A polyclonal antibody is an extraction of (usually rabbit) blood from an animal that has been insulted with the agent you'd like to detect. The extraction is enriched for antibodies. They are less reliable, because there could also be other antibodies in there. Even the antibodies that recognize what you're looking for could be a population of antibodies, each recognizing a different part (think the blind men and the elephant parable). Presumably, you have tested that a positive control of what you're trying to look for works.
A monoclonal is different. You insult a mouse with a sample of what you'd like to detect, and then resect the spleen, which contains b-cells, cells that produce the antibody. You then fuse the b-cells with a special strain of cancer cell that will immortalize the b-cell (these are called 'hybridomas'). After sorting one cell to a well, you then test to see if the cells in the well have produced an antibody that detects what you're looking for. Therefore, you can be confident that a monoclonal antibody contains only one antibody, that recognizes only one antigen.
You don't necessarily know what the antigen is that is recognized (that's called the epitope). The epitope could be, say, a piece of protein on the outside of the fungus or a different piece of protein on the outside of the fungus. It's even conceivable that even for a monoclonal there are side-reactions against things that are naturally in the sample.
And: Epitope retrieval techniques are really complicated. So figuring out exactly what epitope is recognized is not trivial.
As a result, every B lymphocyte makes one particular antibody that is different to every other B lymphocyte, and which recognises a different molecular pattern to every other B lymphocyte. There's a process in their development which weeds out cells which recognises patterns in your own body, leaving a population of cells which (hopefully) recognise every possible pattern which is not part of your own body.
B lymphocytes then wander round the body, looking for stuff which binds to their antibody; if they find it, they know it must be an invader, and they raise the alarm, triggering an immune response (subject to checks and balances from other parts of the immune system). As part of that, the cell which raised the alarm will proliferate, making millions of cells producing identical antibodies, which bind to the invader and mark it for destruction by other cells of the immune system.
If an invader has more than one molecular pattern (which it will - every patch on the surface of a protein is a pattern, and a bacterium will have all sorts of proteins and other things on its surface), then a corresponding number of B lymphocytes should recognise it, and proliferate in response.
So, if you insult a rabbit with your protein, you will activate all the B lymphocytes which recognise patterns on it. If you purify antibodies from its bloodstream, you will get antibodies recognising all those patterns - and any other antibodies which happen to be in the bloodstream at the time. If you isolate a single B lymphocyte its bloodstream, make it immortal, culture it, and purify the antibodies from that, you will get a single kind of antibody, recognising a single molecular pattern.
In software terms, a monoclonal is a bit like detecting spam by grepping for a single spam-specific word, and a polyclonal is a bit like doing an n-gram comparison with a corpus of known spam.
Not sure if you really meant that since it is kind of contradicted by some later statements, but all antibodies are promiscuous. Thinking you can map one antibody to one epitope is extremely dangerous. It is a matter of quantity (affinity/avidity), not quality.
(I believe you that this is bad science.)
Edit: I answered my own question here: https://en.m.wikipedia.org/wiki/Scientific_Reports (Summary: It's not Nature; it's a "megajournal" affiliated with it with apparently much lower editorial standards.)
A concrete example is the accidental discovery of the cosmic microwave background radiation. If you Google "accidental discovery" you'll find hundreds of other examples.
Or, if you prefer an Asimov quote:
"The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka!' but 'That's funny...'"
I guess the next step would be testing the hypothesis with more people with AD to see if it holds up and then somehow getting approval to do drug trials (and I'm sure there will be no shortage of volunteers.) I can almost see a clamouring of families trying to get their hands on anti-fungal drugs in the future in the hope that it helps their loved ones but we simply won't know if this will help until there's more data.
Hoping for a break through. It's certainly not without precedent that we find something extremely simple / obvious that turns out to be the key. On a side note: it's interesting to think that the crack pots you see writing about candidas infections being the cause of numerous hard-to-treat illnesses -might- actually be right (in a sense.)
Combination of these two factors sadly means that short of major breakthroughs in fungal antibiotic research or in drug delivery to the brain, Alzheimer is not likely to suddenly become more treatable even if the fungal infection theory proves to be true.
Second, antifungals have positively affected AD-like symptoms, though possibly through misdiagnosis.
Nonetheless, if some anti-fungal treatments do prove to be effective against alzheimer's it'll be an amazing advance in medicine. Probably at the level of a Noble prize for the researchers. I'd love to see that happen.
The body is mostly water. The task of removing microorganisms and fungus from water has been well studied.
Science knows of effective agents which are proven to purify water of micro-organisms like bacteria and also fungus. Some of these are being utilized in public water decontamination, and others while also effective are not used because they are less cost efficient to produce.
Water purifying agents have a varying range of effectiveness and also and a varying range of toxicity to the human body. There are a couple of agents in particular however which are both well tolerated by the body and are also remarkably effective at decontaminating water.
The one which my research indicates leads the pack in this area is a white crystalline salt named Potassium Iodide, KI. KI has been used widely by both the military and by campers in portable water decontamination.
A solution of Potassium Iodide in water (known colloquially as Iodine) was a leading and apparently very effective drug during the 19th century in the United States. There are doctors today who prescribe milligram doses of KI (many many times more than the RDA) to treat a wide array of ailments but especially in dermatology. They do not typically see serious side effects although they do frequently recommend monitoring thyroid levels while utilizing higher doses.
Sounds nonsensical to you? Good. Because that's about how reasonable your "the body is mostly water" thesis sounds to someone with a biomedical background.
Let me rephrase this argument as: "The body is mostly water. The task of removing HIV from water has been well studied. Therefore it's easy to remove HIV from the body".
Just to be clear: I have no medical expertise, this is mere conjecture. But fungal infections could perhaps persist in various cells. In neurons. In spoor form. In all sorts of manifestations, where they wouldn't be affected by the same treatment that disinfects water. I don't have any expertise to say one way or the other, but I suspect that if there were a simple solution such as "just treat with Iodine, it'll kill the fungus", this discussion wouldn't be taking place.
This seems like it would make no sense until you stop to consider that idea that in earlier generations of man we ate on average a lot more marine plants than we do today (kelp in particular) which are rich in Potassium Iodide. People ate kelp because it was a "low hanging fruit" so to speak, easily harvested in great quantity from the sea. Perhaps the beneficial organisms in our gut evolved to tolerate KI so that populations could tolerate eating mostly seaweed.
The Japanese still eat a lot of kelp (the average japanese male ingests more than 40mg of KI daily from seaweed), and if you crunch the statistics it looks like they may have significantly less AD among their population than we do in the west:
Moreover, the iodine content of the food was very low and that's bad for your thyroid. The government mandate to add a small amount of KI to the table salt NaCl. https://en.wikipedia.org/wiki/Iodine_deficiency
Iodine, on contact with electron donors, will rapidly reduce them and ionize to the same nontoxic iodide found in potassium iodide, rendering it nearly harmless. However, oxidizing your body cells causes chemical burns by killing them; oxidizing bacteria and fungi kills their cells too. Pure iodine will blister your skin on contact.
Essentially your optimism arises from confusing two related, but very different, substances. Don't feel bad; I've made similar errors any number of times. One out of every ten thousand times that you think you've found an easy way to hack around a difficult and important problem, it's a breakthrough. The other 9,999 times, you're overlooking a fundamental reason your idea won't work.
It's deeply unfortunate that HN is not the kind of place that people will correct your mistakes, as I've done above, instead of silently downvoting you.
If you are using CNS stimulants (amphetamines, methylphenidate, modafinil, cocaine, maybe even caffeine) you might want to cut down your dosage. The hyperfocus they facilitate can be counterproductive when it causes you to overlook your errors and get overexcited over a possible breakthrough. This can blossom into full-blown amphetamine psychosis, which is not an experience I recommend, especially for the people around you.
A useful tool in discovering errors like this is investigating consequences that would ensue should your reasoning turn out to be true. For example:
* Potassium iodide is a chemical that people have been dosed with many times, including soldiers under controlled conditions. If it cured everything from jock itch to acute bacterial meningitis, probably someone would have noticed.
* Bottles of iodine are labeled "for external use only". If it were nontoxic, it would not be labeled in this way.
* Many potassium iodide vendors and customers are enthusiastic promoters of colloidal silver, which actually is a broad-spectrum antimicrobial that is fairly nontoxic to human bodies. (By itself, it's not effective enough to disinfect water with, but in combination with the more toxic copper, ionized silver has been used to disinfect water.) If KI were effective for disinfection, they would be promoting it as such.
* Our bodies use iodide in certain thyroid hormones, so there are enzymes devoted to moving iodide ions around, keeping them from reacting with the wrong things, etc. This is different from e.g. lead, mercury, or tellurium, which have no known biological function and cause toxicity by acting as poor substitutes for other atoms. If iodide were nontoxic and effective at stopping fungal infections, we would have evolved to concentrate it in our bodies and direct it to areas suffering from inflammation. But we didn't.
You will die of hyperkalaemia
The article describe an alternative theory for Alzheimer
> In Alzheimer’s, there are accumulations of big protein chunks in the brain. We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.
It may not be so hard to get data - try anti-fungals and see if the patients get better. There are plenty of patients and the drugs could be tried in countries other than the US. It could be possible to get data in a few weeks rather than years of trials.
There seem to be about a dozen anti-fungals at the moment which could be tried. Presumably the best choice would depend on which fungi was involved. http://www.ncbi.nlm.nih.gov/pubmed/17381184
I got the impression that the disease symptoms result not from the mere presence of the fungus, but from progressive damage over a long time. So, if you don't start to treat until there are symptoms, you could kill the fungus and at best, the person would not get worse. Which is not to be dismissed, but...
It's "not to dismissed"? It's the difference between life and death!
Amyloids have generic secondary structure (can be created from any amino acid sequence under the right conditions) and yeast produce amyloids. They quite possibly raised antibodies towards yeast amyloids and then stained human amyloids. It is strange they do not report staining these brains for amyloid-Beta, it is an obvious thing to do.
The evidence in the paper consists of a few representative pictures. I have never seen human brain stained for amyloid-beta, but if it stained at all I would bet lots of money that I could find at least one clump with "fungal morphology".
Also, ruling out the other explanations (such as they stained for amyloid) is not the audience's job, it is their job. They are the ones with access to the most detailed information, putting them in the best position to think about various explanations for what could be going on.
The interpretation in the paper was it was a misdiagnosis rather than an Alzheimer's cure but you never know.
This has significant implications in terms of direction of future research.
The point of the criticism seems to be that with an improper control group, there still isn't such a correlation, just a suggestion of a possibility of a correlation. But it might be a correlation between, e.g., age and fungal infection.
That's why, but for the variables under study, you want your control group to look as much like your experimental group as possible.
There's not many well understood systems (the other well-studied one is toxoplasmosis and cats), but one researcher on Experiment, Charissa de Bekker, just released a new paper with findings from her project.
The results gave a first clue about the many genes that are involved in this manipulated biting behavior. For instance, that the fungus is likely producing LSD-like compounds and is secreting proteins that could affect serotonin and dopamine levels in the brain, as well as the ant’s ability to communicate through chemosignals with their nest mates. As well, in the paper, they release the entire transcriptome taken from the brains of these ants, giving other scientists a chance to use this as a model system and to begin to target which genes go on to influence behavior.
I was just talking to her about it this week, and so this news is very timely and a bit eerie. But very cool.
Asimov's book on science history is an interesting read, full with similar discoveries that were ignored for many years.
Articles somehow related to the subject:
>No fungal material was observed in brain tissue from ten control individuals, whereas fungal infection was clearly present in brains from ten additional AD patients.
So 100% correlation so far - pretty impressive results.
I wonder about my dad who has an unexplained Parkinson's like nervous deterioration.
Doctors still seem to prescribe blood pressure medication and low-salt diets to people with hypertension, depite the overwhelming number of studies which show that neither prescription has any impact on mortality rates. It doesn't look like they are particularly evidence-driven or self-aware as a profession.
I have no idea why HN has this bias against physicians.
Doctors are human and some are constantly learning new information while others aren't. There are a lot of pressures on them that are perhaps orthogonal to "learning new things" and "keeping up with the best evidence."
You could also do research on, say, Lister or checklists and get the bias that way.
In any case, the relative difficulty of updating previous beliefs does not excuse the failures of doctors which cause a great deal of death and suffering. When engineers fail to update their beliefs, and people die, it is called negligence.
2015: "[...] the NIH made the bold announcement that intensive intervention with a combo of three drugs to reach a new target systolic blood pressure of under 120 mm Hg reduced the rate of heart attacks, heart failure and stroke by 30% and cardiovascular deaths by 25%, "
There's more evidence available.
But you can look at what guidance for doctors is to compare what happens. Here's UK guidance.
Offer drugs to people with stage one but only if there are other symptoms; offer drugs to anyone with stage two (but do careful measuring to ensure they actually have stage two); investigate causes and provide support.
It's pretty frustrating that you misrepresent the research, and what doctors do with that research, to push some anti-doctor spin.
There's plenty of bad stuff that doctors actually do.
The best minds of our generation are too busy selling ads to be bothered with trivial stuff like this.
(For the record, work in healthcare, but no doubt am wasting my time saving the wrong lives.)
Regarding the research, the data presented here are not convincing without larger scale replication with better controls and more standardized assays.
But we do treat people with CNS infections routinely, including CNS fungal infections.
You may conclude that antifungal drugs could help patients with AD. You may also think that vaccination or some other mechanism of prevention could reduce the prevalence of AD. These conclusions are simply not supported by the data.
I am a biomedical data scientist, not a neuroimmunologist, so I asked a colleague in my MD/PhD program who has experience in the latter field. His thoughts:
"There are a number of concerning issues here:
1) They are using polyclonal antibodies. I don't think they addressed possibility of cross-reactivity. Comparing Alzheimer's disease vs control brain is like comparing apples and oranges. There can be very different inflammatory states between the two and yield different antigenic environments.
2) The possibility that neurofibrillary tangles or amyloid plaques are sticky and can non-specifically bind antibodies remains a possibility.
3) Only immunohistochemistry? Could have at least done some qPCR especially since they can grow these fungi for quantiation. The only other paper that observed fungus in CNS of AD patients is by the same group. The high possibility of artifact is has not been ruled out."
*edited grammatical typo
This might be a giant breakthrough, or it might be just a side effect. The uncertainty is not fun at all. But if the arrow points the right way, then yes it's possible that antifungals would be a big part of treatment.
Doctors have the whole "first do no harm" thing that makes prescribing stuff randomly on hope not really an option. Now if patients start clamoring for it that's another story. But until it's shown that antifungal medicine does more good than harm (who knows, maybe killing all the fungus somehow leaves a void that bacteria could come fill) it's probably best not to do so widely.
In this case, since there is no concept of old or new, it's an entirely new class of treatment. So you give the current best-practice treatment without anti-fungal, and you give the same with anti-fungal.
Anyone in the study is agreeing at the onset that they have a 50/50 chance they will either get the current best practice, or the exact same thing but also the anti-fungal. These are volunteers who are helping move the anti-fungal research forward for everyone, in exchange for a chance of getting early access. They can also leave the study at any time after starting, but if they are in the anti-fungal group they would lose access to it if they did.
If that's not enough, there are cases (e.g. in cancer research) of de-blinding the study when there's a clear/strong positive effect and providing early access to all enrolled if it becomes obvious the new treatment is widely beneficial.
So I think we have the theory behind the ethics fairly well wrapped on how to roll out these drugs. I don't think in practice it works so well, the studies are often poorly run and poorly administered making them extremely more costly than they should be.
I am still a bit clueless with all the research we have done with Alzheimer's why we need another control group?
You might be able to do a small study without a control to test feasibility of the hypothesis, but I don't know if that would pass ethics review; would probably depend on the side effects of the anti-fungal. Another less invasive way would be to test for fungal presence in groups with and without the disease, likely through autopsies, since sampling a live brain seems intrusive.
The reality is the control group and the test group are not the exact same people and often it's not even completely true everyone is dealing with the "exact same" disease (different genes, different mutations, different past treatment regimens, etc.). I definitely believe there are cases where a control is setup because "that's how it must be done" and not because it's going to actually provide any useful data at the end of the day to tell you anything about how the test group actually performed.
Another way I've seen this done which is a little less wasteful, and when you have high confidence in your new treatment, is to tweak the standard treatment marginally in some way you think might provide some small improvement in both groups, but in a way that could never justify its own full study. Like you modify the dosing schedule, add some vitimin, diet, or exercise change in some way you think will help both groups. But again you can only afford to do that if you are expecting a very strong effect from your new additive treatment which would blow away your tweak statistically, else you risk hiding a small benefit of the new treatment in your tweak.
In other words, you give every participant the best damn chance and the best care you can legally give them, and 50% of them know they are on something new which could be a blockbuster, and if it is, the whole group will get early access to it anyway.
Those have problems of blinding, and treatment vs no treatment is difficult to get through ethics committees.
Obviously depends on the patient population (in/out patient) but IMO a huge component of the cost is pushed off on patients having to spend a day getting to the study facility to give blood and urine versus dropping it at a local lab.
Then again, if Theranos tells us anything about variability of lab results, you certainly have to take every precaution to protect the integrity of your data.
At some point you need to start considering that something is seriously wrong with the research methods or theories. This fungal idea is good to explore, but the evidence provided here is not convincing at all.
>We describe here three patients with the Alzheimer's Disease (AD) whose behavioral symptoms were improved remarkably as a result of the turmeric treatment...
Turmeric has strong anti fungal properties.
"Moreover, antifungal treatment in two patients diagnosed with AD reversed clinical symptoms [51,52]. The interpretation of these results was that perhaps these patients were misdiagnosed."
 Ala, T. A., Doss, R. C. & Sullivan, C. J. Reversible dementia: a case of cryptococcal meningitis masquerading as Alzheimer’s disease. J Alzheimers Dis 6, 503–508 (2004).
 Hoffmann, M., Muniz, J., Carroll, E. & De Villasante, J. Cryptococcal meningitis misdiagnosed as Alzheimer’s disease: complete neurological and cognitive recovery with treatment. J Alzheimers Dis 16, 517–520 (2009).
Perhaps the fungi avoid the immune system by being very slow and relatively non-disruptive, and the reduced effectiveness of the immune system in old age allows it to take hold and spread.
I'm curious if the title makes sense to people in the field or is this weird to them too?
I had the same concern as GP. I don't understand the title; the controls seem not to have fungi in their brain, which had always been my assumption about, for example, my brain.
There is also a tendency when scientists are extremely confident they have found something incredibly important to understate it. I always think of the Watson and Crick "It has not escaped our notice ..." statement in this context.
This is all based on guesswork though, so that's why I'm curious about what people in the field think.
plot(x,dbeta(x,.5,.5), xlab="Prestige", ylab="BS")
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 - https://github.com/magnars/multiple-cursors.el
 - http://emacsrocks.com/e13.html
 - http://orgmode.org/worg/org-contrib/orgtbl-ascii-plot.html
One problem with biomedical research is the crackpots.