Ib my younger days I used to get all excitef about new scientific breakthroughs. After decades I know better and apply the heuristic of disregard whenever I come across the hidden punch-line "In mice".
It really is a very good metric for preventing you to get sucked into hype that will 99.99 percent of the time result in exactly zero real world impact 10 years later.
"Conclusions:
Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms."
Maybe I'm too chicken to receive someone elses poo but I took what I consider to be the more scientifically controlled middle ground, mixing large amounts of probiotics with MCT oil and using it rectally. 36 strains, about 2 trillion CFU. To my surprise I have found several doctors that love this idea and one that also does it. It's not as diverse and that is exactly why I do it. I know what cultures I am getting and what benefits each one has.
I open the capsules and mix them. I've tried to get the company to sell me a bag or can of the probiotics but they won't do it. Not a big deal though, it doesn't take long to open them. I just use the large containers of coconut MCT oil. If there is something that would be better for the bacteria and for the large intestine cells I would love to know.
- Bypass the stomach acid, preserving more bacteria
- Keep the bacteria out of the small intestine mostly to avoid SIBO and avoid having to chase the probiotics with Betaine hcl, Ginger root, digestive enzymes, etc... to keep the small intestine clear which can trigger inflammation. Also not having to pre-coat the small intestine with cranberry molecules to cover any section that is missing the mucous layer.
- Feed the colon and large intestine cells MCT oil without having to consume it.
- Anecdotally I feed better for several days after doing this. I can do faster power-walks for longer. I do not run to protect my cartilage.
- The only GI improvement that I can feel is the lack of discomfort from taking large amounts of probiotics orally.
- Very large amounts taken orally can result in small amounts making it past the intestine cell junctions and triggering a small immune response which may have both positive and negative ramifications but that's a much bigger topic.
- Less likely to disturb the mucous layer.
Drawbacks:
- To be useful requires a large amount of bacteria and that requires a large amount of MCT oil and getting into positions to get it up into the large intestine. Well ... it has to come out some time and being liquid one must stay near the restroom. There's no holding it in. Some kind of paste injector tube would be better, probably something similar in form factor and design as the vaginal yeast infection treatments perhaps. If this were a product I would buy it even though it would be harder to get it into the large intestine.
- The first few hours after can feel weird as the body has to adjust.
I have not. Just guessing but I think it might have to be custom made or uncomfortably tight. Maybe others have done this. The doctor I know that does this makes these little frozen things in a custom freezer tray meant for enemas.
Another challenge with this is that the formula I use has prebiotics so it's just a matter of time before gas builds up and things could get painful. I will likely just stick with my method of staying near the restroom.
Do you mind sharing how you decided which 36 strains to include and what they are? Bonus points for links to studies (or articles with good references).
I plan to add a health section to my awful blog. That is where I would be linking to the list of cultures and links to the benefits and risks for each one. If you want to read up on which formula I am currently using ahead of time it is here [1] and if you mouse over the images one of them lists which strains they use. I alternate between them and a couple of other blends. Most of the strains have some studies on nih.gov which is best searched using google with "site:nih.gov probiotic culture_name benefits"
Have you done actual GI / microbiome tests before and after to see any cause/effect? Sounds a bit extreme when you could just follow the 4 K's of Kefir, Kombucha, Kimchi, and Kraut over a long period of time.
I have not. I can not find any labs that I can trust and that have not been hacked on a regular basis.
Sounds a bit extreme
It may be. I reset my gut bacteria some years ago and use this to improve the overall gut-scape. The 4 K's are great but my personal preference is to use this method that if for no other reason it is banned by WADA. If they consider it cheating then I like it that much more.
There are online communities of people attempting FMT on themselves. I remember seeing them even cite an online source of FMT supplies from some sketchy company operating internationally to avoid regulations. Others used very understanding family members or friends as sources.
I haven’t followed the topic for a long time, but I distinctly remember how many people were disappointed with the results of their self administered FMT. This is probably because they had unreasonable expectations about their health conditions being caused by the microbiome. The only real success stories were from people who had C. Diff and treated it with a combination of antibiotics and FMT.
However, there were a lot of negative stories. Some people had major bowel problems for a while. One person even died, though it was speculated that it was due to some of the microbiome altering antibiotics he was experimenting with.
Interesting research topic, but please don’t DIY it.
> The first person known to die as a result of a fecal transplant is a 73-year-old man who developed a fatal infection with antibiotic-resistant bacteria that were in the donor's stool sample.
> News of the man's death surfaced in June; he was one of two patients in separate clinical trials who became ill after receiving fecal transplants from the same donor
Interesting. So 'chiral' is another word for 'handedness' - your hands are chiral, in that you can't rotate your left hand in such a way that it looks like your right hand (yes I know what the Greek word for 'hand' is).
So I assumed that these would be gold atoms with a chiral molecule around them - the ligand, that is. However, from a quick search it appears that there are these gold nanoparticles that are chiral shapes. In other words, the structure of the particle is chiral, not the molecule itself.
In any case, I doubt you can get them over the counter any time soon, but who knows.
Seems like there are a variety of different techniques but Figure 2d in that review shows an image referencing - 'Lee, H.-E. et al. Amino-acid- and peptide-directed synthesis of chiral plasmonic gold nanoparticles. Nature 556, 360–365 (2018)'
The last thing I read about the link between amyloid-β accumulation and Alzheimer's was that the entire field was full of fake data ( https://www.science.org/content/blog-post/faked-beta-amyloid... ). In particular, even treatments that directly reduce amyloid-β in the brain did not restore cognitive abilities.
At least this paper tests both cognitive abilities as well as "amyloid-β pathologies." I'm not at all an expert in this field but gold nanoparticles sounds like something you'd see on a late night infomercial, lol.
That may or may not be the case, but you're rather detracting from the original comment, either deliberately or not.
The issue in the Alzheimer's world is the possibility that the very disease mechanism concept underlying the vast majority of research and interventional trials into which countless multiple billions have been poured, is incorrect.
Within that space, this is orders of magnitude more fundamental and serious than a flip aside that lots of trials have problems, so who cares about another?
> the very disease mechanism concept underlying the vast majority of research and interventional trials into which countless multiple billions have been poured, is incorrect.
Not "is incorrect," but might be incorrect. And we almost certainly won't know it is correct until we actually have a therapy.
Those pursuing cures could have waited until there was more solid science, but they and their funders took on the risk, knowing full well that the amyloid hypothesis is not proven.
This is not some indictment of science, this is normal risk taking for a problem that hugely affects society.
But the entire framing of the comment is that the amyloid hypothesis is taken as fact and not possibility, when in fact the core research question is whether it is true or not.
It is the best possible explanation so far, but four decades of research have not reached a definitive conclusion.
An open problem is not a problem for science, that's the fundamental focus of science. The problem is people misrepresenting what science is and what it aims to do.
(Late back to this but) It's far more skewed than you're making out. That the a-beta hypothesis is true, is/was the vastly dominant prevailing belief in the field, to the extent that it hasn't been a question that many 'experts' were willing to meaningfully address.
To be clear: for decades, researchers wishing to pursue lines of inquiry contrary to the a-beta hypothesis struggled for traction and funding, and saw their careers struggle as a result[0]. As such, trying to disprove the a-beta hypothesis was not the core research question for many/most, for long time.
(Edit: forgot to say, thanks for continuing the conversation, it is much appreciated! This comment may come across snippier than I intended, but please know I appreciate your effort here even though my experiences lead me to a different conclusion.) This article is just sensationalization of the standard scientific process. Grants do get awarded by friends and it does appear very much like a cabal. Or things like this:
> A top journal told one that it would not publish her paper because others hadn’t.
Oh the horror, not getting published in a top journal! Turns out that most good science gets published outside the top journals.
This sort of behavior is bad, and has always been part of the process, and may actually be better today than it was a century ago, as the clubs are not nearly so tight as they were back then.
Early in my career I remember reading some of ET Jaynes' (an early Bayesian reasoning guy) discussions of his early career, and how he had to very very carefully choose his topics so that he wouldn't upset the big personalities in physics and thereby have his entire career crushed. It's better these days than it was then!
There will be sour grapes about funding, just as there are when VCs all jump on the hype train for the same idea, but my only scientific exposure to the amyloid hypothesis for the past 20 years has been in terms of it being an unproven hypothesis. Starting down exploratory routes for explanatory hypotheses should have been pursued, and was pursued, and will continue to be pursued, but the question of "how much" is exceptionally difficult to answer.
Perhaps I'm biased from being in Science too long, but I've seen so many sensational Stat News article that never pan out when pushed upon. I wouldn't trust them at all with stuff like this.
>For more than 150 trials, Carlisle got access to anonymized individual participant data (IPD). By studying the IPD spreadsheets, he judged that 44% of these trials contained at least some flawed data: impossible statistics, incorrect calculations or duplicated numbers or figures, for instance. And in 26% of the papers had problems that were so widespread that the trial was impossible to trust, he judged — either because the authors were incompetent, or because they had faked the data.
Firstly, this is only from one journal, Anesthesiology. Second, the phrase "at least" indicates that while 44% had some amount of (presumably) flawed data, only 26% of the studies were bad enough to be judged fake or severely flawed by this one (admittedly esteemed) researcher in the field of anesthesiology. It's important to be skeptical and do your homework when you hear sweeping and/or shocking results. It's also important to read carefully, especially with science journalism because it is written for clicks and broad audiences, not to reduce ambiguity and adhere to strict standards of accuracy.
I didn’t go look up the quote but based on your version here it sounds like roughly half (44%) had some kind of suboptimality, and of those roughly a quarter (26%) had serious problems preventing them from being relied on.
That means 11% of the total papers should be discarded, which means 89% of the papers can be used.
As per usual, science reporting fails to use precise language. It can be interpreted either way, although I think your interpretation is the slightly larger leap based on phrasing. In any case, it is far below the 70% (and not directed broadly at all scientific research) that GP states.
It's hard to discern discourse in a field one is unfamiliar in, I'd tried with the Alzheimer's fiasco. Here's my tuppence:
The plaques are known to be linked to Alzheimer's, the debunking of one paper that messed with its figures does not detract from the whole body of research. The inefficacy of plaque-targeting treatments may not be proof that the plaques are not causal in nature, only that their damage is not reversible/fully understood.
In a massive field, one researcher does not constitute "full of faked data," despite how concerning it is.
The problem is viewing individual papers as the unit of truth in science. The "self-correcting" nature of science will actually reject entire papers, and entire directions of inquiry. Including, maybe, a casual relationship between beta amyloid and AD, but maybe not.
The other key part of science is holding everything in a state of uncertainty. There's some "facts" but mostly just hints and clues. And with Alzheimer's disease in particular we are trying to make progress with completely inadequate vision; we really can't even measure so much of what we want to measure. Feynman said it back in the 1960s, too, physicists have failed to deliver the tools to biologists to really measure what needs to be measured. There have been advancements, and DNA sequencing technology in the past decade has been turned into the most clever sorts of information theoretic microscopy by combining DNA sequences with many other biochemical processes. But we as a species still can not measure a lot of the things we'd like to measure.
But he's correct, amyloid plaque theory was founded on bad data. Amyloid plaques as causal agents is unclear, but it was made to appear clear by poisoned data, and many studies conducted afterwards, in good faith, assumed that the information and conclusions were sound. However it doesn't appear to be the case, and instead something along the amyloid beta pathway is more likely to be the true causal factor, and plaques an association. It has spawned something of a wild goose chase in Alzheimer's research and treatment.
The faked data is not foundational to the field, if we are to believe the article linked from that comment.
> But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find 56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. Just not Lesné’s oligomer.
And
> Did the 56 Work Lead to Clinical Trials? That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB56 oligomer itself (I’ll be glad to be corrected on this point, though).
I appreciate your commitment to modernist capital-S Science here :) I'm familiar with how the field ought to work but after working in Andrew Gelman's lab for some years, also with how it can fail us. Here I think the researcher in question has had a much larger impact than you are allowing for. Here's a choice quote:
> Every single disease-modifying trial of Alzheimer’s has failed.
> The huge majority of those have addressed the amyloid hypothesis, of course, from all sorts of angles. Even the truest believers are starting to wonder. Dennis Selkoe’s entire career has been devoted to the subject, and he’s quoted in the Science article as saying that if the trials that are already in progress also fail, then “the A-beta hypothesis is very much under duress”. Yep.
The hypothesis was under great duress even in 2004, when I took a protein structure course that spent a lot of time on prions and the beta amyloid. Many people have devoted their careers to chasing this down, only one as far as we know published impactful fake data.
However, the particular faked data, despite lots of citations, has apparently not lead to any clinical trials:
> Did the AB*56 Work Lead to Clinical Trials? That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB*56 oligomer itself (I’ll be glad to be corrected on this point, though).
I wish to retract this comment, as it was not based on full information. I was going off of the data fr the linked article, but here are many more cases of fraud from leaders in the field:
> In particular, even treatments that directly reduce amyloid-β in the brain did not restore cognitive abilities.
Correct, but this doesn’t constitute “fake data”. It could be that amyloid-β is a marker rather than a causative factor. Or it could be that amyloid-β related damage is downstream, and remove amyloid-β after the damage has been done won’t remove the other damage.
It’s too quick to wave away an entire field because a single theory didn’t pan out. Most medical research proceeds with a lot of dead ends before it is figured out.
Medicine isn't my field, but I wonder why the chirality, why gold, why microbiota as target, why those particular diseases?
As in, I might be searching wrong, but I can't find previous research that would hint in this particular direction, and I think it's reasonable to be skeptical about any "random button pushing"-looking research showing positive results.
A lot of biology is still a black box for us. You investigate a block box by pushing its buttons and recording the results. Hopefully, there are enough buttons and eventually response patterns begin to emerge. Or someone invents a way to open the box, just a little.
I can't speak to chiral gold, but as for exploring the connection between microbiota and neurodegenerative diseases, this is a hot area of study. Take a sentence from the abstract:
>The gut–brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling.
You can pretty much formulate a few dozen google searches from various keywords in that sentence + "microbiome," "microbiota," and/or "GI immune signaling," etc and come up with hundreds of papers. The GI tract is host to the majority of our immune system. Many of the molecules used for signaling (and all kinds of other tasks) come directly from the bacteria there, or else are dependent on bacterial metabolites as inputs.
On a related note, I expect we will hear more about the metabolome in health and medicine research. As microbiome is the set of all microbes in the body, metabolome is the set of all metabolites (bacterial and endogenous) in the body. In this study, serum levels of an indole were found to be altered in Alzheimer's patients:
>indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls.
In another study of MS patients, two other indoles, as well as butyrate, were found to be lower in serum concentration compared to healthy controls [1]:
>Highlights - Gut microbiota and metabolites profiles of individuals with
MS differ from healthy controls. Individuals with MS have reduced serum levels of
indolepropionate. Individuals with MS have reduced serum levels of indolelactate and its producing bacteria. Individuals with MS have lower levels of species and genes
involved in butyrate production.
Indoles in particular may be an interesting avenue of research [2]:
>What is the function of the indole in bacteria?
Indole has recently been implicated as an important small molecule signal utilized by many bacteria to coordinate various forms of behavior. Indole plays a role in numerous bacterial processes, including: biofilm formation and maintenance, virulence factor production, antibiotic resistance and persister cell formation.
Something of an educated guess, but microbiota because there are current hypotheses that rely on the gut-brain interaction, gold probably because its inert, and chirality is most likely because their target requires specific kinetics.
Alzheimer's is the most common form of dementia, affecting tens of millions of mostly elderly people, characterized by the brain getting “gummed up” by various mechanisms like reduced interconnectivity of your neurons, the formation of these plaques of a protein called amyloid beta on the brain tissue, tangles of a different protein called tau, and little “pearls” of a sort called vacuoles wrapping not sand grains but little lumps of hardened proteins. So there's a theme of proteins being where they're not supposed to be and misfolding and so on.
There are several partial causes of these protein problems, including genetic factors, chronic high blood pressure, smoking history, depression history. One can alternatively characterize this as a sort of inflammatory response, which puts it in a bucket with Parkinson's and ALS and other things tied to oxidative stresses and long-term inflammation.
I am not a physician but was trained as a physicist, part of where I know about this stuff comes from trying to research a speculative YouTube video that I never got around to making called “the biophysics of weight loss” where I would tell people that from a physics perspective, the scale in your bathroom lies, calories are necessary but not sufficient to understand the problem, feedback networks are complicated, and just in general tried to educate the public about basic physics from a direction that is not Newtonian mechanics. (So if you want to start with energy, what is the most frequent interaction with measured amounts of energy everyone has? It's either diet or the wattage ratings on electric bulbs, diet seemed more fun.)
So where this gets interesting for me is, in trying to talk about the complex feedback loops and signaling and satiety around diet, diet and lifestyle factors do seem to affect these chronic levels of inflammation. Just a simple example, your blood has to maintain a strong homeostasis with respect to how much sugar is in there, too little and your cells don't have what they need, too much and bacteria could thrive inside of you. One mechanism the body uses is, if we detected the blood as too sugary, we dump this signaling molecule called insulin in there too. Muscle tissue will take up blood sugar without insulin, but fat cells need the insulin as a “key” to open a lock that lets sugar in for long-term storage as fat. But the fat cells have what we in computing would call backpressure—they don't just respond directly to insulin, they calibrate their response to what they can handle. If too much sugar is coming in and I can't store it, I reduce my sensitivity to the insulin, so that I take in less sugar for a given amount. If this happens chronically enough, you get a general insulin resistance, and that leads to high blood sugar, type-2 diabetes.
Well, elevated blood sugar does something else that is linked to Alzheimer's: the Maillard reaction. This is the crusty delicious browning that happens when we sear a steak, or bake bread. The natural sugars in the muscle and natural proteins in the flour are enough in either case, the formula is sugar plus protein plus heat equals denatured brown crusty proteins. You are warm enough on the inside that this does “sous vide” your proteins very slowly, it is part of aging. So if your blood sugar is high, you age faster. The term in the literature is “advanced glycation” if you want to read more about this.
I don't have diet recommendations, I am just interested because I can ask prospective students “if we turned you into a hot dog, how far would it stretch” and other silly things like that. I will say, keto was originally invented to help with epileptics, and it does that by moving the brain off of sugars and to a fuel that the brain “prefers” (in the sense of having fewer barriers to letting it in) called ketone bodies. Intermittent fasting also does this on shorter timescales.
Anyway, the story about the gut microbiome maybe playing into this is even more complicated,...
Read Ed Yong's book "I Contain Multitudes". This area has been more/less blocked for many decades and with recent innovations and pipelines we may be able to start finding causal patterns.
71 comments
[ 6.6 ms ] story [ 168 ms ] threadAnimal models are used in research. Is this news to you? Do you think people don’t know that?
In this context of social media it's very useful as a reminder.
This headline would potentially be Nobel worthy if in humans.
So it's not even generalizable to all mice, much less humans.
More studies are needed.
It really is a very good metric for preventing you to get sucked into hype that will 99.99 percent of the time result in exactly zero real world impact 10 years later.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10019775/ Fecal microbiota transplantation in Parkinson's disease—A randomized repeat-dose, placebo-controlled clinical pilot study
"Conclusions: Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms."
Or maybe I have discovered a fetish.
Do you get them in pills and then mix it with coconut oil or what? (Or does it need to be pure MCT)
- Bypass the stomach acid, preserving more bacteria
- Keep the bacteria out of the small intestine mostly to avoid SIBO and avoid having to chase the probiotics with Betaine hcl, Ginger root, digestive enzymes, etc... to keep the small intestine clear which can trigger inflammation. Also not having to pre-coat the small intestine with cranberry molecules to cover any section that is missing the mucous layer.
- Feed the colon and large intestine cells MCT oil without having to consume it.
- Anecdotally I feed better for several days after doing this. I can do faster power-walks for longer. I do not run to protect my cartilage.
- The only GI improvement that I can feel is the lack of discomfort from taking large amounts of probiotics orally.
- Very large amounts taken orally can result in small amounts making it past the intestine cell junctions and triggering a small immune response which may have both positive and negative ramifications but that's a much bigger topic.
- Less likely to disturb the mucous layer.
Drawbacks:
- To be useful requires a large amount of bacteria and that requires a large amount of MCT oil and getting into positions to get it up into the large intestine. Well ... it has to come out some time and being liquid one must stay near the restroom. There's no holding it in. Some kind of paste injector tube would be better, probably something similar in form factor and design as the vaginal yeast infection treatments perhaps. If this were a product I would buy it even though it would be harder to get it into the large intestine.
- The first few hours after can feel weird as the body has to adjust.
:)
[1] - https://www.amazon.com/NewRhythm-Probiotics-Digestive-Prebio...
I have not. I can not find any labs that I can trust and that have not been hacked on a regular basis.
Sounds a bit extreme
It may be. I reset my gut bacteria some years ago and use this to improve the overall gut-scape. The 4 K's are great but my personal preference is to use this method that if for no other reason it is banned by WADA. If they consider it cheating then I like it that much more.
I haven’t followed the topic for a long time, but I distinctly remember how many people were disappointed with the results of their self administered FMT. This is probably because they had unreasonable expectations about their health conditions being caused by the microbiome. The only real success stories were from people who had C. Diff and treated it with a combination of antibiotics and FMT.
However, there were a lot of negative stories. Some people had major bowel problems for a while. One person even died, though it was speculated that it was due to some of the microbiome altering antibiotics he was experimenting with.
Interesting research topic, but please don’t DIY it.
> The first person known to die as a result of a fecal transplant is a 73-year-old man who developed a fatal infection with antibiotic-resistant bacteria that were in the donor's stool sample.
> News of the man's death surfaced in June; he was one of two patients in separate clinical trials who became ill after receiving fecal transplants from the same donor
https://www.livescience.com/fecal-transplant-death.html
So I assumed that these would be gold atoms with a chiral molecule around them - the ligand, that is. However, from a quick search it appears that there are these gold nanoparticles that are chiral shapes. In other words, the structure of the particle is chiral, not the molecule itself.
In any case, I doubt you can get them over the counter any time soon, but who knows.
edit: Here is a nice looking review that is free to read : https://www.nature.com/articles/s44222-022-00014-4
Seems like there are a variety of different techniques but Figure 2d in that review shows an image referencing - 'Lee, H.-E. et al. Amino-acid- and peptide-directed synthesis of chiral plasmonic gold nanoparticles. Nature 556, 360–365 (2018)'
At least this paper tests both cognitive abilities as well as "amyloid-β pathologies." I'm not at all an expert in this field but gold nanoparticles sounds like something you'd see on a late night infomercial, lol.
[0] https://news.ycombinator.com/item?id=37572394
The issue in the Alzheimer's world is the possibility that the very disease mechanism concept underlying the vast majority of research and interventional trials into which countless multiple billions have been poured, is incorrect.
Within that space, this is orders of magnitude more fundamental and serious than a flip aside that lots of trials have problems, so who cares about another?
Not "is incorrect," but might be incorrect. And we almost certainly won't know it is correct until we actually have a therapy.
Those pursuing cures could have waited until there was more solid science, but they and their funders took on the risk, knowing full well that the amyloid hypothesis is not proven.
This is not some indictment of science, this is normal risk taking for a problem that hugely affects society.
That's why the part you quoted is preceded by "the possibility that".
It is the best possible explanation so far, but four decades of research have not reached a definitive conclusion.
An open problem is not a problem for science, that's the fundamental focus of science. The problem is people misrepresenting what science is and what it aims to do.
To be clear: for decades, researchers wishing to pursue lines of inquiry contrary to the a-beta hypothesis struggled for traction and funding, and saw their careers struggle as a result[0]. As such, trying to disprove the a-beta hypothesis was not the core research question for many/most, for long time.
[0] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...
> A top journal told one that it would not publish her paper because others hadn’t.
Oh the horror, not getting published in a top journal! Turns out that most good science gets published outside the top journals.
This sort of behavior is bad, and has always been part of the process, and may actually be better today than it was a century ago, as the clubs are not nearly so tight as they were back then.
Early in my career I remember reading some of ET Jaynes' (an early Bayesian reasoning guy) discussions of his early career, and how he had to very very carefully choose his topics so that he wouldn't upset the big personalities in physics and thereby have his entire career crushed. It's better these days than it was then!
There will be sour grapes about funding, just as there are when VCs all jump on the hype train for the same idea, but my only scientific exposure to the amyloid hypothesis for the past 20 years has been in terms of it being an unproven hypothesis. Starting down exploratory routes for explanatory hypotheses should have been pursued, and was pursued, and will continue to be pursued, but the question of "how much" is exceptionally difficult to answer.
Perhaps I'm biased from being in Science too long, but I've seen so many sensational Stat News article that never pan out when pushed upon. I wouldn't trust them at all with stuff like this.
https://www.science.org/content/article/misconduct-concerns-...
>For more than 150 trials, Carlisle got access to anonymized individual participant data (IPD). By studying the IPD spreadsheets, he judged that 44% of these trials contained at least some flawed data: impossible statistics, incorrect calculations or duplicated numbers or figures, for instance. And in 26% of the papers had problems that were so widespread that the trial was impossible to trust, he judged — either because the authors were incompetent, or because they had faked the data.
Firstly, this is only from one journal, Anesthesiology. Second, the phrase "at least" indicates that while 44% had some amount of (presumably) flawed data, only 26% of the studies were bad enough to be judged fake or severely flawed by this one (admittedly esteemed) researcher in the field of anesthesiology. It's important to be skeptical and do your homework when you hear sweeping and/or shocking results. It's also important to read carefully, especially with science journalism because it is written for clicks and broad audiences, not to reduce ambiguity and adhere to strict standards of accuracy.
That means 11% of the total papers should be discarded, which means 89% of the papers can be used.
It is at least 26%, because that was the percentage of studies that provided access to their data that proved faked or fatally flawed.
It may be substantially higher.
The plaques are known to be linked to Alzheimer's, the debunking of one paper that messed with its figures does not detract from the whole body of research. The inefficacy of plaque-targeting treatments may not be proof that the plaques are not causal in nature, only that their damage is not reversible/fully understood.
The problem is viewing individual papers as the unit of truth in science. The "self-correcting" nature of science will actually reject entire papers, and entire directions of inquiry. Including, maybe, a casual relationship between beta amyloid and AD, but maybe not.
The other key part of science is holding everything in a state of uncertainty. There's some "facts" but mostly just hints and clues. And with Alzheimer's disease in particular we are trying to make progress with completely inadequate vision; we really can't even measure so much of what we want to measure. Feynman said it back in the 1960s, too, physicists have failed to deliver the tools to biologists to really measure what needs to be measured. There have been advancements, and DNA sequencing technology in the past decade has been turned into the most clever sorts of information theoretic microscopy by combining DNA sequences with many other biochemical processes. But we as a species still can not measure a lot of the things we'd like to measure.
> But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find 56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. Just not Lesné’s oligomer.
And
> Did the 56 Work Lead to Clinical Trials? That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB56 oligomer itself (I’ll be glad to be corrected on this point, though).
> Every single disease-modifying trial of Alzheimer’s has failed.
> The huge majority of those have addressed the amyloid hypothesis, of course, from all sorts of angles. Even the truest believers are starting to wonder. Dennis Selkoe’s entire career has been devoted to the subject, and he’s quoted in the Science article as saying that if the trials that are already in progress also fail, then “the A-beta hypothesis is very much under duress”. Yep.
And the original expose is quite interesting if you haven't read it yet https://www.science.org/content/article/potential-fabricatio...
However, the particular faked data, despite lots of citations, has apparently not lead to any clinical trials:
> Did the AB*56 Work Lead to Clinical Trials? That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB*56 oligomer itself (I’ll be glad to be corrected on this point, though).
Marc Tessier-Lavigne https://stanforddaily.com/2023/02/17/internal-review-found-f...
Berislav Zlokovic https://www.science.org/content/article/misconduct-concerns-...
Hoau-Yan Wang https://www.science.org/content/article/co-developer-cassava...
Sylvain Lesné - the researcher from grandparent comment's article
This list taken from Chris Said on Twitter https://x.com/chris_said/status/1724448550493315436?s=46
Correct, but this doesn’t constitute “fake data”. It could be that amyloid-β is a marker rather than a causative factor. Or it could be that amyloid-β related damage is downstream, and remove amyloid-β after the damage has been done won’t remove the other damage.
It’s too quick to wave away an entire field because a single theory didn’t pan out. Most medical research proceeds with a lot of dead ends before it is figured out.
As in, I might be searching wrong, but I can't find previous research that would hint in this particular direction, and I think it's reasonable to be skeptical about any "random button pushing"-looking research showing positive results.
Faff around and find out is the essence of the scientific method.
That said, I never trust a paper that gets posted directly to HN much. But then, single papers are never to be trusted!
>The gut–brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling.
You can pretty much formulate a few dozen google searches from various keywords in that sentence + "microbiome," "microbiota," and/or "GI immune signaling," etc and come up with hundreds of papers. The GI tract is host to the majority of our immune system. Many of the molecules used for signaling (and all kinds of other tasks) come directly from the bacteria there, or else are dependent on bacterial metabolites as inputs.
On a related note, I expect we will hear more about the metabolome in health and medicine research. As microbiome is the set of all microbes in the body, metabolome is the set of all metabolites (bacterial and endogenous) in the body. In this study, serum levels of an indole were found to be altered in Alzheimer's patients:
>indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls.
In another study of MS patients, two other indoles, as well as butyrate, were found to be lower in serum concentration compared to healthy controls [1]:
>Highlights - Gut microbiota and metabolites profiles of individuals with MS differ from healthy controls. Individuals with MS have reduced serum levels of indolepropionate. Individuals with MS have reduced serum levels of indolelactate and its producing bacteria. Individuals with MS have lower levels of species and genes involved in butyrate production.
Indoles in particular may be an interesting avenue of research [2]:
>What is the function of the indole in bacteria? Indole has recently been implicated as an important small molecule signal utilized by many bacteria to coordinate various forms of behavior. Indole plays a role in numerous bacterial processes, including: biofilm formation and maintenance, virulence factor production, antibiotic resistance and persister cell formation.
[1] - https://www.cell.com/cell-reports-medicine/pdf/S2666-3791(21...
[2] - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175420/
There are several partial causes of these protein problems, including genetic factors, chronic high blood pressure, smoking history, depression history. One can alternatively characterize this as a sort of inflammatory response, which puts it in a bucket with Parkinson's and ALS and other things tied to oxidative stresses and long-term inflammation.
I am not a physician but was trained as a physicist, part of where I know about this stuff comes from trying to research a speculative YouTube video that I never got around to making called “the biophysics of weight loss” where I would tell people that from a physics perspective, the scale in your bathroom lies, calories are necessary but not sufficient to understand the problem, feedback networks are complicated, and just in general tried to educate the public about basic physics from a direction that is not Newtonian mechanics. (So if you want to start with energy, what is the most frequent interaction with measured amounts of energy everyone has? It's either diet or the wattage ratings on electric bulbs, diet seemed more fun.)
So where this gets interesting for me is, in trying to talk about the complex feedback loops and signaling and satiety around diet, diet and lifestyle factors do seem to affect these chronic levels of inflammation. Just a simple example, your blood has to maintain a strong homeostasis with respect to how much sugar is in there, too little and your cells don't have what they need, too much and bacteria could thrive inside of you. One mechanism the body uses is, if we detected the blood as too sugary, we dump this signaling molecule called insulin in there too. Muscle tissue will take up blood sugar without insulin, but fat cells need the insulin as a “key” to open a lock that lets sugar in for long-term storage as fat. But the fat cells have what we in computing would call backpressure—they don't just respond directly to insulin, they calibrate their response to what they can handle. If too much sugar is coming in and I can't store it, I reduce my sensitivity to the insulin, so that I take in less sugar for a given amount. If this happens chronically enough, you get a general insulin resistance, and that leads to high blood sugar, type-2 diabetes.
Well, elevated blood sugar does something else that is linked to Alzheimer's: the Maillard reaction. This is the crusty delicious browning that happens when we sear a steak, or bake bread. The natural sugars in the muscle and natural proteins in the flour are enough in either case, the formula is sugar plus protein plus heat equals denatured brown crusty proteins. You are warm enough on the inside that this does “sous vide” your proteins very slowly, it is part of aging. So if your blood sugar is high, you age faster. The term in the literature is “advanced glycation” if you want to read more about this.
I don't have diet recommendations, I am just interested because I can ask prospective students “if we turned you into a hot dog, how far would it stretch” and other silly things like that. I will say, keto was originally invented to help with epileptics, and it does that by moving the brain off of sugars and to a fuel that the brain “prefers” (in the sense of having fewer barriers to letting it in) called ketone bodies. Intermittent fasting also does this on shorter timescales.
Anyway, the story about the gut microbiome maybe playing into this is even more complicated,...