedrock".

A lot of papers that came after were producing results in the framework it established.

Because of the nature of a disease like Alzheimer's not many studies can easily measure the final effectiveness of their addition to the space on patients.

derbOac2• 4 years ago

To me this is one of the most damning things about this: all the people citing these papers and probably burying negative results. Yes, fraud is unacceptable, but what about all the people using it to further their careers?

These types of cases tend to focus on the fraud, but then everyone eventually walks away and then there's no larger discussion of how this was enabled by the field to have such a hold.

I don't buy the idea that it's all so quixotic and involves so many variables to get right that who knows what's causing a lack of replication. I've heard whispers like this about other big effects in other fields. People know what's going on, and often it's right there in published results but ignored.

isitmadeofglass• 4 years ago

What does this mean then?

Imagine I post an article that’s fraudlent and ”proves” that small rocks of a certain size and color keep away tigers. You won’t then see 200 articles saying they tried to replicate this and failed. What you see is 2000 articles dealing with how to find rocks of this exact size and color, siting my paper to support why it’s relevant to be looking for rocks in that category.

civilized• 4 years ago

If the results are fraudulent, why didn't anyone notice in the past 16 years that they failed to replicate?

AB6742• 4 years ago

The main thing is that it's never valuable to exactly replicate a study, from a commercial, career or publication perspective. Other studies may 'incidentally' cover the same ground, but then there are any number of variables which can explain why "this seemed to be different, but".

That being said, numerous papers have been published undermining the 'amyloid beta as primary disease driver' theory already. Or at least, finding no statistical correlation between AB and neuron death or that sort of thing. The most valid hypothesis that I've seen is that AB is just a supporting element for another amyloid, tau, which does correlate with toxicity.

mtlmtlmtlmtl2• 4 years ago

If this is true, it is beyond fraud. These are crimes against humanity.

My paternal grandfather got diagnosed at around 70, and my father is 62 now, definitely getting more forgetful but normal for 60+... Still, I worry about him regularly. My father is a clinical psychologist, he's helped people all his life.

These news make me so angry I can hardly see straight. I genuinely hope this sociopath waste of skin gets Alzheimers himself, and has to relive every moment of his disgusting crimes as his brain slowly turns to mush and he forgets every person he ever loved(if he is even capable of love...)

JPLeRouzic3• 4 years ago

This guy might well have cheated but how could he be responsible for the huge mess which is the amyloid-β research (and amyloid-β lobby as told by Statnews [0])?

Sylvain Lesné, has no Wikipedia page. He seems to publish roughly a paper per year while some famous scientists publish one every month. He is not at the origin of the amyloid-β hypothesis which is more than 100 years old.

Even more there are thousand papers published about Aβ*56 and Alzheimer's disease. How could this guy responsible for this mess?

And if what he published was wrong, why this was discovered only 18 later if thousands scientists are working in the field?

My understanding is that there is a need to find a scapegoat for the amyloid-β and pointing to an obscure guy is in the interest of many big fish.

[0] https://www.statnews.com/2019/05/21/alzheimers-disease-amylo...

fabian2k4• 4 years ago

As far as I understand this is not about the Aβ hypothesis itself, but the toxic oligomer hypothesis.

spfzero• 4 years ago

The OA points out it was, or was one of, the most cited papers in subsequent AB research. They make the argument that it has mislead many other researchers and cause a waste of many millions in funding. He's not an obscure guy in the field of AB research.

dralley• 4 years ago

That's precisely why it should have been caught earlier.

xigency• 4 years ago

So the observations it made were pivotal to expanding research, but none of the following studies discovered counter-evidence? It seems like something is missing here.

jibe• 4 years ago

Even more there are thousand papers published about Aβ56 and Alzheimer's disease. How could this guy responsible for this mess?*

Because he started it?

https://www.nature.com/articles/nature04533

But it is ultimately in indictment of everyone who went along unskeptically, collecting grant money.

JPLeRouzic3• 4 years ago

Because he started it?

This paper is from 1988:

https://pubmed.ncbi.nlm.nih.gov/2893291/

elliekelly• 4 years ago

What (if any) recourse is there against those who have falsified scientific data? It almost feels like fraud on the {scientific research} market. Billions of dollars and, perhaps even worse, countless human hours, have been wasted in reliance ob completely fabricated information. For what? An ego boost? Citations? I don’t work in science so I truly don’t understand the motive(s) on the other side of the equation.

dormento• 4 years ago

And people who might've benefited from an actual, more reliable treatment who might have been developed, had the scientist refocused to other hypotheses.

This is infuriating.

MattGaiser2• 4 years ago

Presumably the same incentives as everywhere else. Money.

hackerlight2• 4 years ago

Personal gain, whether that's money or status, at the expense of other people.

derbOac2• 4 years ago

This is so typical of contemporary academics, at least in biomedicine, I don't know where to start. For me, this is exemplary of a lot of what I see in the field, that happens every day, to larger or smaller degrees. It's not the exception.

There's so many elements to this story that echo things I've encountered, and read about in studies of trends. For every case of outright fraud like this might be, there's dozens of "soft fraud" (read: "questionable research practices") that get the benefit of the doubt or are never brought to light. No one has discussed this here yet, but part of the story is that the program officer on one of the accused' recent grants was a coauthor with him on this very research -- consistent with trends discussed in the literature (of the largest predictor of grant receipt being coauthoring papers with grant review panel members or officers). So there's this fraud, potentially involving someone who then goes on to help decide who gets research dollars.

Your reaction is something I've wrestled with a lot. Many times there are no consequences really. People talk about lost reputation or something, but in cases of soft fraud nothing really happens. It just all kind of evaporates into a fog of scientific dispute between parties. In cases of blatant, legal fraud, someone can be fired or lose a position, but that requires significant evidence.

For what? Yes, ego, citations, money, titles, accolades as a "rising star" or a "genius" or whatever it is.

The saddest thing to me really, aside from all those harmed by bogus treatments, or forgoing real treatments, is all the researchers with legitimate ideas, who go against trend, who are pushed out because doing the hard work isn't glitzy and has lots of dead ends. You end up in this system where the buzz is what matters, and riding waves of self-perpetuating hype is what gets you to the top. Appropriate skepticism and careful thought, meanwhile, costs you because that takes time and risk.

fabian2k4• 4 years ago

When I started reading the article I thought the title was a bit click-baity for Science. But then I noticed that the theory it refers to was not the amyloid hypothesis itself, but the toxic oligomer hypothesis that emerged later. That theory is pretty much the main potential explanation on why every single drug targeting Aβ failed that still keeps Aβ fibrils relevant. It's a very convenient theory because it keeps the main original observations about the fibrils relevant while explaining why therapies that target them don't work.

One part that is really important that is mentioned in the middle of the article is that these systems are very difficult to handle, and it's almost impossible to make many of them nicely reproducible. Fibril and oligomer formation depends a lot on the environment and reacts to tiny differences.

I find this kind of fraud deeply frustrating, there is so much wasted effort in the wake of faked high-profile results.

chmod6005• 4 years ago

"very difficult to handle, and it's almost impossible to make many of them nicely reproducible"

Those same qualities that make a study hard to reproduce should also create skepticism that the first study was done properly.

fabian2k4• 4 years ago

It's more insidious than that. In a field where the core subject is difficult to handle it is nothing unusual if a different lab cannot recreate known experiments on their first try. This doesn't mean anything is wrong with the original research, it might just mean that the second lab didn't control all the variables.

The part that is difficult and annoying is that the variables are not necessarily known, it takes a lot of time and experiments to actually nail down those. And even then for some sensitive stuff every detail can matter, like the exact type of tube you did the experiment in or the vendor, batch and age of every chemical you used. Very often you can control this enough to have consistent results for a set of experiments, but that kind of stuff is really hard to control across different labs.

buscoquadnary• 4 years ago

It turns out applying those might not even be enough.

https://slatestarcodex.com/2014/04/28/the-control-group-is-o...

szundi• 4 years ago

If they wrote this in the article then bad interpretations are coming from readers.

It makes sense to publish this, maybe someone else can make it stable and reproduce.

spoonjim2• 4 years ago

I worked for a pharmaceutical company that tried to open a second factory producing more of the same thing that it was already successfully making and it never worked. They built the entire factory, it didn't work, they spent years and millions of dollars trying to debug it, it simply never worked out. They ended up just essentially running the US factory at three shifts to meet the increased demand. To this day I don't think anyone knows why the European production line never worked. Things can fail to reproduce without fraud.

panabee3• 4 years ago

as a non-scientist outsider, a few questions if you don't mind:

1. is it common for a non-reproduced experiment to gain prominence as a leading hypothesis and spur related research?

2. if so, why? if not, why did this hypothesis take hold?

3. how can we make science more reproducible?

reproducibility is held as a tenet of science, but this example, assuming it is true, would violate the principle.

londons_explore• 4 years ago

Trust, but don't verify, because verification is expensive and unrewarding both financially and career-wise

ethbr0• 4 years ago

1. Yes. Science has a snowball effect as a result of committee-driven grant decisions. Research in a hot current topic attracts more grant funding more reliably.

2. It does because some fields of science are intrinsically long-duration, highly sensitive to variables, or only testable at scales that exceed our experimental capability. That's just a consequence of physics and natural laws of reality. E.g. nutrition, chemical toxicity, economics, high energy physics.

3. We can cheat and find proxies or more tenable micro-systems to experiment on. But often those have their own problems (e.g. rodent models) or aren't feasible.

Reproducibility is a goal of science. It's not always an achievable goal.

When it's not, we do the best we can, as with drug testing pipelines.

ta9882• 4 years ago

One of the issues is that by chance the models used have an unexpected behavior that seems to confirm the initial hypothesis is sound.

And this is not rare. Sometimes it is fraudulent, people know things are faulty but continue anyway. In other cases it could be by ignorance of the existence of the phenomenon behind the faulty behavior or simply because that phenomenon has not been discovered yet.

elihu2• 4 years ago

The standard of truth in science is reproducibility. But publication usually happens before results have been independently reproduced. Papers are peer reviewed, but generally peer reviewers are just ensuring that the results are sufficiently interesting to warrant publication and there aren't any obvious methodology mistakes.

For the purpose of funding, publication in important journals or conference proceedings is the important thing. And the public generally tends to treat publication as the standard of truth. But publication kind of works on the honor system and is susceptible to fabricated results.

Maybe there should be more funding towards reproducing (or not) important results?

galangalalgol• 4 years ago

What are the other hypothesis that would have been explored in the absence of the toxic oligamer papers?

AB6742• 4 years ago

It's not even the toxic oligomer hypothesis that is undermined - it is only the role of amyloid beta as a primary driver of Alzheimer's pathology. This isn't even out of nowhere, there's been plenty of data finding no strong association between AB levels and pathology. Most data seems to point to AB being more of a supporting element, with tau amyloids actually being associated with toxicity and resultant functional deficits.

chmod6005• 4 years ago

Proposal: if a paper isn't reproduced in ten years after publication, then it gets automatically retracted (which can be reversed as soon as it is reproduced). Any papers that cite the retracted study (in a way that the conclusions depend on it) would also get retracted. That would be powerful incentive for all the researchers who cite the study to try and reproduce it so their papers don't get retracted.

You could still search these retracted studies when doing research, of course. You just can't cite them.

axg113• 4 years ago

This is a powerful idea. Most problems in science are incentives problems. Sadly there's little or no incentive for journals to adopt this policy.

cjmb2• 4 years ago

I agree.

Correcting the many incentive problems in modern American science would need a hypothetical body with significant funding leverage over journals & scientists to exert executive action. Sadly there is no such centralized funding body, so the problem must be unsolvable.

anakaine• 4 years ago

The same issues exist. The next dodgy scientist on the hamster wheel looking to get a name for themselves will claim reproducibility and then publish a follow up in the spirit of publish or perish. You could further entrench the issue with this approach, unfortunately.

lamontcg2• 4 years ago

Better solution might be for the government to just fund reproducibility studies, and even departments of reproducibility. Take the profit motive out of it, find good scientists who are painstaking but maybe not innovative and fund them to reproduce major results. The scientists would never get the credit for major breakthroughs, but could occasionally be wrecking balls that called research like this into question. With consistent and reliable funding from the government their reward could be stability of employment rather than innovative fame (of course these days some partisan politics would probably gut it, which is why we can't have nice things).

abeppu• 4 years ago

Is there a level of collaboration among so many people that at least data can be re-used without being "reproduced"? I.e. the field as a whole has put enough work into an apparatus or infrastructure that we can regard the initial observation to have been trustworthy? We shouldn't have to build a second LHC before we believe any claims from the first one, right?

mtlmtlmtlmtl2• 4 years ago

Actually the LHC does have two detectors with completely independent research teams, often doing the same experiment.

chmod6005• 4 years ago

Hypothesis comes before data collection in the scientific method.

You can share equipment, but if you share data, then it's the same experiment not a new one reproducing the first.

Sharing data would not only miss fraud, it would miss experimental errors (e.g. spilled beer in the petri dish), p-hacking, etc.

MattGaiser2• 4 years ago

What percentage of research is ever replicated? Are there a lot of scientists doing replication studies?

swatcoder• 4 years ago

All that does it create an industry for replication labs, and then a market where these labs compete to develop the most "guaranteed" replications for the least cost, and then a whole lot of replications which check the box but actually rely on strained interpretations, questionable modifications to process, uncaught fraud, etc.

That sounds worse than what we have since it just eviscerates the significance of what replication means in the first place.

sebastialonso• 4 years ago

It's almost like the free market is not the silver bullet algorithm many seems to think it is.

smt88• 4 years ago

This would work. For-profit replication labs could be part of it, but the market would have to be regulated such that:

- any university receiving public funding must participate in mandatory replication

- some % of any grant would be reserved for replication

- replication labs would be licensed/accredited, subject to government inspections

- labs would not be able to choose who replicates their work

- replication labs would be rewarded for the work, not for the outcome

dmatech2• 4 years ago

We just need to cement the notion that no theory is truly proven or beyond attempts to disprove it through replication. Attempts to discourage replication should be a red flag.

Fomite2• 4 years ago

The amount of money for an NIH R01 non-modular budget hasn't changed since 1999. Which means due to inflation, the average "gold standard" grant budget covers half as much as it used to, roughly.

Wherein are you going to fund mandatory replication studies - some of which are massive cohort studies, so you're going to need a whole new population cohort - let alone the...citation police...to review every citation not just for its existence, but for its content.

c3534l2• 4 years ago

How about the threshold for publishability is that two independent groups come up with the same conclusion? So you have to partner with another team somewhere else in the world in order to get published, and then you get joint credit.

chmod6005• 4 years ago

I think there's a powerful incentive to be first, which drives people to research in the face of so much doubt. Trying to convince one lab that the idea is worth funding is hard enough. Two labs is just unrealistic.

My idea hacks around the problem by not diminishing that huge incentive to be first. Even if your paper is retracted due to lack of repro study, you were still the first, and if it does repro you are back to full credit.

I just add an extra incentive to get people who cite the study to verify that its reproducible. And at the same time, give the original author more incentive to include lots of details in their papers so it's more likely to be reproduced, and lock in their fame.

macinjosh• 4 years ago

FTA:

"“So much in our field is not reproducible, so it’s a huge advantage to understand when data streams might not be reliable,” Schrag says."

I am just a lowly engineer, but this alarms me. Why is anything that has not been reproduced considered valid science by anyone? Why aren't our standards higher?

If you can't reproduce an experimental result, it is useless information is it not? At least an experiment that can be reproduced yet fails to prove a hypothesis can teach you something. An experiment that cannot be reproduced yields no useful information. In fact, it can even mislead!

I just don't understand the motivations at play. These are obviously intelligent people who know that you can't fake reality, so why do they publish fraudulent papers? Just for short-term gain? Do they become blinded by belief in their hypothesis?

ncmncm24• 4 years ago

They are blinded by assuming good faith and competence.

Most scientists consider most of their colleagues more or less incompetent, and even where they accept experimental results, often reject the experimenter's interpretation of the result, often correctly. Scientists advise us to ignore the abstract, ignore the interpretation, ignore the conclusion, and trust only the data, at most. But we mostly don't get to do that for fields not our own.

High prestige is detrimental in that it short-circuits this skepticism. This happens not only in Alzheimer Syndrome work. It put psychology research in the grip of behaviorism, statistics in the grip of non-causality, political science in the grip of dialectics.

niemandhier2• 4 years ago

Biological systems are so complex that reproducing results is extremely hard even if the authors publish their method in detail, simply because they might not know why it works for them.

This is hard to understand for software people, since code tends to behave reproducible as a default.

Basically the only way to reproduce a difficult finding is to learn the procedure at the original lab.

An example: A friend of mine could not reproduce his own findings in another lab. Turned out the precise type of the lamp build into the setup mattered.

Another example: I could not reproduce a finding the was something I wanted to build upon. Turned out the precise method to dissolve one of the chemicals in the buffer as the problem. It was even hinted in the paper, but who would describe in detail what he means by “ vigorously stirred” ?

ncmncm24• 4 years ago

This is why almost all results from running rats in mazes are spurious.

There was an early, very good paper identifying all the details needed to make a valid maze experiment. Nobody cites it, so nobody reads it or acts on its results.

ALittleLight• 4 years ago

Biological systems being complicated and unintuitive is an excellent explanation for slow or no progress. It's entirely orthogonal to the question of why published results are not reproducible, misleading, or wrong. If some problem is super hard that explains why I can't answer it, it doesn't explain why I continually publish fake answers.

My understanding of the situation is that academics and scientists work in a weird bureaucracy, there is an incentive to publish, academics are very bad at detecting fraud and worse at punishing it and statistical manipulation is easy and endemic. These things explain why there's so much academic research that can't be reproduced and why some academic fields are basically the modern equivalent of astrology.

axg113• 4 years ago

The most powerful results in science are continually reproduced by being built upon to uncover further new knowledge. I'm no expert in the toxic oligomer hypothesis or Aβ hypothesis, but it appears that these paths have led to very little new knowledge.

api2• 4 years ago

It reminds me of the eating cholesterol hypothesis for artery blockage and heart disease. Most artery blockages are made of cholesterol therefore eating cholesterol must be the culprit. Simple, straightforward, and now apparently wrong. The cholesterol buildup is a symptom of something else.

Seems likely with Alzheimers that the amyloid buildup is a symptom not a cause.

ramraj072• 4 years ago

Still half a billion dollars of NIH money went into this sub field.

The article points to how the main accused got an R01 approved AFTER this misconduct started to come out, and the guy awarding it was one of the coauthors of the first fabricated papers.

ta86452• 4 years ago

There is so much of this, through many fields of science today. Incentives that corrupt and undermine the scientific method. And yet, many people will deny that there is justification in skepticism of say, relatively new mRNA vaccines.

Yes, it's good that science usually deals with such problems in the long run, but how is the average person supposed to trust that the latest scientific assurance, isn't 15 years away from being retracted like in this example?

JulianMorrison• 4 years ago

A big part of the problem is things moving so fast that a lot of stuff doesn't have a long run. Covid and its vaccines being an example. In the end the reason to trust them was a mix of "if not this, then what?" and "it doesn't seem to be killing people".

fabian2k4• 4 years ago

We have a lot of really good evidence that the vaccines are preventing a lot of deaths.

ncmncm24• 4 years ago

We cannot be confident that "science usually" overcomes faulty models. The best we can say is that science has often been seen to succeed at this, in well publicized cases. Many less visible fields might never overcome their biases. Usually a field cannot correct course until a whole generation trained on a false premise dies or retires.

Economics is a field that has been particularly resistant to correction, but is far from alone. Geology and statistics are recovering from a similar handicap.

As Max Planck is often quoted, "Science advances one funeral at a time." Often vindication is finally delivered only after all the opponents are dead, and the ultimate victor has retired from a career blighted by them. Probably much more often people are driven out of the field and never vindicated.

Lynn Conway was driven out of computer architecture (where she invented out-of-order execution in the '60s, thus long delaying that advance) before finding success many years later in VLSI chip design methods.

upsidesinclude6• 4 years ago

This is what makes statements like "trust the science" so sickening. Science isn't religion and it isn't always honest

ncmncm24• 4 years ago

The science is only more reliable than non-science, not reliable in any absolute sense. And scientists are as fond of superstition as anybody.

Masks were described as useless for countering COVID transmission because of what turned out to be superstition around "airborne transmission", itself finally traced to a result that properly only applied to tuberculosis.

Belief in ivermectin efficacy was a similarly widespread superstition among mostly non-scientists.

We have generally had much better results from science. Science was finally obliged to abandon its "airborne transmission" model by people who knew better publicizing correct information. But most ivermectin fans still cling to it.

m348e912• 4 years ago

You have to think that this type of news does add ammo for climate science deniers, covid vaccine skeptics, and ivermectin/hcq proponents to make the case consensus science != absolute science. Regardless, I do think most people agree that all science should have the opportunity to be subjected to earnest and thoughtful scrutiny, and it shouldn't be a career ending endeavor to do so.

throwawaylinux• 4 years ago

The science is only more reliable than non-science, not reliable in any absolute sense.

What "the" science?

The scientific method is proven to be a very good way to make predictions about the world based on observations. The body of scientific work built up is immeasurably valuable and incredibly good at predicting things.

Some random corporation or politician or person claiming to have The Science on their side, and that anybody who disagrees or questions them is a heretic and an unbeliever? That's not reliable and it's not science.

rtsil2• 4 years ago

One problem the amount of press and hype that these type of research receive in the mass media (same thing for the "cancer cure breakthrough"), likely promoted by researchers and labs looking for funding, and which generally amount to nothing. The general public may forget about a specific claim, but they don't forget the number of false or misleading headlines they've read over the years.

Add to that a blatant case of forgery like this on a high priority subject, and you have the recipe for antivaxx, covid denialism and overall decline of the trust in science.

upsidesinclude6• 4 years ago

"Superstition" does a disservice to the fact that many scientists internationally were reporting on efficacy with ivermectin. Meanwhile the information coming from "reputable" sources in the world have proven to be less than accurate if not complete misrepresentation

Edit:

There is no such thing as 'the science'. There is science. Which is testing and questioning to determine facts. Anything more must be "trust in the science of..." some actual thing. And that actual thing is not public policy. We have sufficient evidence that the CDC and NIH are interested in appeasing their corporate sponsors and otherwise believe themselves to be beyond reproach

CRConrad4• 4 years ago

Science isn't religion and it isn't always honest

Weird. Reads to me as if you're saying religion is honest?

upsidesinclude6• 4 years ago

That is an inference in error.

Merely two things that are true and referred to in the opposing sense.

Religion is built upon dogma, which science should not be. Honesty is built upon truth, which science should be.

ThePhysicist• 4 years ago

Reminds me of that famous paper about Majorana fermions [1] that got retacted because they edited a figure (I'd say with malice) to support their sensationalist claim. In the unedited image the claimed effect is all but gone. The publication of the paper led to a flurry of research funding and a partnership with Microsoft (who were keen on using Majorana fermions for topological quantum computing).

1: https://physicsworld.com/a/retraction-of-nature-paper-puts-m...

ChrisMarshallNY• 4 years ago

I remember the story about the addiction "study" ("Porter Jick") that was used as the basis for declaring OxyContin "non-addictive." It was dramatized (but fairly accurately) in Dopesick.

It was a letter to the editor, by a doctor, describing a small study on hospitalized patients, and was seized upon by Purdue, as the basis for their entire sales pitch.

When there's money to be made, people can look the other way, quite easily.

schnitzelstoat2• 4 years ago

"It is difficult to get a man to understand something when his salary depends upon his not understanding it." - Upton Sinclair

jajag• 4 years ago

Ashe declined via email to be interviewed or to answer written questions posed by Science ... But she wrote, “I still have faith in Aβ*56,”

Richard Dawkins won't be impressed.

LeonB• 4 years ago

I felt like the author’s choice to quote that specific part of whatever she wrote was a pretty harsh choice. As a reader you see that and jump to the exact conclusions you’re alluding to here.

f38zf5vdt• 4 years ago

There are so many correlations of vascular injury with dementia that it seems obvious that the fibrils would not be causative but rather correlated to dementia. I personally believe that dementia is related to or caused by repeated small vascular injuries that eventually cause degradation of the brain. That is, transient ischemic attacks that are completely subclinical aside from the injury that is visible after autopsy.

dang2• 4 years ago

How an Alzheimer’s ‘cabal’ thwarted progress toward a cure - https://news.ycombinator.com/item?id=21911225 - Dec 2019 (382 comments)

The amyloid hypothesis on trial - https://news.ycombinator.com/item?id=17618027 - July 2018 (43 comments)

Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017) - https://news.ycombinator.com/item?id=17444214 - July 2018 (109 comments)

mekoka• 4 years ago

Reminiscent of this equally upsetting article a couple of years ago https://news.ycombinator.com/item?id=21911225

lightup• 4 years ago

At the U of MN? Say it ain't so. My proud alma mater. Hacking linux kernel. Round up. Someone should start a list of what tax dollars pay for.

cleandreams• 4 years ago

Just to note the human cost, my father died of Alzheimers. It's not impossible this fraud prevented lives from being restored and even saved.

onionisafruit3• 4 years ago

What makes me the most angry about this is the huge difference between what the scientist personally gained from this fraud and the cost of believing in these results for that past 16 years. Maybe he is a bit richer because of this, but it comes at the cost of hundreds of millions of dollars being spent on research that is destined to be fruitless.

In the time since he published, I lost my father after investing hope that a trial that is supposed to prevent amyloid plaques and now my mother-in-law is slipping further into dementia.

nextos2• 4 years ago

As an insider, I am tempted to say research in most diseases is driven by lots of fraudulent and oversold results.

Maybe not direct image manipulation as in this case with Alzheimer's, but certainly there is always a lot of monopolistic rich-gets-richer behavior.

Nearly all professors at top universities I have met develop intimate relationships with funders and journals, which they use to steer the field in their preferred direction. As the posted article says "You can cheat to get a paper. You can cheat to get a degree. You can cheat to get a grant. You can't cheat to cure a disease."

I have been asked directly to misrepresent results on several occasions. In the most recent one, a professor who has received all prizes and accolades in his field threatened me and others when we refused to misrepresent research results. I could afford to do this, but my workmates who have families to support were on the brink of giving up to the bully.

prox• 4 years ago

We need a glassdoor-ish site for these kind of underhand dealings and fraud.

Also, make a paper/proof trail and get it to court/media/government.

onionisafruit3• 4 years ago

Thank you for making a stand on this. My doctor has a "No Free Lunch" sign in his office saying he won't talk to pharmaceutical reps. Maybe the research side needs a similar pledge to avoid being corrupted by funding. I don't know what it would be though.

maegul• 4 years ago

It’s also important I feel to stress that this behaviour exists at multiple levels of magnitude. A professor may not be bending journals and whole fields to their will, but can expect and pressure consistently positive results from their lab, to the point of being actively reckless with the truth and blind to the flaws in their theories.

Just getting caught up in the practice of self-promotion and the trumpeting of one’s “novel and impactful” ideas while managing a lab from the top without having done actual frontline research work in some time can take you pretty far from scientific integrity IMO.

With no culture of being proud of reporting negative or contradictory results, I’d say “excessive scientific zeal” is an easy and common trap. Even a slightly forceful lab-leader or PI can end up swaying a group of people into some grey dishonest zone of scientific practice.

dayvid• 4 years ago

I know two people personally who dropped out of PhD programs due to fraud in their departments. I never asked them too much about it, but I'm imagining it's related to not wanting to lose potential funding or waste years of research to a wrong conclusion.

CoastalCoder• 4 years ago

I have been asked directly to misrepresent results on several occasions. In the most recent one, a professor who has received all prizes and accolades in his field threatened me and others when we refused to misrepresent research results.

I wonder if intentional research fraud should carry legal consequences.

emmelaich2• 4 years ago

Can you tell us what level of fraudulence is present in research for other mysterious diseases? Such as MS or Crohn's or ..

axg113• 4 years ago

Fraud and fabrication of results are abhorrent, but this is too simplistic a take. These fraudulent results didn't single-handedly spawn 16 years of fruitless research. Instead blame the incentives that create a system where nobody validates a result for 16 years.

If academic science were in a healthy state, novel results would be validated 100s of times. The current system is setup such that only novel results are rewarded. There is no reward for validation. During my PhD I was actively discouraged from performing experiments/studies that weren't "new". Everything ultimately comes back to the funding model. Scientists are only funded for groundbreaking work, measured by the number of publications. In turn, journals will only accept previously unpublished work.

upwardbound4• 4 years ago

The fraudster's refusal to confess for 16 years as they saw the field go astray and elderly people suffer is a crime against the health of so many people. If I were a prosecutor I would try to get them for fraud, criminal negligence, or even manslaughter. If I were a vigilante, I would have some strong "words" with this perpetrator who caused so many elderly people to suffer. I hope they are brought to justice within their lifetime while they are still alive to be punished.

upwardbound4• 4 years ago

1,000% agree. I hope he is brought to justice and sees time behind bars.

mkl95• 4 years ago

Is there any relevant (non-fabricated) research about the causes of fabrication in research? Is it just money or is there something else?

nomel• 4 years ago

If it's anything like the data fabrication I've seen in industry, it's lack of ethics, laziness, mixed with deadlines/constraints beyond the individuals control, with a dash of arrogance that the conclusion is still correct, regardless, and it'll be fine.

I've also seen very qualified people have a massive holes in their perception, making them somehow unaware that they're generating garbage, and even defending the garbage when it's pointed out.

dmatech2• 4 years ago

And this is why I'm increasingly suspicious of "consensus" in the scientific establishment. With careers, egos, reputations, and grant money at stake, it's tempting to use one's power to entrench this consensus.

Scientific consensus has value, but science also requires that people be open to having their pet theories be validated through replication.

epgui2• 4 years ago

I'm a scientist, and I don't think things so easily become consensus. In order to get to consensus, a model needs to have been tested from many different angles. It's never enough to get to statistical significance, things either get replicated or, more often, triangulated.

Consensus is an extremely time-consuming thing to build, and it's extremely important to be aware of when there exists a consensus, where there isn't one, and what the consensus is.

It isn't an appeal to authority fallacy, it's a form of deferral to expertise, and it's one of the most important heuristics we have.

ramraj072• 4 years ago

Absolutely not true. I’ve seen things become consensus because of one single questionable image in one paper from a “trusted” lab.

In my alma matter field the question was whether her2 receptor recycles (has implication of all breast cancer antibody therapies that target her2) and a paper from a Genentech lab had ONE FIGURE (where different data points from different experiments) as proof. An entire sub field including projects in my own lab were spawned assuming this.

Whenever I point out this flaw in lab meetings I’d be shut down by my professors as “they know the authors they trust them”.

rmatt20002• 4 years ago

This is why I grit my teeth whenever I hear a politician say something like "the science is settled". Anyone who understands the scientific method knows to say "the science is settled, except if <some specific thing> happens".

c3534l2• 4 years ago

Its fair to be skeptical and to use your critical thinking abilities, but I worry that people go "oh, this generally credible source isn't perfectly reliable, I guess I'll go listening to crackpots and charlatans." Almost as bad is when you become convinced you have the answers, despite not being remotely qualified to speak on the subject. This is how you get flat earthers and 5G conspiracy theorists.

jrumbut• 4 years ago

I've begun to tune out societal criticism that doesn't come from someone with a better idea, who isn't willing to stand in one place and defend a proposal.

The experience of saying how you would do it better and getting it torn to shreds really brings you back down to earth.

telchior• 4 years ago

What does consensus mean, exactly? It doesn't sound like Aβ-56 had full buy-in; the article mentions people complaining about an "amyloid mafia" and half of all funding still going to alternate research, so clearly there were a lot of people who weren't part of whatever the "consensus" was.

What's really interesting to me is that such vast sums can be spent, a number of people apparently did not like the Aβ*56 hypothesis and had substantial reason to oppose it or try to find holes in it with substantial rewards for doing so, yet the ones to find problems were some dudes (without any funding at all) just poking around.

smm112• 4 years ago

Compare who has it, to who doesn't have it.

My un-scientific version of this is that if you have a large bowl of ice cream for desert every night for 55 years, you may develop Alzheimer's Disease.

onionisafruit3• 4 years ago

I've never heard this before. The people I have lost to Alzheimer's were very healthy up to the point where the disease started manifesting.

smm112• 4 years ago

https://www.cnn.com/2022/08/01/health/ultraprocessed-food-de...

Archelaos• 4 years ago

The article mentions that the main reason for suspecting that results were fabricated is that many images from the researcher's papers seem to have been manipulated. As someone who is not particularly familiar with AI but occasionally picks up on it here on HN, I am now wondering how difficult or easy it is these days to take a manipulated image of a western blot and feed it to an AI tool trained on unmanipulated western blots to create a deepfake that is then virtually indistinguishable from a true one. -- Can perhaps anyone here familiar with deepfake technology provide an assessment?

Taniwha• 4 years ago

I love how the researchers are shorting the stock - they're not insiders because the data is public available for anyone (with the requisite very domain specific knowledge) to see.

There a whole lot of the sorts of investor who are normally shorting stuff who must feel that this is somehow insider information

ta9882• 4 years ago

I worked in a lab doing research based on that amyloid hypothesis (working on other projects). The only thing that got out of it were molecules that were really good at messing up the assays used but had 0 biological effect in vivo. So in the end the lab optimized the protein and cell assays to make them were more sensitive to artifacts. This wasn't made on purpose, just a combination of human and institutional factors that combined as a perfect storm. Several dozens of academic papers were published on that... That's what happens when you have isolated labs in a university that doesn't favor and nurture collaborations but focuses instead on political and economical aspects. Now all the people that took the wrong decisions have either retired or got fancy positions elsewhere.

kyaghmour• 4 years ago

Patential link with diabetes: https://www.health.harvard.edu/blog/whats-the-relationship-b...

pedalpete• 4 years ago

"Potential"

I work in the neurotech/sleeptech space, and specifically in stimulation of slow-wave oscillations.

These SWOs decrease as we age, which is linked to the build-up of amyloid plaque, and increased insulin resistance. They aren't necessarily linked to each other, but rather to the decreased capabilities in the brain, from what I understand.

a-dub2• 4 years ago

forensic image analysis is cool and all, but i think maybe instead of:

"A neuroscience image sleuth finds signs of fabrication in scores of Alzheimer’s articles, threatening a reigning theory of the disease."

it would be better to see:

"A neuroscientist conducts an irrefutably strong study that upends 16 years of theory on the disease process behind Alzheimer's."

i don't care if someone cheated, i care that their results are discredited by scientific processes, not forensic review.

appleflaxen3• 4 years ago

The scientific process is the systematic identification of what is true.

Wikipedia: "the scientific method involves careful observation, applying rigorous skepticism about what is observed, given that cognitive assumptions can distort how one interprets the observation."

So identifying fraud is the scientific process.

a-dub2• 4 years ago

sure. but i think i'd rather see biologists debunk prevailing theories in biology by doing biology while in the process getting better at biology rather than dabbling in forensic image analysis. (although, who knows, maybe said dabbling could lead to some new meaningful insights down the line)

i guess the bigger point is that the act of topical inquiry should have inbuilt mechanisms for discarding ideas and approaches that turn out to be dead ends, without having to rely on them actually being fraudulent (they can be, and often are, completely legitimate, yet also completely wrong).

we shouldn't be discovering bad ideas in science by fraud detection, we should be discovering them by mainstream scientific process.

1-6• 4 years ago

How does this finding affect companies that have created therapeutics related to Beta Amyloid such as Eli Lilly or Biogen?

rmatt20002• 4 years ago

I wonder if the Univ. of Minnesota is has any potential liability here?

narrator3• 4 years ago

Methylene Blue is in phase 3 trials with Taurx[1] The patented version will be slightly tweaked version of the century old drug so they can make some money on it. Still, it would be one for the ages that an out of patent cheap drug makes decades and billions of research obsolete. They say it clears tau, but it probably works some other way like being an antimicrobial that can cross the blood brain barrier.

A doctor I know takes Kordon methylene blue which is pennies a dose.

[1]https://taurx.com/the-science/clinical-trials

pengaru2• 4 years ago

A Phase 3 clinical trial of LMTM (TauRx0237 or LMT-X), a derivative of methylene blue, failed to show any benefit against cognitive or functional decline in people with mild to moderate Alzheimer's disease. Disease progression for both the drug and the placebo were practically identical.

https://en.wikipedia.org/wiki/Methylene_blue#Alzheimer's

narrator3• 4 years ago

The cite for that was from 2016. The latest study has yet to publish results.

https://clinicaltrials.gov/ct2/show/NCT03446001?term=TRX0237

de6u99er• 4 years ago

Journals are often uninterested in negative results, and researchers can be reluctant to contradict a famous investigator.

hcknwscommenter3• 4 years ago

Something doesn't quite make sense here. It seems there is good evidence that certain figures in Lesne's papers are fraudulent. Certainly that is a huge red flag and it is likely that some (or all) of the findings are wrong. But that doesn't mean that the paper's ultimate conclusions are necessarily incorrect. I mean, thousands of papers go on to report on Aβ56, do they all just assume that Lesne's findings are true without further investigation? That seems highly unlikely. What's notable is that the entire article here never once refutes the most important finding of the original Lesne paper (Aβ56 can produce alzheimer's like symptoms in rats).

appleflaxen3• 4 years ago

What's notable is that the entire article here never once refutes the most important finding of the original Lesne paper (Aβ56 can produce alzheimer's like symptoms in rats).

You refute a paper by showing that part of it is incorrect. The research sleuths have provided incredibly strong evidence that the very existence of Aβ56 is demonstrated (in the paper) by a sham line on the western blot.

It's like somebody has demonstrated that a photo of a "ghost" is actually a double-exposed film, and you are stating "What's notable is that the entire article here never once refutes the most important finding of the original photo (that ghosts can haunt the waffle house)."

fithisux2• 4 years ago

Covid jabs are the next frontier in fabrication.

ken47• 4 years ago

Within its statistical boundaries, the scientific method is absolutely trustworthy. Humans though? Not so much.

WhitneyLand• 4 years ago

“The immediate, obvious damage is wasted NIH funding and wasted thinking in the field because people are using these results as a starting point for their own experiments,” says Stanford University neuroscientist Thomas Südhof, a Nobel laureate and expert on Alzheimer’s and related conditions.”

I guess he’s the Nobel prize winner, but I would’ve thought the immediate and obvious damage was unnecessarily delayed research progress while people are dying.

Over a decade? Who knows what the overall impact was.

icermann2• 4 years ago

I think many of us has heard about the Xerox copying machine changing digits on copies, using a "visually similar enough" replacement algorithm. https://www.theverge.com/2013/8/6/4594482/xerox-copiers-rand...

I wonder if you could get the same unexpected result when copying images of Western blots?

It's probably not the case here but it could be devastating for a researcher to be accused of fabricating data by using an affected copier/image editor/file format.

appleflaxen3• 4 years ago

No. The xerox machine had a digital analysis phase with a feedback loop between the image being recorded and the output being printed.

A western blot is a direct measurement.

It's like asking whether the xerox example might explain why the splatter pattern is identical in sections of two putatively different Jackson Pollock paintings.

icermann2• 4 years ago

Maybe I didn't make myself clear, but the image in the article looks like it could have made both one and two passes through a Xerox machine before it ended up in the paper.

bluenose69• 4 years ago

A new wrinkle in all of this is the current practice of promoting research to the public. Many (most? practically all?) universities employ nontechnical people whose jobs it is to identify newsworthy research results that can be dumbed-down and puffed-up in press releases.

Granting agencies do the same thing, either directly via newsletters and press releases, or indirectly, by encouraging research teams to hire public-relations people.

Members of the public cannot be expected to be able to read, let alone understand, the dizzying array of specialized articles that are published on any given topic. Heck, this is a real challenge even for scientists looking at work that is slightly outside their domain of expertise. Some form of overview is necessary, but press releases, usually biased and ill-informed, are just not the way forward.

But will press releases go away? No chance. This is how students get attracted to universities, and it's how alumni get encouraged to donate for that oh-so-important sports complex.

Gatsky• 4 years ago

She and others in the lab often ran experiments and produced Western blots, Larson says, but in their papers together, Lesné prepared all the images for publication.

This is a well known thing scientific fraudsters do, “touche finale”. Any scientist knows preparing figures for publication is tedious, no PI in their right mind would routinely do that.

dav_Oz• 4 years ago

One needs a theory of mechanism to develop an intervention i.e. "new drug". The simpler the better.

But given the tremendous complexities involved in biological systems one has to be very careful with the data. Quite frankly most in the field are not sufficiently trained or aren't rigorous enough in dealing with uncertainties and I wouldn't blame them it's mind-boggling and paralysing.

This of course can be exploited given the incentives stated above combined with the public's unawareness of e.g. statistical significance vs clinical significance etc., with the myriad mathematically correct ways of presenting data, and a handwaving attitude about reproducibility, this really opens up the floodgates for someone in a lab to become "creative", an entrepreneur. Which of course should be highly discouraged in the context of scientific research and in order to relieve some pressure the community once in a while condemn the most daring of examples without imhv looking too deep into the entrenched mechanisms enabling this.

A PhD student (biomedicine) once jokingly told me about the old HeLa contamination "problem"[0] in labs experimenting with cells. I must have reacted shocked as he laughingly added: Well, that was quite a long time ago, the problems now, only compounded.

So, in order to get the full picture it is "healthy" to zoom out and look at the other side of the spectrum i.e. longitudinal studies (with its own sets of limitations). One impressive one relating to Alzheimer's is the famous nun study[1].

[0]https://en.m.wikipedia.org/wiki/HeLa#Contamination

[1]https://en.m.wikipedia.org/wiki/Nun_Study

kazinator• 4 years ago

These dots don't connect for me very well in this article:

In 2006, Schrag’s first publication examined how feeding a high-cholesterol diet to rabbits seemed to increase Aβ plaques and iron deposits in one part of their brains. Not long afterward, when he was an M.D.-Ph.D. student at Loma Linda University, another research group found support for a link between Alzheimer’s and iron metabolism.

Yet, fast forward to December 2021 or early 2022:

Three of the papers listed Lesné, whom Schrag had never heard of, as first or senior author.

If Schrag was doing research in the same area, at around the time Lesné's results started to dominate, propelling his career, it's odd that Lesné's existence somehow eluded Schrag for 16 years.

Did Schrag switch to something else at around that time and never give it a second thought for a decade and a half?

Nelkins• 4 years ago

I think we are going to find out that diet plays an enormous role in all sorts of metabolic diseases in the coming years. Specifically as it pertains to Alzheimer's, increasingly strong evidence is coming out that your risk can be reduced by avoiding excess carbs/glucose, and also by avoiding oxidized foods (in the typical Western diet, usually polyunsaturated fats that have been sitting in a bottle).

Presentations like these are very compelling:

https://www.youtube.com/watch?v=O36CNNdgDGQ

https://www.youtube.com/watch?v=-tiGIIGOQS0

sfrautschy2• 4 years ago

This is ridiculous. Dozens if not hundreds researchers have confirmed the high MW oligomers correlated with pathogenesis. I have. To say that he found this or everything relied on this theory is absurd. We've know this since the early 90's when Lesne was in high school or earlier (e.g Cotman's work at UC IRVINE and Christian Pike now at USC , my work etc.) . this is way before Lesne even considered a career. I can't stand this ridiculous media that make this out a scandal and create false disinformation that the entire hypothesis is based on this.

sfrautschy2• 4 years ago

This is ridiculous. Dozens if not hundreds researchers have confirmed the high MW oligomers correlated with pathogenesis. I have. To say that he found this or everything relied on this theory is absurd. We've know this since the early 90's when Lesne was in high school or earlier (e.g Glabe and Cotman's work at UC IRVINE and Christian Pike now at USC , my work etc.) . this is way before Lesne even considered a career. It used to be called "micelles' or soluble abeta. Also the post doc supervisor repeated the data and found the same thing so she took him at his word. I can't stand this ridiculous media that make this out a scandal and create false disinformation that the entire hypothesis is based on this.

atombender• 4 years ago

I recommend reading the comments on AlzForum [1]. From the discussions (which are from real Alzheimer's researchers), it sounds like this fraud is significant in terms of Dr. Sylvain Lesné's work, but that the news has been vastly blown out of proportion, and not significant to the field as a whole.

[1] https://www.alzforum.org/news/community-news/sylvain-lesne-w...

panabee3• 4 years ago

thanks for sharing this. it would be ideal if these comments could get integrated into the original article. it's interesting that ashe commented here and not when contacted by the journalist.

hopefully this fraud didn't truly cause unnecessary delays in pursuit of a cure.

Potential fabrication in research threatens the amyloid theory of Alzheimer’s

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