A prospective Alzheimer’s trial reports(blogs.sciencemag.org)
blogs.sciencemag.org
A prospective Alzheimer’s trial reports
https://blogs.sciencemag.org/pipeline/archives/2020/02/10/a-prospective-alzheimers-trial-reports
80 comments
I've worked in both experimental physics and experimental biology (specifically in drug discovery, an early phase that can lead to clinical trials).
Failed experiments in biology don't make much progress compared to failed experiments in physics. beyond the inability to control for wide range of variables that are normally managed in physics, most people in biology aren't good at running high quality, reproducible experiments that falsify hypothesis. I have seen many coworkers run the same exact gel over and over until they get one that "looks like what they were expecting". I don't see the same level of experimental inadequacy in physics.
The best approaches in biology now seem to throw away the idea that we can construct a rational narrative to explain the biology that causes a complex disease, and more on collecting very large amounts of high quality data to produce sophisticated statistical models that deal with the underlying complexity in a useful way.
Failed experiments in biology don't make much progress compared to failed experiments in physics. beyond the inability to control for wide range of variables that are normally managed in physics, most people in biology aren't good at running high quality, reproducible experiments that falsify hypothesis. I have seen many coworkers run the same exact gel over and over until they get one that "looks like what they were expecting". I don't see the same level of experimental inadequacy in physics.
The best approaches in biology now seem to throw away the idea that we can construct a rational narrative to explain the biology that causes a complex disease, and more on collecting very large amounts of high quality data to produce sophisticated statistical models that deal with the underlying complexity in a useful way.
ON the other hand, those methods of collecting large amounts of high quality data might only seem promising because they're effectively just ways to run thousands or millions of gels at once before picking out the ones that "look right." The fundamental incentives to not publish null results and to publish or perish haven't disappeared. It's not that people aren't capable of running high quality, reproducible experiments, or that the tools aren't there, it's just that people need to publish to advance in their careers. These new high throughput screens get your quick publications and let you overfit models to the data you collect, and it might seem like a transformation now, but if people weren't incentivized to spend a couple hundred bucks to replicate a gel in the past, do you think they'll actually be incentivized to spend thousands of dollars and computation time to try and replicate screens and the models derived from them?
I gave a talk on basic bioinformatics algorithms to my pathologist colleagues once, explaining that it all amounts to collections of good guesses and you really need to know how this was done before you believe it. They just sat there, waited for the lecture to end, and went back to their jobs, accepting whatever the molecular labs were telling them that week. They simply have no mechanism to push back except to play gatekeeper, and they can't even be an informed gatekeeper.
The issue here is that for the past 25 years, multiple teams have spent years and lots of resources on the same idea despite it failing to work every previous time.
Negative results are valuable. The same negative result over and over starts to feel a lot more like sunk-cost fallacy.
Negative results are valuable. The same negative result over and over starts to feel a lot more like sunk-cost fallacy.
On the other hand, if you test the same hypothesis again and again and again, and don't finish up a trial and use interim data readouts to inform decisions, then after enough time, by pure chance, you'll apparently be able to pull an effect size out of the air and convince wall street and apparently even maybe regulators that your drug now works!
I really hope the FDA tells biogen to take a hike. The last thing people need is false hope, and the last thing we need as a society is to be spending billions of dollars on an alzheimers drug that doesn't work. For something that important (and that profitable), the least biogen could have done is run that trial through the end.
I really hope the FDA tells biogen to take a hike. The last thing people need is false hope, and the last thing we need as a society is to be spending billions of dollars on an alzheimers drug that doesn't work. For something that important (and that profitable), the least biogen could have done is run that trial through the end.
From a previous post by the blogger on a separate drug washing out:
And I think I’ll add this every time we have a big drug trial wipe out: keep in mind, that under a safety-only regulatory regime, that people would have been taking this drug (and paying for it, one way or another) for the last few years now, and it would have done them no good at all. When they could have been actually taking something that might help them. We do not know enough about investigational drugs to approve them without efficacy data.
And I think I’ll add this every time we have a big drug trial wipe out: keep in mind, that under a safety-only regulatory regime, that people would have been taking this drug (and paying for it, one way or another) for the last few years now, and it would have done them no good at all. When they could have been actually taking something that might help them. We do not know enough about investigational drugs to approve them without efficacy data.
And the great thing about safety-and-efficacy regimes is that until you get a drug to work, the market can't be filled. If the FDA makes exceptions for biogen, then the alzheimers market for new drugs shrinks, disincentivizing research into drugs that will actually work. Why invest billions to make drugs that work if you can make that same money by pumping trash into the market?
There's a post for that one, too :)
https://blogs.sciencemag.org/pipeline/archives/2018/05/25/fe...
and
https://blogs.sciencemag.org/pipeline/archives/2018/06/21/we..., which concludes:
the next wave will not be just people who have seized on this plan opportunistically, but who have targeted it right from the start. Who will pick out terrible diseases for which there are no therapies at all, the better to insure a supply of completely desperate patients and families, and provide them with utterly useless therapies at stiff, stiff prices. Utterly harmless therapies, though – don’t want to get sued while you’re raking in the bucks. I’m talking polysaccharide therapy for pancreatic cancer, antioxidant phytonutrients for Alzheimer’s: in other words, corn starch and grape juice. What the hell. The customers are going to die, anyway. Why should they die with their money as well?
the next wave will not be just people who have seized on this plan opportunistically, but who have targeted it right from the start. Who will pick out terrible diseases for which there are no therapies at all, the better to insure a supply of completely desperate patients and families, and provide them with utterly useless therapies at stiff, stiff prices. Utterly harmless therapies, though – don’t want to get sued while you’re raking in the bucks. I’m talking polysaccharide therapy for pancreatic cancer, antioxidant phytonutrients for Alzheimer’s: in other words, corn starch and grape juice. What the hell. The customers are going to die, anyway. Why should they die with their money as well?
It's unfortunate that in this legal situation the most it seems regulators can do is avoid giving snake oil regulatory legitimacy and hope that people are dissuaded by "these statements have not been evaluated by the fda, and XYS is not approved to diagnose or treat any disease." At the very least though, it would be nice if the FDA didn't then turn around and give legitimacy to fancier snake oil - hopefully they do the right thing with biogen haha.
You can thank orrin hatch for the total unregulation of the suppliments racket. Or curse him, which is probably the better course of action.
https://blogs.sciencemag.org/pipeline/archives/2019/02/12/th...
for actual drugs, the FDA can and does show up at your plant unannounced with guns for two weeks for an unannounced audit more or less whenever they want.
I await the day they can drop the hammer on the woo-aisle at whole foods with very poorly concealed anticipatory shadenfraude. Right now the best they can do is to sue POM Wonderful and the like : https://www.forbes.com/sites/chloesorvino/2016/05/02/the-ver...
https://blogs.sciencemag.org/pipeline/archives/2019/02/12/th...
for actual drugs, the FDA can and does show up at your plant unannounced with guns for two weeks for an unannounced audit more or less whenever they want.
I await the day they can drop the hammer on the woo-aisle at whole foods with very poorly concealed anticipatory shadenfraude. Right now the best they can do is to sue POM Wonderful and the like : https://www.forbes.com/sites/chloesorvino/2016/05/02/the-ver...
I wonder if going after Purell is a way to start testing the extent of their power?
https://www.nytimes.com/2020/01/28/health/purell-fda-ebola-v...
https://www.nytimes.com/2020/01/28/health/purell-fda-ebola-v...
Often failed experiments, in their failure, give an indication of an entirely new direction. Many groundbreaking discoveries are made that way.
For example, the discovery of synthetic dyes came about from trying to synthesize quinine.
https://en.wikipedia.org/wiki/William_Henry_Perkin
The discovery of the vacuum tube was an accident resulting from Edison playing round with light bulbs trying to figure out why the filaments were breaking.
https://en.wikipedia.org/wiki/Thermionic_emission
For example, the discovery of synthetic dyes came about from trying to synthesize quinine.
https://en.wikipedia.org/wiki/William_Henry_Perkin
The discovery of the vacuum tube was an accident resulting from Edison playing round with light bulbs trying to figure out why the filaments were breaking.
https://en.wikipedia.org/wiki/Thermionic_emission
Ah, but if you "build an experiment (at any scale) to test out an idea that you think is going to work", you've already gone wrong.
This is the Tao of the null hypothesis: if you build an experiment to test out an idea you think won't work, things can only go one of two ways—either you'll be proven right, or you'll discover something about the universe. Either way, you get to brag!
This is the Tao of the null hypothesis: if you build an experiment to test out an idea you think won't work, things can only go one of two ways—either you'll be proven right, or you'll discover something about the universe. Either way, you get to brag!
I always thought that was sort of the point of the business side of "Fail Fast".
Try it now, if it doesn't work, now you know something valuable and you can try something else.
As someone who suffers from a lot of analysis paralysis, distraction ... sometimes I find just making myself keep typing and trying things in order to fail quickly and learn from it leads to much faster / sooner successes rather than burying myself up in all the minuta and every aspect of something and... not doing it.
There was an old TV show called Connections where they tracked various inventions and progress over history, and IIRC it is telling that almost every positive step they note involve someone failing to do something else they were trying, but still finding out something valuable that adds up to the next step for something else and so on.
https://en.wikipedia.org/wiki/Connections_(TV_series)
Try it now, if it doesn't work, now you know something valuable and you can try something else.
As someone who suffers from a lot of analysis paralysis, distraction ... sometimes I find just making myself keep typing and trying things in order to fail quickly and learn from it leads to much faster / sooner successes rather than burying myself up in all the minuta and every aspect of something and... not doing it.
There was an old TV show called Connections where they tracked various inventions and progress over history, and IIRC it is telling that almost every positive step they note involve someone failing to do something else they were trying, but still finding out something valuable that adds up to the next step for something else and so on.
https://en.wikipedia.org/wiki/Connections_(TV_series)
Unfortunately, even though these amyloid drugs keep on failing, the "try something else" part of the "if you fail, then you've learned something and can try something else" equation doesn't seem to really register with the industry for whatever reason. We keep pouring money into amyloid trials when it's pretty clear that there's still a lot of basic research to be done to find new leads to pursue.
It's also probably not encouraging that the Connections TV show spans ... often hundreds of years, or more.
A lot of us are just falling for someone else.
A lot of us are just falling for someone else.
This is a teaching that really stuck with me from one of my university professors as well. I really wish this was something that was taught more to the general public, I think especially in schools. At least for me, it's something I'd never heard said in a succinct way until I was in university.
I wish this idea would sink in for scientists! Academia (my experience is in biological sciences) has a long tradition of hiding negative results and only valuing the rare positive results in a sea of messy data and unexplainable failure.
I doubt many scientists don't know this. However the current situation is largely if not all motivated by how funding is provided. Instead of a culture issue, I'd say it's a money issue.
Out of interest, roughly what proportion of experiments in physics "don't work"? Does data that fails to support the experimental hypothesis get published prominently in physics journals?
99% of experiments in fundamental physics "don't work" in this sense. All of them get published. If you got funded to build an apparatus, people are going to want to know what you saw.
You can check for yourself, by looking at the experimental papers on the arXiv [0]. Every paper here that mentions data, but doesn't have the word "discovery" in the title, is a negative result. There are thousands of such papers.
0: https://arxiv.org/list/hep-ex/current
You can check for yourself, by looking at the experimental papers on the arXiv [0]. Every paper here that mentions data, but doesn't have the word "discovery" in the title, is a negative result. There are thousands of such papers.
0: https://arxiv.org/list/hep-ex/current
I suppose you could think of it as an unexplored continent that has very specific requirements to survey each region. You mount an expedition, and you probably just find more trees and brush. The important thing, though, is that now that area is on a map, and the map keeps getting bigger.
I'm having no luck finding any URLs, but if you look at histories of many physical constants, you see that new measurements tend to lie within error ranges of the most recent previous measurements.
But occasionally, there's a jump to a substantially different value.
The explanation is that scientists debug their setups and equipment until they get a result that's plausible, relative to prior published measurements. Because otherwise, people would be driven to figure out what they did wrong. And it could be embarrassing.
But once they do, they tend to stop tweaking, and publish.
So it's only scientists who don't manage to get plausible results, and yet are confident that they've debugged well enough, who publish results that end up becoming new standards.
But occasionally, there's a jump to a substantially different value.
The explanation is that scientists debug their setups and equipment until they get a result that's plausible, relative to prior published measurements. Because otherwise, people would be driven to figure out what they did wrong. And it could be embarrassing.
But once they do, they tend to stop tweaking, and publish.
So it's only scientists who don't manage to get plausible results, and yet are confident that they've debugged well enough, who publish results that end up becoming new standards.
Reminds me how some rejections from HR felt like a motivator. When I could finally talk a bit about what was needed I could isolate the flaws and redesign the "theory".
I wonder if it's passion that makes researcher pain-free regarding failure. Or if they also dreaded it but learned how to dodge or tame it.
I wonder if it's passion that makes researcher pain-free regarding failure. Or if they also dreaded it but learned how to dodge or tame it.
Something interesting I stumbled upon recently: https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Patholo...
Specifically these quotes:
> Some case-control studies claimed that carriage of ALDH2x2 allele was a risk of late-onset Alzheimer's disease independent of the apolipoprotein E gene (the odds for LOAD in carriers of ALDH2x2 allele almost twice that of non-carriers). Moreover, ALDH gene, protein expression and activity are substantially decreased in the substantia nigra of Parkinson's disease patients. These reports are in line with findings implementing toxic lipid oxidation-derived aldehydes in these diseases and in neurodegeneration in general.
> The ALDH2-/- mice display age-related memory deficits in various tasks, as well as endothelial dysfunction, brain atrophy, and other Alzheimer's disease-associated pathologies, including marked increases in lipid peroxidation products, amyloid-beta, p-tau and activated caspases. These behavioral and biochemical Alzheimer's disease-like deficits were efficiently ameliorated when the ALDH2-/- mice were treated with isotope-reinforced, deuterated polyunsaturated fatty acids (D-PUFA).
D-PUFA is interesting (and being investigated for use in other diseases, e.g. Huntington's) but it's just addressing the proximal cause of the neurodegeneration (= the build-up of peroxidation products in the brain) rather than the mechanism by which those products are produced.
I'm much more curious to know whether introduction of exogenous ALDH2 into the body (perhaps above wild-type expressed levels of ALDH2) might be neuroprotective/prophylactic against neurodegenerative disease. As far as I can search, though, nobody's ever even extracted+purified an ALDH2 enzymatic solution, let alone tested it for such effects.
Specifically these quotes:
> Some case-control studies claimed that carriage of ALDH2x2 allele was a risk of late-onset Alzheimer's disease independent of the apolipoprotein E gene (the odds for LOAD in carriers of ALDH2x2 allele almost twice that of non-carriers). Moreover, ALDH gene, protein expression and activity are substantially decreased in the substantia nigra of Parkinson's disease patients. These reports are in line with findings implementing toxic lipid oxidation-derived aldehydes in these diseases and in neurodegeneration in general.
> The ALDH2-/- mice display age-related memory deficits in various tasks, as well as endothelial dysfunction, brain atrophy, and other Alzheimer's disease-associated pathologies, including marked increases in lipid peroxidation products, amyloid-beta, p-tau and activated caspases. These behavioral and biochemical Alzheimer's disease-like deficits were efficiently ameliorated when the ALDH2-/- mice were treated with isotope-reinforced, deuterated polyunsaturated fatty acids (D-PUFA).
D-PUFA is interesting (and being investigated for use in other diseases, e.g. Huntington's) but it's just addressing the proximal cause of the neurodegeneration (= the build-up of peroxidation products in the brain) rather than the mechanism by which those products are produced.
I'm much more curious to know whether introduction of exogenous ALDH2 into the body (perhaps above wild-type expressed levels of ALDH2) might be neuroprotective/prophylactic against neurodegenerative disease. As far as I can search, though, nobody's ever even extracted+purified an ALDH2 enzymatic solution, let alone tested it for such effects.
> I really don’t know what else to say at this point. I’ve been writing this blog since 2002, several years after my own experiences with Alzheimer’s drug discovery, and ever since then I have chronicled the failure of drug after drug aimed at the amyloid hypothesis. Different mechanisms, different dosing, different patient populations, different trial designs: none of it has worked. Not once. I myself include the most recent Biogen/Eisai antibody efforts in that list – yes, the one that they’ve submitted to the FDA and are trying to get approved, a decision about which I have made my position abundantly clear.
What's remarkable isn't the failure of this trial, but the complete lack of efficacy for any drug working through the "amyloid hypothesis."
https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_...
Either this hypothesis is completely wrong, or all of the drugs in all of these trials aren't able to address the amyloid.
Given the weight of evidence, it seems like there's not much left of the amyloid hypothesis to even poke a hole through.
What's remarkable isn't the failure of this trial, but the complete lack of efficacy for any drug working through the "amyloid hypothesis."
https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_...
Either this hypothesis is completely wrong, or all of the drugs in all of these trials aren't able to address the amyloid.
Given the weight of evidence, it seems like there's not much left of the amyloid hypothesis to even poke a hole through.
Amyloid plaques are clearly not the problem, but I thought we already knew that? When did these experiments get launched?
There are people who appear to be genetically immune to Alzheimer's yet build up massive amyloid plaques. They do not show any symptoms of the disease, so shouldn't this have been ruled out by now?
There are people who appear to be genetically immune to Alzheimer's yet build up massive amyloid plaques. They do not show any symptoms of the disease, so shouldn't this have been ruled out by now?
Looking back through Derek Lowe's posts, I don't think he considered the amyloid hypothesis dead until around 2016 or so.
The study was started in December 2012, according the clinicaltrials.gov posting. At that time, you had the first round of amyloid blockers that didn't work, but you were in the midst of the hail-mary round of "maybe it works if you catch it early/in this group of people/etc." tests. Indeed, this is one of those studies.
The study was started in December 2012, according the clinicaltrials.gov posting. At that time, you had the first round of amyloid blockers that didn't work, but you were in the midst of the hail-mary round of "maybe it works if you catch it early/in this group of people/etc." tests. Indeed, this is one of those studies.
I found this old presentation making a set of hypothesis regarding Alz etiology, possible mechanisms and possible treatments somewhat interesting: https://www.youtube.com/watch?v=j1FmK4582mA.
I am obviously biased towards this concept, as I have personally seen my mom slow reverse her early dementia with the help of an experimental Mercury removing drug, but since Alzheimer is really only confirmed by Autopsy, and we happen to live close by a Chlor Alkali plant that has been dumping Hg to the environment for decades, we would never know if she would have eventually died / get diagnosed of Alz.
I am obviously biased towards this concept, as I have personally seen my mom slow reverse her early dementia with the help of an experimental Mercury removing drug, but since Alzheimer is really only confirmed by Autopsy, and we happen to live close by a Chlor Alkali plant that has been dumping Hg to the environment for decades, we would never know if she would have eventually died / get diagnosed of Alz.
Mercury poisoning can also cause things like memory loss and neuropathy. It seems like a reasonable explanation given your anecdata.
https://en.wikipedia.org/wiki/Mercury_poisoning
https://en.wikipedia.org/wiki/Mercury_poisoning
Right, although apparently it can as well, at a very low levels cause the same degeneration to neurons as seen in Alzheimer disease, unlike any other heavy metal tested as far as I know. I found this video pretty interesting: https://www.youtube.com/watch?v=XU8nSn5Ezd8
yeah, mercury is dangerous with how toxic it can be at low levels in an organic form. If you have a case for mercury poisoning, is it possible to sue the company responsible via class action lawsuit or the like? Sorry to hear about what you're going through, I hope the drug works and wish you all the best.
If I reduce your load of gunshot wounds near zero but to a nonzero value, the pathogenesis of your disease will still worsen. This blogger will then claim that the gunshot wound hypothesis is flawed!
The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit. That's all the data shows. The failure of these drugs does not preclude the role of amyloid formation in the diseases.
In particular, there is no known dose-response relationship for amyloid-beta or other pathogenically-implicated amyloid proteins.
The conclusion is similar: these drugs aiming to reduce amyloid load are illogical. But the subsequent claim that the amyloid hypothesis is wrong does not follow.
The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit. That's all the data shows. The failure of these drugs does not preclude the role of amyloid formation in the diseases.
In particular, there is no known dose-response relationship for amyloid-beta or other pathogenically-implicated amyloid proteins.
The conclusion is similar: these drugs aiming to reduce amyloid load are illogical. But the subsequent claim that the amyloid hypothesis is wrong does not follow.
> The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit.
No, this trial was designed to test whether preventing amyloid plaque formation can prevent Alzheimer's. To the extent that it does not (which appears to be the conclusion), then it's safe to say that amyloid hypothesis is wrong.
In other words, if these patients do not acquire amyloid plaque, but still acquire Alzheimer's at the same rate and severity, then amyloid plaques logically cannot be the cause of Alzheimer's.
This should no longer surprise anyone. These studies, coupled with the existence of people who have been found to be loaded with amyloid plaque and yet do NOT get Alzheimers [1], should be plenty to change the direction of research.
1 - https://www.sciencemag.org/news/2019/11/colombian-woman-s-ge...
No, this trial was designed to test whether preventing amyloid plaque formation can prevent Alzheimer's. To the extent that it does not (which appears to be the conclusion), then it's safe to say that amyloid hypothesis is wrong.
In other words, if these patients do not acquire amyloid plaque, but still acquire Alzheimer's at the same rate and severity, then amyloid plaques logically cannot be the cause of Alzheimer's.
This should no longer surprise anyone. These studies, coupled with the existence of people who have been found to be loaded with amyloid plaque and yet do NOT get Alzheimers [1], should be plenty to change the direction of research.
1 - https://www.sciencemag.org/news/2019/11/colombian-woman-s-ge...
I don't believe Derek is denying the role of amyloid formation in Alzheimer's here. Just questioning the efficacy of this particular therapeutic hypothesis. Note that the therapeutic hypothesis and mechanistic hypothesis can co-exist and be slightly disjoint due to the lack of a deeper understanding of the disease. That's how I interpret this post, at least.
This seems quite consistent with the idea that microtubules are the locus of the real action of consciousness and memory. The amyloid theory would then be confusing cause and effect. If that's so, plaques don't cause Alzheimers; they are the side-effect of a process that causes Alzheimers: disintegration of microtubules.
Spending billions in basic research that investigates the causes of Alzheimer without a potential patentable drug is not economically valuable for private companies. If the cause is found it might not require expensive new drug to cure. This research should be funded by the governments.
Basic research already is mainly funded by governments. The research in this article is an attempt at a drug being developed by a private company, which is seperate from research that investigates the cause of Alzheimers disease.
Once the root cause is discovered, if it somehow needs no drug or device intervention to be treated, then great! Otherwise, the private sector would step in to take those drugs to market and pay for those trials then.
Once the root cause is discovered, if it somehow needs no drug or device intervention to be treated, then great! Otherwise, the private sector would step in to take those drugs to market and pay for those trials then.
What's the next best guess for a target now that the amyloid hypothesis seems to be a failure?
Anyone have any breakdown of what this means for the laymen out here on HN? I get the gist this was a major (but not unpredicted) failure, but am I reading it wrong? Was this for one category of drugs, or a hypothesis about the cause of Alzheimer's in general, or both?
There was a good HN discussion a few weeks back about this: https://news.ycombinator.com/item?id=21911225 It's becoming increasingly clear that the entire Amyloid-beta plaque hypothesis has been wrong and last 20+ years of Alzheimer's research and drug development has been wasted.
Yes. My comment triggered most of that discussion.
I have really good solid evidence for another common disease being caused by infection or microbiome dysbiosis. But I am encountering a lot of resistance in the field despite my theory, models and data being much more solid than the status quo to explain said disease and my research coming from a famous lab.
I guess it's really hard for lots of people to accept most of their careers were spent chasing the wrong hypothesis.
I've reached a tipping point where I think I can only push it further and develop a drug in a startup. Alzheimer's and Parkinson's are also something I want to tackle because the mechanism is analogous. If someone wants to help or some VC is interested, just let me know. Contact email is in my profile. These diseases have a big CS / information theory component.
I have really good solid evidence for another common disease being caused by infection or microbiome dysbiosis. But I am encountering a lot of resistance in the field despite my theory, models and data being much more solid than the status quo to explain said disease and my research coming from a famous lab.
I guess it's really hard for lots of people to accept most of their careers were spent chasing the wrong hypothesis.
I've reached a tipping point where I think I can only push it further and develop a drug in a startup. Alzheimer's and Parkinson's are also something I want to tackle because the mechanism is analogous. If someone wants to help or some VC is interested, just let me know. Contact email is in my profile. These diseases have a big CS / information theory component.
What’s the disease?
My personal experience and the research I’ve read makes me believe you are absolutely right.
My personal experience and the research I’ve read makes me believe you are absolutely right.
Probably something like MS or another auto-immune disorder that could be microbiome and/or dopamine related. Could also be type 1 diabetes, RA, Crohn's, etc. Those would be my guess.
No idea if this is nextos's thing, but there's evidence for inflammation as a root cause of depression. cf Bullmore, the Inflamed Mind.
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What's the disease and what's the resistance from the field? Microbiome stuff isn't as hot an area of investment as it was a few years back, but there's tons of biotech funding to go around (assuming you're in the US) and if you have solid data and an actionable drug, it shouln't be extraordinarily difficult to form a company around it in this economy.
If the past 20 years of research & drug development have been wasted, how does the average person help steer the ship away from clearing the plaque, and more towards identifying and treating the cause of the plaque in the first place?
Kinda both. Increased presence of amyloid (a type of protein) plaques are common in patients with Alzheimer's disease, so it was hypothesized that these plaques contribute to alzheimers. The drugs mentioned specifically targeted these plaques (via monoclonal antibodies). These drugs didn't slow the progression of alzheimers in the patient population that was certain to get it. The drugs could have failed for two reasons I think: 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue) or 2) the amyloid plaques themselves are actually being broken up by the drug...but the plaques may not really be a cause of alzheimers (in which case the hypothesis is the issue).
> 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue)
Shouldn't it be possible to have a look at the patients brains to see if there's any difference in plaque formation in those that underwent treatment vs those who had the placebo.
Shouldn't it be possible to have a look at the patients brains to see if there's any difference in plaque formation in those that underwent treatment vs those who had the placebo.
> 2) the amyloid plaques themselves are actually being broken up by the drug
This is actually what several studies have shown--the amyloid plaques were being removed by the drugs, but the progression of Alzheimer's was not slowed or halted.
This is actually what several studies have shown--the amyloid plaques were being removed by the drugs, but the progression of Alzheimer's was not slowed or halted.
Different disease, but if you really want to be depressed: https://blogs.sciencemag.org/pipeline/archives/2017/05/18/no...
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tldr: No effect for the two antibodies tested.
As that last-linked blog post makes clear, I don’t find that evidence compelling, and most certainly not compelling enough to approve the drug as it stands. But with the way the FDA is behaving these days, God only knows what’s going to happen. People are investing on just that basis, although rarely stated in quite those words. But if you can look at the ruins of all the attempts to show efficacy with anti-amyloid antibody therapies and decide that the Biogen/Eisai data represent a real ray of hope, you have a sunnier disposition than I do.
I share the cynicism! Early drugs targeted amyloid plaques because it seemed like a good idea. But after so many failures, I can't think of any reason so much time and money is spent on a failed hypothesis other than hoping for a false positive. Because a false positive, even with very modest results, would result in a ridiculously profitable drug given the complete lack of Alzheimer's treatments we currently have.
I share the cynicism! Early drugs targeted amyloid plaques because it seemed like a good idea. But after so many failures, I can't think of any reason so much time and money is spent on a failed hypothesis other than hoping for a false positive. Because a false positive, even with very modest results, would result in a ridiculously profitable drug given the complete lack of Alzheimer's treatments we currently have.
Because there’s very little money is invested in Alzheimer’s research. People were very conservative in their choices.
We were spending a lot more on AIDS research 20 years ago than on Alzheimer’s today:
https://www.ncbi.nlm.nih.gov/books/NBK222902/
This produced great results for AIDS, which many people thought would never be treatable.
Anyway, medical research is expensive. Considering the number of people who will get Alzheimer’s and the cost to deal with the disease, you would have thought we’d have been spending more on research for the past several decades.
Maybe soon we will all agree that it’s probably worth investing more on research?
We were spending a lot more on AIDS research 20 years ago than on Alzheimer’s today:
https://www.ncbi.nlm.nih.gov/books/NBK222902/
This produced great results for AIDS, which many people thought would never be treatable.
Anyway, medical research is expensive. Considering the number of people who will get Alzheimer’s and the cost to deal with the disease, you would have thought we’d have been spending more on research for the past several decades.
Maybe soon we will all agree that it’s probably worth investing more on research?
According to your link, we spent $1.9 billion in 1999 on AIDS research. You don't have a link for Alzheimer's today, but this link claims we're spending $2.5 billion in 2019 on Alzheimer's:
https://www.alz.org/get-involved-now/advocate/research-fundi...
https://www.alz.org/get-involved-now/advocate/research-fundi...
$1.9 billion in 1999 dollars adjusted for inflation is $2.93 billion in today's dollars.
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“ We have propelled the federal government to rise to this challenge, resulting in a more than six-fold increase in federal Alzheimer’s and dementia research funding since 2011 ”
Your article says we’ve had a 6x increase. So, we’re approaching 1999 levels not accounting for inflation?
I believe we’re at around $35 billion for AIDS research.
https://www.kff.org/hivaids/fact-sheet/u-s-federal-funding-f...
So AIDS is still 10x greater?
Your article says we’ve had a 6x increase. So, we’re approaching 1999 levels not accounting for inflation?
I believe we’re at around $35 billion for AIDS research.
https://www.kff.org/hivaids/fact-sheet/u-s-federal-funding-f...
So AIDS is still 10x greater?
Your site says $2.6 billion for AIDS research. Most of the $35 billion is for treatment, both local and in support for global treatment programs.
By comparison, we spend closer to $200 billion/year on Alzheimer's treatment. Managing patients who are in severe cognitive decline is not cheap.
By comparison, we spend closer to $200 billion/year on Alzheimer's treatment. Managing patients who are in severe cognitive decline is not cheap.
Frankly, I don't think we necessarily need more money in Alzheimer's research. We just need to stop burning that cash on amyloid drugs and clinical trials for amyloid drugs. What the whole saga of oncology over the past few decades has revealed is that understanding the actual cause and pathology of a disease is crucial to unlocking new treatments and cures - it wasn't until we understood cancer as a cellular disease that we developed chemotherapy, and it wasn't until we understood it as a genetic disease and characterized the role of the immune system that we began making progress with targeted therapies and immunotherapies.
We don't understand neurodegeneration yet, and we're probably lumping together hundreds of different disease pathologies under the name "alzheimers," each needing a different treatment approach. If we took the money we've been burning on the same dead end and redirected it to basic research, that might be what best helps crack the code.
We don't understand neurodegeneration yet, and we're probably lumping together hundreds of different disease pathologies under the name "alzheimers," each needing a different treatment approach. If we took the money we've been burning on the same dead end and redirected it to basic research, that might be what best helps crack the code.
> We were spending a lot more on AIDS research 20 years ago than on Alzheimer’s today:
I still remember in the early aughts when my professor was part of a research group in 1995 that found a genetic link in Germans from Russia with Alzheimer’s. At the time it was heralded as a huge break through. 25 years later and The needle has barely moved on their research and accomplishments.
In reports published today in the journal Science, researchers say they have isolated a defective Alzheimer’s gene culled from an 8-year-long investigation of several Volga German families, including two from Eastern Washington. Discovery of the gene, and a protein it produces, could speed development of drugs to combat the brain-destroying disorder.
https://www.spokesman.com/stories/1995/aug/18/pioneer-famili...
Seeing your loved ones suffer through Alzheimer’s is one of the most agonizing and depressing things I've had to experience.
I still remember in the early aughts when my professor was part of a research group in 1995 that found a genetic link in Germans from Russia with Alzheimer’s. At the time it was heralded as a huge break through. 25 years later and The needle has barely moved on their research and accomplishments.
In reports published today in the journal Science, researchers say they have isolated a defective Alzheimer’s gene culled from an 8-year-long investigation of several Volga German families, including two from Eastern Washington. Discovery of the gene, and a protein it produces, could speed development of drugs to combat the brain-destroying disorder.
https://www.spokesman.com/stories/1995/aug/18/pioneer-famili...
Seeing your loved ones suffer through Alzheimer’s is one of the most agonizing and depressing things I've had to experience.
Sorry to hear about your experiences with Alzheimers.
That gene, presenilin 2, is part of the amyloid processing complex and plays a role in the amyloid hypothesis (which is highlighted by the news article and the paper itself, https://science.sciencemag.org/content/269/5226/970,) meaning that the very study that this hacker news thread is about, as well as hundreds of other studies and trials, are all investigating this hypothesis. Unfortunately, while the article you've linked says that this discovery helped "solve the mystery of early onset AD," it so turns out that the proposhed mechanism did not live up to scrutiny. Could this protein have different effects (such as a role in calcium ion leakage as later papers suggest)? Perhaps, and it might prove a crucial part of treating alzheimers in the long run, but it doesn't look like that research was in any way overlooked. Research is hard, it's only been a couple decades since new potential mechanisms of action of that gene were identified, and this is a complex disease, but the needle is moving.
That gene, presenilin 2, is part of the amyloid processing complex and plays a role in the amyloid hypothesis (which is highlighted by the news article and the paper itself, https://science.sciencemag.org/content/269/5226/970,) meaning that the very study that this hacker news thread is about, as well as hundreds of other studies and trials, are all investigating this hypothesis. Unfortunately, while the article you've linked says that this discovery helped "solve the mystery of early onset AD," it so turns out that the proposhed mechanism did not live up to scrutiny. Could this protein have different effects (such as a role in calcium ion leakage as later papers suggest)? Perhaps, and it might prove a crucial part of treating alzheimers in the long run, but it doesn't look like that research was in any way overlooked. Research is hard, it's only been a couple decades since new potential mechanisms of action of that gene were identified, and this is a complex disease, but the needle is moving.
FYI, AIDS is an acronym (though the periods are dropped) for Auto-Immune Deficiency Syndrome. So all four letters are capitalized.
A huge amount is invested in Alzheimer’s, but comparing to aids and hiv isn’t a reasonable thing to do:
HIV and AIDS kill people, and they do so quickly.
There’s also a foothold on how to treat it - whereas for Alzheimer’s we don’t even have an understanding of what actually causes it. Once we know the actual cause I suspect we’ll see research funds skyrocket.
HIV and AIDS kill people, and they do so quickly.
There’s also a foothold on how to treat it - whereas for Alzheimer’s we don’t even have an understanding of what actually causes it. Once we know the actual cause I suspect we’ll see research funds skyrocket.
Alzheimers scares me more than HIV/AIDS.
We know how the latter are spread (body fluid contact), and that the virus doesn't live very long outside the body. As a result the precautions needed to ensure I don't personally get it are in general easy to follow. (nothing is perfect but the odds are strongly against me getting it)
Alzheimer's is an unknown. I have no idea if something I'm doing now puts me at risk or not.
We know how the latter are spread (body fluid contact), and that the virus doesn't live very long outside the body. As a result the precautions needed to ensure I don't personally get it are in general easy to follow. (nothing is perfect but the odds are strongly against me getting it)
Alzheimer's is an unknown. I have no idea if something I'm doing now puts me at risk or not.
Alzheimer leads to death also. If it progresses far enough, people lose bodily functions and die. It's very common die from pneumonia when ability to swallow decreases and patients get food into their lungs.
> Once we know the actual cause I suspect we’ll see research funds skyrocket
I agree with your hypothesis, but saying it out loud seems backwards. In an ideal world, wouldn't we see research funds rise now in order to discover the cause (the hard part) rather than for the treatment (the less hard part).
I agree with your hypothesis, but saying it out loud seems backwards. In an ideal world, wouldn't we see research funds rise now in order to discover the cause (the hard part) rather than for the treatment (the less hard part).
no - there's a huge amount of research already happening, but the biggest cost in drug development occurs after you have a target. The reason funding appears low, is because the expensive parts of drug discovery are late in the process - things like the large scale trials, etc. I would not be surprised if (I have not looked it up) a significant contributor to the amount spent on research in HIV is on late stage trials, because realistically at this point the majority of new HIV drugs should actually work, and you need the large scale tests to see if the drugs work better.
I'd like to see sources please, since I don't believe that claim. The years and years of research of many teams all over the world should exceed the amount of money required for large-scale trials by orders of magnitude.
Please note that I don't speak of an individual research team but of all teams globally combined working on that goal.
Please note that I don't speak of an individual research team but of all teams globally combined working on that goal.
I'm sure that for any given drug you'll see a pattern of later research costing more, but as a field, unless we happen to get lucky early on with figuring out the basic science (which we clearly didn't with neurodegeneration), we'll need years (or decades to centuries - emperor of all maladies is an excellent read into the amount of work and time it took to understand cancer to the level we do now) to understand what to spend money on drugs on, and we'll have to pay for all the dead ends there too.
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Nothing but bad news.
If you build an experiment (at any scale) to test out an idea that you think is going to work, and it doesn't work, you made progress. Now you know something really essential -- that thing that seemed like a well-motivated idea has some kind of unknown flaw. With that in hand, you can proceed to try something better, whether it is a refined approach or something entirely new.
Without doing the experiment, that well-motivated idea would still look like something worth trying.
If a large team of people were willing to spend years and lots of resources on an Alzheimer's clinical trial, it was likely to be because they thought it had a real chance of working. If it didn't work, we all benefit from their effort.