[HN Gopher] Potential fabrication in research threatens the amyl...
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Potential fabrication in research threatens the amyloid theory of
Alzheimer's
Author : panabee
Score : 214 points
Date : 2022-07-21 18:54 UTC (4 hours ago)
(HTM) web link (www.science.org)
(TXT) w3m dump (www.science.org)
| tmaly wrote:
| 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.
| [deleted]
| nabla9 wrote:
| 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.
| JumpCrisscross wrote:
| > _seems like huge crime against humanity_
|
| Gently note that diluting this term comes at a cost. There is
| a reason international law reserves its designation for
| states and heads of state.
| legulere wrote:
| Alzheimer isn't a growing epidemic. The incidence is going
| down.
| johndhi wrote:
| f38zf5vdt wrote:
| 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.
| ThePhysicist wrote:
| 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...
| snapetom wrote:
| 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 wrote:
| 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.
| JPLeRouzic wrote:
| > * it was a 2006 study published in Nature that convinced
| everyone to believe the amyloid hypothesis.*
|
| The amyloid hypothesis is one century old.
| dekhn wrote:
| No, it's not. It was introduced in the 90's. "The amyloid
| hypothesis was first proposed in 1991 by John Hardy and
| David Allsop." You're probably thinkinng of the person who
| "discovered" Alzheimer's disease (Alois Alzheimer).
| jamiek88 wrote:
| Oh my god if true, and it looks to be true this is huge.
|
| The amyloid beta (Ab) hypothesis has always been fishy but this
| paper is basically the bedrock of the current investigational
| trajectory.
|
| The Ab 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 Ab 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 wrote:
| >> 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?
| api wrote:
| 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 wrote:
| 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.
| macinjosh wrote:
| 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?
| niemandhier wrote:
| 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" ?
| ncmncm wrote:
| 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.
| summm wrote:
| Do you happen to have a link to said paper?
| ALittleLight wrote:
| 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.
| ncmncm wrote:
| 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.
| axg11 wrote:
| 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 Ab hypothesis, but it
| appears that these paths have led to very little new knowledge.
| api wrote:
| 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.
| dmatech wrote:
| 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.
| JPLeRouzic wrote:
| This guy might well have cheated but how could he be responsible
| for the huge mess which is the amyloid-b research (and amyloid-b
| lobby as told by Statnews [0])?
|
| Sylvain Lesne, 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-b hypothesis which
| is more than 100 years old.
|
| Even more there are thousand papers published about Ab*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-b 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...
| spfzero wrote:
| 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 wrote:
| That's precisely why it should have been caught earlier.
| jibe wrote:
| _Even more there are thousand papers published about Ab_ 56 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.
| JPLeRouzic wrote:
| > _Because he started it?_
|
| This paper is from 1988:
|
| https://pubmed.ncbi.nlm.nih.gov/2893291/
| AlexandrB wrote:
| I think AB and AB*56 are related but different. The article
| is about AB*56.
| fabian2k wrote:
| As far as I understand this is not about the Ab hypothesis
| itself, but the toxic oligomer hypothesis.
| dang wrote:
| Related:
|
| _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)
| smm11 wrote:
| 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.
| ChrisMarshallNY wrote:
| 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.
| mekoka wrote:
| Reminiscent of this equally upsetting article a couple of years
| ago https://news.ycombinator.com/item?id=21911225
| onionisafruit wrote:
| 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.
| nextos wrote:
| 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 wrote:
| 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.
| onionisafruit wrote:
| 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.
| elliekelly wrote:
| 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.
| MattGaiser wrote:
| Presumably the same incentives as everywhere else. Money.
| dormento wrote:
| 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.
| fabian2k wrote:
| 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 Ab failed that still keeps Ab 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.
| chmod600 wrote:
| "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.
| fabian2k wrote:
| 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 wrote:
| It turns out applying those might not even be enough.
|
| https://slatestarcodex.com/2014/04/28/the-control-group-
| is-o...
| panabee wrote:
| 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 wrote:
| Trust, but don't verify, because verification is expensive
| and unrewarding both financially and career-wise
| ethbr0 wrote:
| 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.
| panabee wrote:
| thanks for this response.
|
| given the prevalence of non-reproducibility, what other
| fields do you believe have suspect leading hypotheses?
| Quekid5 wrote:
| Not the person you replied to, but...
|
| _Everything_ is extremely hype-driven -- it turns out
| that "cannot confirm X" isn't very compelling for
| journals, etc. etc. or even the news cycle. Journals,
| etc. thrive on exciting new findings... and that tends to
| lessen the critical looks.
|
| Of course, there are lots of other things to this
| problem: Very narrow fields where people absolutely know
| who their "anonymous" paper reviewers will be, and so
| _must_ include even extremely tangential references to
| those reviewers ' papers, etc. etc.
|
| Usually the sciences self-correct eventually[0], but
| that's only because there is such a thing as objectively
| verifiable facts and overwhelming statistics in science.
|
| [0] Unfortunately often as slowly as "one funeral at a
| time" (Max Planck, I think).
| ta8645 wrote:
| 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 wrote:
| 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".
| fabian2k wrote:
| We have a lot of really good evidence that the vaccines are
| preventing a lot of deaths.
| ncmncm wrote:
| It has been unfortunately necessary to downplay cases of
| debilitation and, even, death apparently traceable to
| vaccination. If vaccination saves the lives of a hundred
| times as many people as it harms, in the "trolley" sense,
| that should be good enough, but in popular imagination it
| is not.
|
| Rational treatment might enable identifying individuals
| particularly at risk and not vaccinating those, but that
| option is closed to us. Instead, a random, suspicious
| fraction of the population pays particular attention to
| negative outcomes and avoids vaccination, to its detriment,
| and most of those at risk for problems get vaccinated
| anyway.
| ta8645 wrote:
| > It has been unfortunately necessary to downplay cases
| of debilitation
|
| I don't think it was necessary at all, and instead is
| very counterproductive. Many people know they're not
| being dealt with honestly by the government and media,
| resulting in more distrust and resistance to vaccination,
| than there otherwise would be.
| ncmncm wrote:
| The number of deaths would objectively be larger if
| people had access to accurate numbers, because even more
| would avoid vaccination and then die of the infection
| vaccinated against.
|
| It is a tragic calculus. "Trolley Problems" are very far
| from theoretical in public health management. We are
| forced by distrust to sub-optimal choices that themselves
| promote distrust. Managing risk of a better population
| would be easier, but few get to choose that.
| theduder99 wrote:
| good point. at least we didn't have to wait 15 years to confirm
| that covid vaccines were a scam. when cdc had to change their
| definition of vaccine that was the nail in the coffin IMO.
| ncmncm wrote:
| 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, thus long delaying that
| advance) before finding success many years later in VLSI chip
| design methods.
| lightup wrote:
| 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.
| jajag wrote:
| > Ashe declined via email to be interviewed or to answer written
| questions posed by Science ... But she wrote, "I still have faith
| in Ab*56,"
|
| Richard Dawkins won't be impressed.
| chmod600 wrote:
| 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.
| anakaine wrote:
| 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.
| lamontcg wrote:
| 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).
| dmatech wrote:
| 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.
| abeppu wrote:
| 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?
| mtlmtlmtlmtl wrote:
| Actually the LHC does have two detectors with completely
| independent research teams, often doing the same experiment.
| MattGaiser wrote:
| What percentage of research is ever replicated? Are there a lot
| of scientists doing replication studies?
| swatcoder wrote:
| 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.
| axg11 wrote:
| 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.
| cjmb wrote:
| 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.
| cleandreams wrote:
| 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.
| mkl95 wrote:
| Is there any relevant (non-fabricated) research about the causes
| of fabrication in research? Is it just money or is there
| something else?
| upsidesinclude wrote:
| This is what makes statements like "trust the science" so
| sickening. Science isn't religion and it isn't always honest
| ncmncm wrote:
| 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.
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