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Alzheimer's Disease

A New Infectious Mechanism for Alzheimer’s?

We have another entry in the “Is Alzheimer’s caused by infectious disease?” drawing, and it’s a good one. A large multicenter team reports that Porphyromonas gingivalis, which is the key pathogen in gingivitis (gum disease) may be the actual causative agent in Alzheimer’s, which is a bold claim indeed. But they have several lines of evidence to back it up, and it’s a hypothesis that has to be taken seriously.

This particular idea has been developing out there already. Here’s a 2016 study looking at Alzheimer’s patients with peridontitis and finding that infected patients had more rapid cognitive decline. And this 2015 paper reported that gum disease was associated with higher amyloid levels in the normal elderly as well. In 2017, it was shown that deliberate infection gum-disease bacteria caused amyloid pathology and cognitive decline in a transgenic mouse model. This new paper draws quite a few more connecting lines – here we go:

The bacteria secrete some virulence factors called gingipains, which are cysteine proteases. This paper’s immunoassays for these proteins show much greater reactivity in Alzheimer’s brain tissue as compared to controls (up to 96% of the AD samples, 39% of the controls). There is a strong correlation between gingipain levels and tau, and also between gingipain and ubiquitin, and there’s a physical localization of the gingipain antibody staining and tau tangles as well. In fact, the samples show a spectrum of all these proteins, with the Alzheimer’s samples invariably on the high side and the controls invariably on the low. The authors suggest that they are in fact seeing preclinical Alzheimer’s showing up in the controls, and that this could be a diagnostic marker all by itself. There were no such correlations with samples from patients with Huntington’s, Parkinson’s, or ALS. They also demonstrate the presence of P. gingivalis DNA in post-mortem Alzheimer’s brain samples (both hippocampus and cerebral cortex) and in the CSF of living patients who are believed to have the disease as well. These PCR readouts matched the immunoreactivity results.

Infecting tau-expressing cell cultures with P. gingivalis led to breakdown of the tau protein, apparently through the actions of those gingipain proteases. Incubation of the pure protein with the proteases confirmed this, with numerous cleavage sites, and some of the fragments generated have previously been detected in Alzheimer’s CSF and proposed as possible disease markers. Meanwhile, exposing SH-SY5Y neuronal cell cultures to gingipains led to cell aggregation and other morphological changes, but if the proteases were covalently inactivated with iodoacetamide beforehand, no changes were seen.

There’s more. The team members from Cortexyme, a biotech in the Bay Area, developed more gingipain inhibitors through a med-chem effort. Looking at some of their patents, these appear to be tetrafluorophenyl esters as covalent inhibitors – two compounds in particular (COR271 and COR286) are the subject of this paper. These compounds block the cell death of the SH-Sy5Y cells, whereas broad-spectrum antibiotics were ineffective. Lilly’s gamma-secretase inhibitor semagacestat also did nothing in this assay (which to be sure is pretty much how it performed in the clinic). Injecting mice with gingipains into the hippocampus led to neuronal degeneration, but this too could be abrogated by pretreatment with the small-molecule inhibitors.

Update: I’ve heard from a longtime colleague in the industry who believes that I’m being unfair to Lilly’s efforts on semagacestat. I take his point – it was an excellent compound, and that in an area where it’s very hard to get excellent compounds. Lilly’s chemists and preclinical scientists did great work in getting it to the clinic, but (unfortunately) it did nothing for Alzheimer’s patients themselves. . .a result that anyone in this AD field is all too familiar with.

The they tried infecting aged mice with oral exposure to the P. gingivalis bacteria. Six weeks of exposure led to brain infection in all the mice so treated, along with elevated amyloid levels. Infection with bacteria that had had their gingipains genetically deleted showed no such effects. The amyloid response, as they note, is consistent with the idea that it’s an antimicrobial peptide that is induced by infection, and indeed the bacteria themselves were shown to be sensitive to exposure to beta-amyloid protein in cell culture. But oral dosing of their inhibitor compounds significantly protected the mice from infection in that model. The amyloid-as-antibiotic hypothesis is quite appealing intellectually, as it ties the well-documented amyloid/Alzheimer’s connection to alternate explanations of the disease. It also brings in the immune system and inflammation components of the disease, as many have noted. An improved compound (COR388) is currently in human clinical trials. It has already made it through Phase I, and enrollment in Phase II is expected this year.

OK, this is a pretty solid paper. You can find some gaps in it – for example, there is some switching between tau and amyloid markers along the way (the authors do propose that the documented spread of tau pathology is consistent with the idea of neuron-to-neuron bacterial infection). But overall, this is impressive work, and it is the most thorough case I’ve yet seen for an infectious-disease component to Alzheimer’s and the identification of an actual Koch-postulate causative agent. I am very happy to hear that this hypothesis is being put to the test in the clinic, and I am similarly very eager to see what happens. This is the best shot at something new in Alzheimer’s in a long time.

82 comments on “A New Infectious Mechanism for Alzheimer’s?”

  1. Isidore says:

    It will be interesting to see if epidemiological data shows correlation between populations (states, countries, ethnic groups) with higher incidence of gingivitis and Alzheimer’s sufferers. I imagine that one difficulty may be that generally where gum disease is more widespread so are other diseases and life expectancy may be lower as well, hence people may die before developing Alzheimer’s. Still, I imagine after this paper many are scouring such data for any indication of a connection.

  2. Kent G. Budge says:

    Suppose this turns out to be correct. What is the most promising treatment? An antibiotic with the ability to penetrate the blood-brain barrier, I suppose, but which would those be?

    1. Jb says:

      Treatment? How about prevention? So basically brush your teeth and see your dentist 2x per year?

      1. Jackie Reid says:

        I have always visited dentist twice a year and i have my teeth cleaned by hygenist every 3 months
        I am 45 and have gum disease with pockets 5 to 7
        I will have to get 4 teeth taken out this year due to how bad it is
        So maybe also something else needed except hygiene etc

        1. Rob Sons says:

          Check out the WaterPik. I had bad gingivitis, with some gum pockets hitting 5, and consistent cavities (1-2 yearly) for the first ~30 years of my life. Got a WaterPik, use it once per day, all of my gum pockets are in the normal range now, and haven’t had any cavities for the last 18 months.

    2. zero says:

      Antibiotics are like CPR. When you need them you really need them, but you shouldn’t need them for long. Fix the problem instead of treating the symptoms.

      Since the bacteria are already crossing into the brain there are few good options.
      Inhibitors to block these disease-causing compounds will probably be the most reliable and the earliest out of the clinic. The downside is this is life support instead of a cure, but it’s a hell of a lot better than the current state of the art.
      A P.gingivalis vaccine might be a more permanent solution, if such a thing is possible.

  3. SirWired says:

    Just as a head’s up, gingivitis and gum disease (periodontitis) are not the same thing.

    Gingivitis is merely gum inflammation. This is what happens if you don’t floss for a few days; your gums hurt and bleed some. If you brush and floss diligently for a few days, it will generally clear up on its own.

    Gum disease involves a pocket opening up between your gum and tooth, and nasty gunk building up there. It leads to chronic infection and the loss of supporting bone. Fixing it requires professional care (the pockets are not accessible with just a brush and floss), and possibly remedial surgery.

    1. cB says:

      Perhaps people eith early AD forget to brush and floss

  4. anon says:

    Does that mean we all have to “floss” our brain?

    1. Reviewer #3 redacted says:

      most definitely!

    2. Paul D. says:

      Mental floss

  5. luysii says:

    About the mouth. One of the most difficult wounds to heal is a human bite, probably because of the multitude of bacteria in the mouth. In training, a surgeon told us he’d rather have feces in a wound than saliva.

    1. Maria says:

      A komodo dragon bite is worse

      1. luysii says:

        Actually the surgeon was a bit more graphic, as surgeons tended to be back then. The GI tract when diseased sometimes breaks leaking you know what into the abdominal cavity. The surgeon said he’d prefer treating that then an abdominal cavity that someone had spit into.

      2. Tim C says:

        turns out they recently looked at the physiology again, and komodo dragons have venom after all

    2. neo says:

      Why have I never gotten an infection from biting my tongue?

      1. Dr Hugh Calder says:

        You have an immune system

  6. nemous says:

    How about people with dentures who may not have gingivitis?

  7. Pieinthesky says:

    Wow, talk about a fool’s errand!…All those hundreds of millions of dollars expended on clinical candidates designed to rid the brain of amyloid accumulation, when it could turn out that it was an antimicrobial response? A lot of egg on a lot of faces if this hypothesis gets validated. Infection, Inflammation, Mutation – is this the unholy trinity/root cause of most disease then?

  8. Allchemistry says:

    So people who loose all of their teeth at a young age have a lower risk of developing Alzheimer?

    1. Wow, Now that’s smart!

  9. metacelsus says:

    Although I’m still not completely convinced, if this finding is true it would be great news. We know how to kill bacteria, and if Porphyromonas are the cause of most Alzheimer’s cases, then Alzheimer’s would be largely preventable. In contrast, it would be much harder to get rid of something like HHV-6 from the brain.

  10. MrXYZ says:

    Need to read the article to get a better understanding but the first thought that popped in my head was whether the poking and prodding that happens in a dental examination could actually be contributing to AD.

    1. SirWired says:

      Gum disease is not treatable without that “poking and prodding”.

      1. MrXYZ says:

        I don’t disagree. My question remains – if this hypothesis is true (a very very big if), would this imply that certain types of dental procedures could contribute to AD?

        1. loupgarous says:

          Especially if autoclaving doesn’t entirely remove things that might act as nucleants for misfolded proteins from dental instruments (harking back to the “prion” hypothesis for AD).

  11. Anonymous says:

    Have not read this in its entirety, but AD is a FAMILY of diseases. Some may be due to aluminum (remember that 1980s theory?). Some may be bacterial. (There’s a guy at MGH with a bacteria theory, too.) Some might turn out to be associated with a virus. Or secondary to some other exposure. I think it is reasonable to take down a big (family) tree one limb at a time. As I have said In the Pipeline before, I do not think it was sensible to focus on one limb (or amyloid twig) as if it was the root and trunk for so many years.

    1. Bob Thebuilder says:

      Also, the herpes virus

    2. DrOcto says:

      My OCD really kicked in when you used the word family twice in your post, but didn’t mention familial alzhiemers.

  12. Matt B says:

    Anyone remember the paper about iatrogenic spreading of amyloid pathology? I seem to remember it was about the misfolded protein itself, but what if it’s just bacterial infections picked up in a hospital? Not just gingivalis, but a whole group of bacteria, or the whole bacterial kingdom?

  13. LD says:

    Interesting paper, but there are tons of other bacteria that releasing all kinds of virulence factors with similar effect on inflammation pathways as gingipains. I bet if they try other virulence factors from other bacteria they will have the same effect on amyloid pathology in sterile mice models! It is something to do with inflammation for sure for AD but it could be not exclusive only for Porphyromonas gingivalis.

  14. pm says:

    Could there be an association, between toothpastes that reduce teeth and gum sensitivity, and untreated gum disease? Dentists will recommend such products, for dental pain that in fact can be completely cleared up with better dental hygiene.

    1. SirWired says:

      Sensitive toothpastes reduce tooth pain only; they do not have an effect on gum pain, if any.

      In any case, while gingivitis can be painful, actual periodontitis is often painless.

  15. DP says:

    For decades, Paul Ewald has been arguing, on an evolutionary basis, that many common diseases of currently unknown etiology, such as cancers, heart attacks, stroke and Alzheimer’s, may likewise be also caused by chronic low-level microbial infection.

  16. BiotechFanatic says:

    As far as Koch-postulates go: presumably the microbes are found in some abundance in non-AD patients too. Then is the hypothesis that downstream inflammation is the disease state driver and such patients for whatever reason have a muted response? In which case would targeting the infective agent already be too late once symptoms have emerged clinically?

  17. NPs says:

    Are Porphyromonas gingivalis infections/gingivitis spread orally?

    Curious if there is potential for higher AD risk in life long partners with spouses who developed AD.

    1. DrAlex says:

      I was wondering the same thing. It looks like 6X worse.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945313/

  18. ScientistSailor says:

    Do these bacteria make peroxy nitrites?

    1. MikeC says:

      I’ve been scrolling with an eye out for Lane to explain why this is what he has been saying all along and how gingipain is tied to peroxynitrite

      1. ScientistSailor says:

        We haven’t heard from him in a while. Maybe he found something else to obsess over?

        1. Isidore says:

          Actually a few months ago Derek politely but firmly urged him to refrain from responding on Alzheimer’s Disease post (although welcome to post on other topics). And Lane appears to be rather agreeable and certainly non-confrontational.

          1. Derek Lowe says:

            That he is, and I’m very glad that he’s honoring the agreement. It’s good of him.

        2. KazooChemist says:

          Lane posted just yesterday in the Exercise and Signaling thread.

  19. Mach4 says:

    Kochs postulates would be operative with those who loose their teeth due to Pg infections. They should be more susceptible to AD.

    Then check the populations that are low-dose Doxycycline for gingivitis- which also is active against Pg, although the compound hits MMPs and is the only FDA approved MMP inhibitor.
    They should be less prone to AD.

  20. Scott Stewart says:

    Pfizer/Zoetis had a canine vaccine against Pg that had a conditional license for periodontal disease, but was pulled for inability to show efficacy.

  21. Chris Phoenix says:

    Does any of this explain why it’s almost always a geriatric disease?

  22. flem says:

    Does this connect with herpes simplex link to AD? I’m going back to Listerine along with a two week course of Valtrex.

  23. Barry says:

    Would we expect a vaccine against P. Gingivalis to be efficacious where infection is already established? That’s 34% of the control group (and 78% of those with periodontal disease)

  24. johnnyboy says:

    It’s certainly a provocative finding, and worthy of more research. The skeptic in me does find that all that concurring evidence is perhaps a bit too neat to be true ? In particular, the bacterial DNA in brain/CSF samples seems a bit much. I can accept bacteria chronically present in the mouth, producing toxins that go systemic and penetrate through the BBB into the brain, causing chronic degenerative changes. But whole bacteria happily migrating into the brain tissue, without causing a raging meningitis ? Let’s see another lab replicate these findings before getting too excited.

    1. Mel Snyder says:

      Please note the number of investigators and range of labs involved in this study. It suggests replication may have already been demonstrated.

    2. DrAlex says:

      The DNA in CSF is actually fragmented, not whole bacteria. This is discussed in their clinical results poster. The bacteria is intracellular and living inside the neurons, not the CSF.

  25. Rowan Eisner says:

    So people have also been calling AD a form diabetes so what’s the connection? It seems that diabetes predisposes to gingivitis. Could that be exacerbated by insulin storing sugar in tissues? It would be interesting to see if there were a difference in AD rates between diabetics who take insulin and those who manage it through diet.

  26. That a link might exist between AD and PG colonization/infection is not new, although I think this is the first study to claim a causal asociation. Suggested mechanisms include bacterial LPS-mediated neuroinflammation or a general hike in systemic inflammation.

    Association between putative “susceptibility” genes for AD, cardiovascular disease and diabetes, all conditions considered to be of inflammatory origin and PG has also been made. And, predictably, the gut microbiome may also be in the act, with transgenic mice expressing the Aβ amyloid gene having a different microbiome from wild-type mice.
    So, all in all, an area of research worth further exploration, although I’m personally sceptical that gingivains are any more than a small part of the story.

  27. anon says:

    Man’s best friend?

    “P. gulae is a natural inhabitant of the oral cavity of companion animals such as dogs, and a recent study demonstrated that dogs can transmit P. gulae to the oral cavity of their owners (62). Research is underway to determine whether P. gulae may be contributing to the gingipain load in AD brains.”

    http://advances.sciencemag.org/content/5/1/eaau3333

  28. Barry says:

    Seems like the epidemiology should show a lower incidence of AD among dentists. Does it?

  29. me says:

    Just good dental care is insufficient to prevent gingivitis, according to this study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625327/

    and indeed mouthwash appears to be somewhat effective, though not entirely.

  30. anon says:

    My Waterflosser and recent order for Periogen, an Edison Award winner (Nobel prize for innovation), puts me one step ahead of the crowd. Periogen is the first product proven to reduce dental tartar that leads to gingivitis, then to periodontal disease.

    1. drsnowboard says:

      No, your inability to gauge the intelligence of this audience and the unremitting smell of spam you exude makes you much more likely to succumb.

      1. anon says:

        Thank you for your reply, drsnowboard.

        I carefully considered the appropriateness of suggesting a commercial product on this thread. If there were some generic category that I could have referred to that removed tartar, then I would have posted that instead. However, there does not appear to be any other product that has shown this ability.

        I have trust in the ability of this audience to gauge the scientific validity of the commercial claims made on behalf of these products. If I had not had this trust, then I would not have
        posed such an intellectual challenge. A quick internet search will verify that Waterflossers have went through clinical testing and are accepted by the ADA. Further, there is an overwhelming quantity of positive testimonials online from verified buyers. I noticed an immediate improvement in my dental health, and also noticed a rapid change in my mental health ( more cheerful) after beginning to use the Waterflosser.

        A Clinical trial for Alzheimer’s using Waterflossers which have been clinically proven to reduce gum disease and peritonitis appears warranted.

        I also noticed after a one week 0 carb ketogenic diet that my mouth felt much cleaner. This might be another avenue of research.

        1. Nick K says:

          Off-topic question: why do so many Americans say “have went” (sic) instead of “have gone”?

          1. Mukund M. Mehrotra says:

            Because so many Americans, now, are from non-English speaking countries. And BTW, a famous scientist has recently said that the language of science is ‘Broken English.’

          2. Nick K says:

            I have only ever heard this solecism from native-born Americans. People born overseas never make it.

          3. DH says:

            I have never heard a native American English speaker over the age of 6 use the term “have went”. If your experience is different, I wonder if it’s a regional dialect. Do you recall which part of the country people who you’ve heard use that expression are from?

          4. Nick K says:

            DH: I don’t think this is a regional or even US thing. I have heard it, and also “I should have went” from natives of New Jersey, Michigan, and Colorado, and Toronto. The latter two people were teachers of English!

        2. Pegasus says:

          Dear spammer, few points:

          First, tartar or dental plaque are not the cause of “gum disease” or “periodontitis”. That the only treatment for the condition is unsuccessfully *trying* to remove both from the teeth’s surface is witness of the medical backwardness concerning periodontitis in general, and of dentistry in particular.

          Second, gum disease and periodontitis are very broad terms to vaguely define a condition with which most people will lose alveolar bone and some or all their teeth in time. Because virtually all people will lose their alveolar bone and teeth to varying degrees with age anyway, the vague definition only helps to confuse things a bit more. Gum disease is not pre periodontitis, periodontitis is an infectious disease on its own. Maybe time to stop believing that keeping your teeth clean and flossed will save you from periodontitis. The people you exchange saliva and other fluids with (share glasses, cigarettes, bongs, cuttleries or previously bitten food and also perform oral sex) and luck will determine whether you get infected with the responsible organisms and go on to develop this chronic disease. And the jury still out to determine whether infected periodontitis moms pass on the bacteria on to their fetuses.

          Recent research has found p gingivalis in placenta, and moms suffering periodontitis are known to be at much higher risk of having preterm births.

          Finally, it is pretty clear to me that a mix of bacteria and viruses are the cause of periodontitis, therefore peeriodontitis is an infectious disease. There’s a bit of research about how the presence of certain herpes viruses (EBV, HCMV, HHV1 etc) increase severity, and even there is recent research about how the different strains of the same bacteria believed to cause periodontitis (say, p gingivalis) have varying degrees of virulence, from barely any to very virulent. There is even a 2013 paper written about how a single pathobiont produced massive bone loss in very short time after being inoculated into germ free mice.

          Therefore the often cited 1998 study claiming that 25% healthy people has also p gingivalis in their mouths ergo p gingivalis is not the cause should simply stop being repeated ad nauseam until it is documented how certain p gingivalis strains, say w83 (one of the most virulent by far) were also found in 25% of healthy people.

        3. Pegasus says:

          Lastly, because I digress, your seemingly useful water flosser will not only never clear a chronic bacterial infection, I have a reasonably educated guess that using a water flosser daily can likely increase the risk of periodontitis -not peritonitis you shill- bacteria entering the blood stream and being distributed all over your body through transient bacteremia, and who knows if this daily bacteremia can increase the risk of heart attacks, increase risk and rate of progression of RA, AD etc.

  31. Crocodile Chuck says:

    Nobody has identified the root cause for this: a leaky blood: brain barrier.

    I bet you won’t find bacteria in the brains of children & young adults.

    The identity of the bacteria is incidental, P.gingivalis is just the most common blood borne bacteria. Fungi & viruses get through the BBB, too. If its not one darn thing, its another.

    The leakiness is a gradual thing, over our lifetimes.

    Rx for all the people upthread wondering what to do:

    High intensity interval training including intense spin cycling workouts. Keeps those arteries, arterioles & capillary bed springy & flexible for those tight junctions with their astrocyte end feet!

    1. passionlessDrone says:

      Another reason to goto Orange Theory! Sweet!

  32. Professor Electron says:

    Three quick thoughts. As posted above, is this correlation rather than causation? Is early stage dementia leading to poor oral hygiene and hence gum disease results? The data comparing with other brain diseases is good evidence that it is causative, but a control group or study of dementia rate in patients with persistent gum disease would be better. Second, why is exercise such a good preventative for Alzheimer’s? Finally, what about the link with herpes simplex that has also recently been suggested. Two independent mechanisms for two different diseases with similar symptomolgy?

    All ideas welcome given recent progress with Alzheimer’s treatments.

  33. cancer_man says:

    Hi Derek,

    You may know that Rudolph Tanzi has been a science adviser for ChromaDex, which markets NR (Niagen) since he thinks NR has a potential to decrease the likelihood of getting AD.

    But I was curious if you could comment on a new study by Elysium which sells the vitamin B3 supplement NR with pterostilbine, which shows ALS patients who received 1200 mg of NR a day improved after 4 months not only more than the placebo group but also those in another trial for the recent drug for ALS, Radicava, which costs $140,000 per year.

    https://alivebynature.com/elysium-basis-demonstrates-significant-improvement-treating-als-patients-in-human-research-study/

    details here:

    http://sci-hub.tw/10.1080/21678421.2018.1536152

  34. ric says:

    Looking at the original patent document, the compounds appear to be arginine-derived alfa-(tertrafluorophenoxy)-ketones, not esters

  35. An Old Chemist says:

    Today’s Biospace (Jan 28) has also covered this research finding:
    https://www.biospace.com/article/a-link-between-gum-disease-and-alzheimer-s-/

  36. Frank says:

    Another report on the same topic appeared in October 2018:
    Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice.
    Vladimir Ilievski, Paulina K. Zuchowska, Stefan J. Green, Peter T. Toth, Michael E. Ragozzino, Khuong Le, Haider W. Aljewari, Neil M. O’Brien-Simpson, Eric C. Reynolds, Keiko Watanabe
    PLoS ONE 13(10): e0204941.

  37. bacillus says:

    I’d have been more convinced if they’d been able to culture the bug from the infected mouse brain and /or shown it to be present in histological specimens (e.g. by direct visualization or using antibody to a surface marker of the bacterium).

  38. An Old Chemist says:

    Under the newly enacted “Right-to-Try Act”, Cortexyme should be able to enroll a few Alzheimer disease patients and test their lead compound’s effectiveness. Their phase-I study has already shown that the drug is safe.

    1. Darren says:

      check out their phase 1b results. small “n” and short period of time, but interesting results. I imagine a bigger study will start soon.

  39. PhotoDeTox says:

    Wait a second: if amyloid is supposed to protect us from these AD-causing bugs, then consequently in all this anti-amyloid clinical trials should we not have seen a worsening of AD due to destruction of the amyloid-protection?

    1. Anon says:

      treatments that stop abeta production like semagacastat and BACE inhibitors did make people worse. https://www.alzforum.org/news/conference-coverage/bump-road-or-disaster-bace-inhibitors-worsen-cognition

  40. Fran says:

    Consider these two articles:
    http://discovermagazine.com/2018/dec/alzheimers-under-attack

    https://www.nutraceuticalbusinessreview.com/news/article_page/Longvida_significant_improvement_to_neuroprotective_biomarkers/131053

    The first states that 99% of drugs for Alzheimer’s have failed. Your 2017 article “Curcumin will waste your time”, bemoans the fact there are no large-scale trials of this substance and so it’s a “waste of time”. The second shows that a form of curcumin does have some beneficial effects. Whereas I appreciate the role of skeptics in relation to natural products, there is plenty to be skeptical about in standard medical practice. If I may go on to oncology.
    According to the Halsted Hypothesis: “Cancer is a localized phenomenon that later spreads”. Therefore, everything must be done to prevent this: radical mastectomy, radiation and debilitating chemotherapy drugs (for which resistance is expected and for which the pathological complete response rate is ~17%). A study at the Univ. of Michigan Comprehensive Cancer Center formed a cohort of about 75 women who had recently been diagnosed with breast cancer and who also had bone issues. Biopsies of the bone showed breast cancer cells. So breast cancer has metastasized to the bones before it is detected! Oncology has operated for about a century under a false paradigm!
    Clinical Oncology has also been slow to adjust to the discovery of cancer stem cells (which can replicate indefinitely, i.e. do not undergo apoptosis) that comprise 1%-2% of tumors and against which chemotherapy and radiation are generally ineffective. In fact, in response to the assault of chemotherapy drugs and radiation, cancer stem cells evoke an inflammatory response (just as does a cut or burn) mediated by Interlukin 8 and Interlukin 6. Cancer stem cells thrive on IL-6. So, instead of letting sleeping dogs lie, both chemotherapy and radiation generate cancer stem cells and set the stage for turning micro-metastases into macro-metastases – for which oncologists make no pretense of having a “cure”.
    An in vitro comparison of Taxol versus 6-shogaol (a component of ginger) showed that the latter was 10,000 times as effective as Taxol in killing MCF-7 breast cancer stem cells. There are other examples in which natural products are helpful in convential treatment either by acting synergistically with chemotherapy or in mitigating side effects, e.g. curcumin is superior to, and synergistic with, letrozole in endometrial carcinoma; curcumin improves the efficacy of and is synergistic with Gemcitabine in pancreatic cancer…
    Pharmaceutical companies are not going to spend millions on Phase 3 trials on any such “natural” product for which they cannot get a patent and, in any case, oncologists are reluctant to deviate from the NCCN guidelines for fear of being sued. When doctors tell women that they are “cancer free”, it is a hoax. There is currently no cure for breast cancer (maybe ONE patient claimed in mid-2018?).
    New drugs such as Ibrance, that inhibit CDK4 & CDK6 (proteins involved in cell proliferation) and used in combination with an aromatase inhibitor, e.g. letrozole, have been introduced for metastatic breast cancer after 2-3 rounds of chemotherapy (which obviously did not “cure” anything). The median survival is extended from 28 mo to 34.9 mo. (Notice the “scientific” precision of 0.9 mo!). All for a list price $8000/mo.
    You are likely aware that 70% of women diagnosed with early breast cancer do not benefit from chemotherapy, i.e. they just get to enjoy the side effects:

    https://www.cancer.org/latest-news/study-more-breast-cancer-patients-can-safely-skip-chemotherapy.html

    It is quite astonishing to learn that a primary tumor exerts control over the micro-metastases and when it is removed, macro-metastases can suddenly appear in different organs. So even the safe and logical step of the surgical removal of tumors is questionable!
    Oncologists, and medical personnel in general, like to assert that their treatments are “evidence-based”. Well, the evidence is often quite unconvincing and not much better than snake oil served up in white coats.
    Again, you provide a useful service, but I am bothered by your sanctimonious tone on “insufficient evidence” for natural products given the very well-documented evidence of failures in conventional medicine. (Your statements regarding the bioavailablility of curcumin are woefully out of date.)
    I have to admit that I do not have the responsibility of taking care of patients who expect some sort of intervention by their doctors; anything to give them “hope”.

  41. Ingo says:

    I wouldn’t necessarily call this a “solid paper” given the apparent gel splicing, blots showing incorrect bands, among other issues…

    https://pubpeer.org/publications/162673951E7EEF3D4553C8B05C7B48#

  42. Do you know that viruses can infect bacteria as well? Yes, ther can. I mean, HHV viruses can infect P. gingivalis in the first place. In my opinion, many bacteria are only a harmless member of oral flora until some viruses get inside them.
    BTW, why human saliva is more dangerous than gut microbes? Because it’s full of HHV viruses. They are known to continue to live in saliva glands after the first infection.

  43. Fiona Hill says:

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