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142 thoughts on “Of SBM and EBM Redux. Part I: Does EBM Undervalue Basic Science and Overvalue RCTs?

  1. daedalus2u says:

    geo, there is very robust data that says all humans are equally distant from all non-human ancestors. That is always true of all well-speciated species. Humans are well-speciated. All that means is that all humans share common ancestors after human speciation. If humans didn’t share common human ancestors after human speciation then humans would be multiple species instead of just one species.

    That data has been well known for a long time, at least since the data put human speciation in Africa. There was never any data that said otherwise. There still are people who don’t understand the data and tried to spin it to show that Africans are more closely related to non-humans than non-Africans are, but that is simply false and easy to demonstrate that it is false.

  2. JMB says:

    @geo
    You are more familiar with previous posts than I. Wallace Sampson’s last post occurred before I started following SBM. I did read his last post on CFS, and I think Mark Crislip’s comment was a better expert opinion. So I thank you for pointing that out.

    I do like the quote from Richard Feynman, but I also think that qualifying expert opinion by tests of predicted outcomes by the “expert” does constitute one form of organized skepticism. In Sampson’s last post, we could guess that he is predicting that an infectious etiology will not be found. Mark Crislip makes a different prediction,

    Dr. Sampson: 100 bucks to the James Randi Education Foundation by the loser that by 2015 it’s found to be cause of more than 20% of the CFS patients

    So by 2015, one will be a qualified expert based on the test of predicting outcomes, the other will be discredited in spite of previous credentials.

  3. daedalus2u says:

    PM, it is well known that there can be substantial mitochondria damage during sepsis and that this damage is repaired over time (to some extent). Experiments in rats have shown mitochondrial DNA deletion during sepsis, and that this deletion resolves over time.

    That damage is resolved by deleting the damaged mitochondria via autophagy and generating new mitochondria via mitochondria biogenesis. The regulation of mitochondria biogenesis is critical to the resolution of the damage done to mitochondria during sepsis. If there is something that impairs the regulation of mitochondria biogenesis (which happens to be regulated via NO), then the resolution of the mitochondrial damage that occurs during sepsis will be delayed. If it is delayed long enough, the patient experiences CFS. The CFS will resolve when their mitochondria status is restored to normal which can happen spontaneously.

    Geo, I think censure is not the right term. Censure is a severe sanctioning for pretty egregious violations of group norms. In no way do I think that Dr Sampson should have been censured for what he said, even though I disagree with the factual basis of his reasoning. Treating people with CFS can be extremely challenging. I am glad that IANAD and so I don’t have to do it. I think that Dr Sampson’s anger was aimed at the quacks who are exploiting vulnerable people with CFS and not so much at the people with CFS who are allowing themselves to be exploited.

    There really isn’t a better treatment modality for CFS right now. There is no shortage of quacks offering the hope of a better treatment but they are all false hopes. I can say this because I really do understand the physiology behind CFS. I appreciate that my say-so is not a sufficient response, but until I can get the resources to do clinical trials, that is all I have. I am sorry about it too.

    Doctors are people too, and they can get very frustrated when needy people make bad choices and do things that are perceived to be self-destructive. There has been a lot of talk about how to deal with patients who don’t exercise, won’t stop smoking and who don’t eat a healthy diet. Is it “enabling” to give them cholesterol lowering drugs or is it good medicine? How much coercion is appropriate, helpful or counterproductive is very much a part of the idiosyncratic doctor-patient dynamic. Because that dynamic is always unique, there can’t be randomized trials on it because each case is only an anecdote. You can’t do EBM if all you have are anecdotes.

  4. pmoran says:

    Daedalus2: PM, it is well known that there can be substantial mitochondria damage during sepsis and that this damage is repaired over time (to some extent). Experiments in rats have shown mitochondrial DNA deletion during sepsis, and that this deletion resolves over time.

    Not surprising and not obviously relevant to the usual case of CFS.

    You referred me to this –

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

    I had found this abstract myself. Are these findings well-replicated? It also does not answer my question as to whether the observations are contributing to the CFS state or secondary to muscle disuse. Perhaps simple exercise can over time reverse these observations.

    I also wondered how seriously to take this work — the authors referred to the use of “supplements and detoxification” as treatment for CFS.

    Do you have anything else that support your claim that “PM, in CFS, the mitochondria depletion precedes the exercise intolerance.” ?

    I have no evidence that it doesn’t, and I wonder how that could ever be established in the usual case. My concern is
    that you might start dotting your I’s and crossing your t’s
    before being so dogmatic about certain conjectures. This is meant as friendly advice.

  5. daedalus2u says:

    Sepsis does cause mitochondrial damage. This has been replicated many times in animals, here is a result in humans.

    http://www.ncbi.nlm.nih.gov/pubmed/12133657/

    Human and animal mitochondria are virtually identical, so animal results are directly translatable to humans. This is an excellent paper and shows both the increase in ATP due to the high NO from iNOS during sepsis (supported by glycolysis because mitochondria are inhibited by the high NO and high ATP) and the decline in mitochondria function following the fall in ATP. It is the fall in ATP when glycolysis cannot maintain the ATP level above where mitochondria stay “off” that causes mitochondria to “turn on” and in the high NO environment of sepsis, that kills them by inhibiting MnSOD.

    CFS often follows sepsis. The “fatigue” following sepsis is not due to disuse during the few days of sepsis, it is due to the mitochondrial damage that occurs during sepsis. The “fatigue” following sepsis is not apparent until the patient tries to exert themselves and use more ATP than is needed “at rest”.

    Infection is not the only precipitating factor, trauma, allergic reaction, surgery, and no precipitating event have also been reported.

    http://www.ncbi.nlm.nih.gov/pubmed/9201648

    You are correct, in the usual case it cannot be determined if the mitochondria depletion preceded the exercise intolerance because exercise intolerance is the first symptom to be noticed and so muscle biopsies cannot be done in the pre-symptomatic patient to determine mitochondria status in the pre-exercise intolerance state. But when the noticing of the symptoms of CFS is immediately preceded by a febrile illness, and a not uncommon characteristic of febrile illnesses is mitochondrial depletion, an inference of mitochondrial depletion is rather straightforward. To me, it would be perverse to postulate that exercise intolerance preceded mitochondrial depletion.

    In some cases simple exercise over time can resolve symptoms of exercise intolerance. But not in all cases. Since CFS is defined to be cases where simple exercise over a specific time do not resolve symptoms of CFS, then those cases are not what I am talking about.

    The paper doesn’t report anything that is unexpected, but it isn’t that good a paper and isn’t what I have based my formulation of CFS on. It measures ATP levels in neutrophils, which are not the right cells to use, muscle cells would be better, but muscle biopsies are a lot more invasive. Muscle ATP and neutrophil ATP do correlate. I didn’t look at it as carefully as I should have before linking to it. The abstract does talk about using supplements and reporting the results in a future paper. In looking at the author, she has just had her license to practice medicine restricted. Not a surprise because supplements won’t fix the mitochondria problem of CFS.

    I have spent many years and many thousands of hours doing research on NO and NO physiology. That knowledge base cannot be compressed and conveyed in its entirety in comment-sized nuggets. CFS is not the topic of this thread, and hijacking the thread to go into the details of physiology of CFS isn’t something I want to do right now. I have an extensive write-up I did a few years ago that I could send you.

  6. Dr Benway says:

    geo, this isn’t the first thread you’ve derailed for the sake of your grudge against Sampson.

    Science based medicine is not a cult, a political party, or a special interest group. It doesn’t protect its reputation any more than mathematics protects its reputation. Everyone here could be arrested tomorrow for selling crack; wouldn’t change science based medicine.

    There are gray areas in medicine where reasonable people may disagree. CFS is one of those gray areas, as a clear etiology has not been identified and the symptoms are non-specific.

  7. pmoran says:

    Daedalus2: I have spent many years and many thousands of hours doing research on NO and NO physiology. That knowledge base cannot be compressed and conveyed in its entirety in comment-sized nuggets.

    Nevertheless, this is how you will be challenged whenever you start making precise clinical claims.

    What is the incidence of severe sepsis in patients with CFS, as usually defined? A significant period of fatigue after such an episode would not normally be so classified would it?

  8. qetzal says:

    deadalus2u,

    The original topic of this thread was how EBM (as currently practiced) undervalues basic science. In your case, I think it’s the opposite. You overvalue the basic science. Especially the science that fits your beliefs regarding NO.

    Human and animal mitochondria are virtually identical, so animal results are directly translatable to humans.

    No. Human and animal mitochondria are virtually identical, so animal results are likely to be directly translatable to humans. Humans are virtually identical to other animals in almost every aspect of their biochemistry. Yet drugs that work in animals fail to work in humans all the time!

    I appreciate that you’ve devoted enormous time to studying the literature on NO. I acknoweldge that the available data may fully support your hypotheses on how NO and your bacteria might treat disease in humans. But until you have robust clinical data, you cannot rationally conclude that your ideas are right.

    It is the fall in ATP when glycolysis cannot maintain the ATP level above where mitochondria stay “off” that causes mitochondria to “turn on” and in the high NO environment of sepsis, that kills them by inhibiting MnSOD.

    CFS often follows sepsis. The “fatigue” following sepsis is not due to disuse during the few days of sepsis, it is due to the mitochondrial damage that occurs during sepsis.

    Those are interpretations of data. They are not facts. Fatigue following sepsis may be due to mitochondrial damage. It seems like a very reasonable hypothesis, but that’s all it is – a hypothesis.

    Every time you make an unwarranted claim along the lines of “My bacteria will do it,” I become less inclined to believe any of your other claims. Such overconfidence ignores the long history of ideas that seemed to make perfect sense from the basic science, yet still didn’t work. If you’re willing to ignore that, why should I trust that you haven’t ignored other evidence that might contradict your claims?

    EBM practitioners are wrong when they assume that clinical data always trumps basic science. But they are correct to insist that basic science can’t trump clinical data, and that basic science is very rarely (if ever) adequate in the absence of clinical data.

  9. Dr Benway says:

    But they are correct to insist that basic science can’t trump clinical data, and that basic science is very rarely (if ever) adequate in the absence of clinical data.

    Maybe I’d say, basic science plausibility is a necessary screen but an insufficient measure of clinical plausibility.

    Biochemistry and physiology result from genetic algorithms. Consequently, they’re impossible to debug in a systematic manner. Small changes in the genetic code have downstream effects no one can predict.

  10. daedalus2u says:

    No qetzal, as Nietzsche said, “there are no facts, there are only interpretations”. There are only hypotheses. No quantity of clinical data can turn any treatment modality from one driven by a hypothesis into one driven by a fact.

    That my positive statements about what my NO bacteria can do negatively affects your assessment of the plausibility that they can do what I say they can do is about your use of non-data driven reasoning methods. My positive statements either derive from facts and valid reasoning, in which case they add some positive probative value to the premise, or they are false delusions of fantasy in which case they add zero probative value. In no case can they add negative value. I appreciate that this is one of the most difficult aspects of SBM to apply, that any false statement has no effect on the Bayesian plausibility. There are infinitely many false statements that can be made. None of them have any effect on the truth value of true statements.

    You think my claims are “unwarranted” because you do not have the knowledge base to evaluate them. If you did have the knowledge base to evaluate them, you would know that they are not unwarranted. I appreciate that you are unable to appreciate that. I am trying to increase the knowledge base of people who read SBM. Sorry if my tone of certainty is off-putting. There really is a very high plausibility, approaching virtual certainty that I am correct. I always admit the possibility that I am wrong. As Stephen Jay Gould said:

    “In science, ‘fact’ can only mean ‘confirmed to such a degree that it would be perverse to withhold provisional assent.’ I suppose that apples might start to rise tomorrow, but the possibility does not merit equal time in physics classrooms.”

    Provisional assent can be achieved via Bayesian analysis applied to a large body of knowledge. That is all that I am doing. That body of knowledge does not yet include RCTs, it does include some (unpublished) clinical vignettes, including a person who had ARDS, used my bacteria post-hospitalization, and in 2 months had gained 9 pounds, had gone hiking, had resumed his PhD program. His doctors called it a “miracle”, had never seen such a recovery, and had no explanation (and didn’t want to listen to mine). His recovery might have been a coincidence. It actually surprised me. I expected somewhat better improvement, I didn’t expect “miraculous” improvement (his doctor’s words).

    Putting caveats in what I say that I don’t think are warranted would feel like I was being dishonest and disingenuous. I don’t go around using the caveat “unless gravity stops working” for the same reason. If you have any data that is in conflict with anything I have said, I would be glad to hear it, would look at it and very seriously consider it. If it is reliable data, I will incorporate it into my conceptualization of reality and if my prior statements about my bacteria no longer fit, I will no longer hold onto them.

    Right now there is no data (that I am aware of) from basic science or clinical research that is incompatible with any statement I have made about my bacteria. There is a lot of data that is incompatible with other interpretations.

  11. daedalus2u says:

    Dr Benway, for some interventions, clinical trials are not necessary and would be unethical to perform. The example of the use of parachutes has been given before.

    You can’t use a “one size fits all” heuristic in extremely complicated systems no matter how much you want to when the system is much more complicated than your heuristic.

  12. JMB says:

    I think another way of stating the issue is that for evidence from clinical research, we must be careful in interpretation of observed effects. Classification of observed effects in clinical research must differentiate non-specific and placebo effects from the desired physiologic effects altering the disease process. For treatments that have no possible effect based on physics and chemistry, any evidence of effect observed in clinical research would be classified as a non-specific or placebo effect.

    So the RCT is the most powerful scientific method we have, but the interpretation of results must account for non-specific effects and placebo effects. Treatments that are incompatible with current knowledge in physics and/or chemistry must be classified as placebo, until knowledge in physics and/or chemistry changes.

    It is not just a matter of prior and posterior probabilities, it is also a matter of classifying the effect to differentiate physiologic effects from non-specific and placebo effects. Classification matters because the most predictable benefit in the translation of research results to general population use comes from physiologic effects on disease processes. Attempting to reproduce placebo effects from research in general population use has limited success. Non-specific effects generally do not translate into the population use.

  13. JMB says:

    The ultimate goal of science is to advance knowledge. The ultimate goal of EBM or SBM is to advance health in the general population. By using basic science as a classifier to differentiate physiologic effects from non-specific and placebo effects, SBM will be more successful in predicting the result of a healthcare intervention applied to general use, than will EBM.

    @daedulus
    Clinical research is still required of your bacteria. To compare your proposed bacteria use to use to the parachute analogy published in BMJ is incorrect. Even a parachute is dangerous if someone tries to drag a deployed parachute behind the while walking through downtown NYC traffic. Clinical research is necessary to define the parameters for indication for use (for the parachute, the indication for use is when you are falling a great distance), management of patients undergoing treatment (don’t deploy the parachute from a back pack when your back is facing the ground), and dosage requirements (you need a parachute of a certain size to be effective). Even water and oxygen are toxic at certain levels of intake.

  14. qetzal says:

    deadalus2u,

    You think my claims are “unwarranted” because you do not have the knowledge base to evaluate them.

    Wrong. Your claims ARE unwarranted because you’re expressing virtual certainty about a clinically-untested intervention.

    I don’t have the knowledge base to evaluate whether your hypotheses about NO are supported by the available data. That much is true. But I do have the knowlege base to know that basic biochemistry and animal studies are NEVER enough to support your level of certainty. That is even more true for a disease like CFS, which has no validated animal model.

    You can play word games with the meaning of “facts” and “interpretations” all you like, but you would be better served by some honest examination of your statements and beliefs. Look how you’re using anecodotes to try to bolster your claims. You’re even throwing in the old “His doctors called it a ‘miracle’” bit! That’s the same stuff we hear from every other purveyor of woo. It’s baloney when they do it, and it’s baloney when you do it, too.

  15. daedalus2u says:

    qetzal, so you don’t wear a seat belt because there are no RCTs of seat belt use? You don’t wear a helmet when you ride a bike because there are no RCTs of helmets and bike use? You don’t use a smoke detector because there are no RCTs of smoke detector use?

    JMB, when was the RCT that showed it was dangerous to wear a parachute in NYC traffic? I must have missed that one, could you give me a link? ;) You do have a link don’t you, you are not merely asserting as fact the hypothesis that wearing a deployed parachute in NYC traffic is dangerous? I would put a pretty high prior plausibility on that hypothesis, but the way to assert it, with such confidence, I am sure you must have “data” to back it up. I am surprised that any IRB approved such a study. I would have thought it would be unethical. ;)

  16. daedalus2u says:

    qetzal, no again. What you are talking about is methodolatry, worshiping the method of the clinical trial and damning everything for which there is an anecdote.

    An anecdote is data of very limited statistical significance and limited probative value. The probative value of an anecdote is never negative. Taking a body of data that supports a hypothesis and then adding a positive anecdote to that data does not reduce the plausibility of that hypothesis. CAM modalities are wrong, not because they are supported by anecdotes, but because they are not supported by a body of data. Adding a positive anecdote is at worst like adding something completely extraneous, something that doesn’t follow, something that is unrelated to the question being asked. In that case is adds zero probative value. In no case does a positive anecdote take away from positive data.

    I agree that there are many examples where basic research data is insufficient and that clinical trials are needed. Clinical trials are not the perfect source of information that the methodolatry that has grown up around them would indicate. All measurements, clinical trials included, can have type 1 and type 2 errors, false positives and false negatives. That is why you need lots of data, and why you need to add the data together using Bayesian analysis. That is really hard to do, especially with data that is complex.

    Once you have done that Bayesian analysis with non-clinical data and that analysis shows that an intervention has a very high likelihood of helping (99%+) and a very small likelihood of not helping (1%-) and a negligible likelihood of harm (less then 0.00001%), how should one talk about it? A clinical trial doesn’t have the resolution to measure the difference between 99% and 98%. Any RTC that started to show a 99%+ treatment effect would be stopped early to give both legs the treatment because it would be unethical not to.

    Suppose you did do a trial of wearing a parachute in NYC traffic. When would it be ethical to stop it? How about a trial of wearing a helmet while riding a bicycle? Those would be unethical from the start because there is no clinical equipoise between the two legs. One leg is clearly inferior based on prior plausibility.

    Ethical considerations don’t allow you to do a clinical trial when one leg is clearly inferior.

  17. JMB says:

    daedalus

    Interventions with that kind of risk vs benefit ratio usually become a general recommendation such as, don’t smoke, eat a balanced diet, and get exercise. With that kind of risk vs benefit ratio, I would say you have discovered vitamin NO.

    I remember a genius organic chemist who was opposed to fluorine additive to drinking water, and chlorine treatment. In spite of the high prior probability. the risk vs benefit ratio expected from laboratory research was not reproduced in clinical observations, or population outcomes. There are significant limitations to our understanding of physiology that limits our translation of evidence from test tube to an intact animal, and from an animal to humans (or even one human to another).

  18. daedalus2u says:

    JMB, you are exactly right. The “normal” state is with a biofilm of my bacteria on the external skin. It is like a “vitamin” that one absorbs through the skin from commensal bacteria, sort of like vitamins you can get from your gut bacteria.

    The abnormal non-physiological state is to bathe every day and wash the biofilm off. There were no RCTs when people first started to do that, and the practice has become “grandfathered” and so ingrained that no one can even think to question it.

    That is why I can be so confident there won’t be any adverse effects. It is like the “adverse” effects of a nutritious diet, sufficient sleep, and not smoking. Restore the physiological default condition, and health will improve because physiology is working at a more optimum operating point.

  19. qetzal says:

    No, deadalus2u.

    You don’t seem to be reading what I write. I’m not damning your basic science and anecdotal clinical evidence. I’m only saying that it ISN’T ENOUGH!

    If there’s any methodolatry here, it’s from you. You are convinced that basic science is sufficient for you to be virtually certain (your words) that your proposed clinical interventions will be effective. That’s where you’re wrong. Basic science and anecdotal evidence is only enough to establish a reasonable hypothesis of clinical benefit.

    And are you really trying to compare treatment of complex human diseases to smoke detectors or seat belts? If the former were as simple as the latter, you and I would have no dispute. But it’s not, as you well know.

    You do NOT understand human physiology so well that you can predict with virtual certainty all the things you claim for NO. No one does.

  20. Dr Benway says:

    Dr Benway, for some interventions, clinical trials are not necessary and would be unethical to perform. The example of the use of parachutes has been given before.

    Well I probably wasn’t clear. I was referring specifically to making predictions of human biochemistry or physiology on the basis of things we know in more basic sciences, such as physics or chemistry. In that context, we can reject hypotheses that outrage basic science but we cannot accept novel biochemical approaches without some empirical data.

    Systems built upon random events aren’t predictable.

  21. daedalus2u says:

    No qetzal, if the intervention I was using was non-physiologic, you would be absolutely correct.

    I will go even farther and say that there may never be a non-physiologic method of changing basal NO levels. Probably never. Because the physiology is too complex and multi-factorial. NO/NOx physiology is too complex to control via the open-loop control that is the only mechanism available with standard pharmacological practice of oral, topical or injected drugs.

    Maybe when nanobots are available and they can monitor physiology and deliver the right species of NO at the right time and in the right place and in the right amount, but that is many decades away, perhaps centuries, perhaps never.

    Until then, my bacteria on the external skin will be the only method of bringing NO/NOx physiology closer to optimum. The only reason my method will work and others will fail is because my method is what physiology evolved to use. Until you restore the normal background and the normal physiology for regulating that background, NO/NOx physiology is not going to work right. For some things the misregulation won’t be that bad, but for some things it will be depending on the idiosyncratic physiology of the individual.

    I do understand physiology well enough to know that it is self-regulating and so complex that artificial regulation won’t work until that artificial regulation can be as (or more) complex as physiology itself. I am not trying to apply complex regulation to physiology. I am simply restoring a normal part of physiology that modern practices have removed. That restoration allows physiology to better self-regulate. It is the better self-regulation that will produce the improved health effects that I am suggesting.

    I don’t need to understand the details of physiology to know that removing non-physiological impediments to normal physiological regulation will improve self-regulation and improved self-regulation will lead to improved health. Maybe people won’t want improved health that improved NO/NOx will provide but that is a different issue.

  22. daedalus2u says:

    Let me use another example, suppose there was a society where everyone was given a mask at birth and always breathed through this mask that restricted air flow. Suppose that people grew up always breathing through this restriction and never knew about breathing without a restriction.

    Suppose in this society that there was a disease called hypoxia which resulted from insufficient O2 delivery to tissues. Suppose someone came along and claimed he/she could cure this hypoxia by removing the restrictive mask that everyone breathed through. Suppose this person had studied physiology and had come to realize that the reason everyone was hypoxic was because of the non-physiologic masks that people were breathing through, and that by removing the masks, the supply of O2 could be easily and physiologically increased.

    Suppose there were nay sayers who said “what about O2 poisoning”? To which the reply was “there are physiological mechanisms for controlling O2 delivery, breathing without the mask is not a risk”.

    Suppose now that this disease hypoxia was killing millions of people every year, and before it killed them it caused all kinds of bad symptoms, fatigue, dementia, heart disease, obesity, liver failure, depression, psychosis. Suppose there was pretty good evidence linking a lack of O2 to all of these diseases.

  23. Dr Benway says:

    daedalus, natural selection does not favor optimum health.

    The unit of selection is not an individual but a gene. Genes don’t get sick. They replicate, or not.

  24. daedalus2u says:

    Dr Benway, “optimum” health is that health which maximizes the replication of the genes. Generation of “optimum” health is what the genes do to ensure their replication.

    Many “disorders” are not disorders at all, they are “features”. Anaphylaxis is a feature, depression is a feature, Alzheimer’s is a feature, ischemic preconditioning is a feature.

    They are all features that are adaptive in short term specific circumstances and maladaptive in the long term.

    For the most part it is low NO that triggers the physiological subroutines that are adaptive in the short term and maladaptive in the long term. If NO does not go back up after the short term crisis has passed, then the “features” become maladaptive in the long term. The only way to fix it is to raise NO levels to turn off the short term adaptation that will become maladaptive in the long term.

  25. qetzal says:

    Linus Pauling was a pretty smart guy. Smarter than most of us, I imagine. He knew a thing or two about biochemistry, too. And based on his very considerable intelligence and knowledge, he was convinced to a virtual certainty that megadoses of Vitamin C would have all kinds of therapeutics benefits. Treat cancers, prevent colds, etc.

    But despite his virtual certainty, he was wrong. He made what is arguably the worst mistake a scientist can make. He stopped being sufficiently skeptical of his own ideas. He convinced himself that he knew so much, that he could predict with virtual certainty how his ‘orthomolecular medicine’ would work in people without any rigorous clinical testing.

    There is no such thing as virtual certainty when it comes to predicting human response to a novel and untested physiologic intervention. But I guess you’re unable or unwilling to accept that. I won’t bother to try to argue it further with you.

  26. daedalus2u says:

    qetzal, the heuristic you are using is pretty good for non-physiological interventions. For something non-physiologic, I completely agree that you need good clinical data in humans to have good confidence that the intervention will be helpful.

    Linus Pauling was not talking about a physiological intervention. Supraphysiological doses of vitamin C are not a physiological intervention.

    Nitric oxide from a biofilm of ammonia oxidizing bacteria produced from ammonia released by the skin is a physiological intervention.

    Have there been any clinical trials demonstrating that the non-physiological intervention of bathing every day has no adverse effects? Is there any data that shows there are no adverse effects? I appreciate that there are lots of anecdotes, perhaps billions of anecdotes. As I am sure you are fond of saying, the plural of anecdote is not data.

    Why do you choose the non-physiological state of the absence of a biofilm as your default condition? Humans have only existed in that state in the past few hundred years, since the advent of piped hot water for bathing, the same time frame as many of the modern diseases (heart disease, allergies, obesity, kidney failure, stroke) have become leading causes of death and when the average age of menarche dropped from ~17 to ~12. There are humans who do exist with a biofilm of these bacteria, people living in “the wild” where they never bathe. Such people have a very low incidence of heart disease, allergies, obesity, kidney failure and stroke.

    People do argue as to what are the environmental differences between humans living in developed regions and people living in rural undeveloped regions that presumably lead to the very different incidences of heart disease and other disorders. My hypothesis, of which I am virtually certain, is that a large part of those differences are due to differential NO/NOx physiology due to the presence/absence of a biofilm of ammonia oxidizing bacteria. Many of the major health differences are known to involve pathways mediated by NO signaling. Virtually all of those disorders are characteristic of what would be expected if the NO signaling was skewed in the direction expected by a reduced basal level of NO.

    I have instrumental data of NO production in vivo (human) from a biofilm of these bacteria on a subject from spontaneously released ammonia coincident with instrumental measure of a physiological effect that is known to be mediated by NO. I have instrumental measures of NO production in vivo (human) which demonstrate that some of the NO is absorbed. I have instrumental measures that demonstrate long term maintenance of such a biofilm (years) nourished only by natural secretions. My data is only on a single subject, so it is an “anecdote”. That my data is on a single subject does not mean my data is wrong, it only means that it has low statistical significance. The effects I measured are many sigma above background and occurred on many different instances.

  27. Dr Benway says:

    Dr Benway, “optimum” health is that health which maximizes the replication of the genes. Generation of “optimum” health is what the genes do to ensure their replication.

    Have a look from the gene’s perspective. It lives not just in one human meat container but in a complex ecosystem made up of many containers, not all of them human. Forgive the personification –it’s just a metaphor– but the gene feels as much loyalty to any one container as you feel toward any one of your skin cells.

    If some gene containers die early but somehow contribute to greater gene frequency in the entire ecosystem, early container death may become an increasingly popular phenotype.

  28. daedalus2u says:

    Ok, “optimum” was a bad word choice. How about “health that is better controlled to what ever phsyiology calls for it to be at the moment because there is better regulation of NO controlled phsyiological pathways because the basal levels of NO/NOx/RSNO species are under better phsyiological control because the normal pathway of NO/NOx production by a surface biofilm of ammonia oxidizing bacteria is not artificially removed”.

    Is that better?

  29. Dr Benway says:

    “…health that is better controlled to what ever phsyiology calls for it to be at the moment…

    I agree that biological creatures have self-regulatory mechanisms that largely maintain favorable internal conditions. However, it’s a mistake to assume that *all* these self-regulatory systems are there to serve your best interests. Some are actually trying to kill you.

    Maybe higher NO levels boost the senescence system. Who knows?

  30. pmoran says:

    You certainly have a interesting, even a fun hypothesis, Daedalus2. It deserves to be true, even if its not.

    You seem to be aware of some limitations to it, but not others.
    I think the main problem is the way you make certain assertions and then are unable to support them with the evidence required. You need a little more — actually a lot more — of the caution that goes with normal scientific discourse and enquiry.

    Perhaps this is getting into trade secrets, but is there bacteriological evidence that the skin flora of non-washing primitive tribes differs from ours? — even quantitatively, as the effects of washing don’t last long, especially in hot weather.

  31. pmoran says:

    D2:”Linus Pauling was not talking about a physiological intervention.

    Actually, just like you, he thought it was a physiological intervention, and, also like you because of animal experiments strongly suggesting that humans might need vastly more Vitamin C than was normally obtainable in the diet.

    I saw the Linus Pauling connection, like qetzal.

    If our worst suspicions are correct, and a weak-to-moderately tenable set of hypotheses has you by the tail rather than vice versa, your path is now laid out for you.

    You will continue to find evidence that supports your theory and makes it even harder for you to accept that your clinical expectations are wrong, while being less sensitive to anything that might undermine them.

    When clinical testing starts you will be reluctant to accept negative results and will try it out this way and with that until you get a positive or two. By that time your patented product will be on the market and testimonial after testimonial will be flooding in.

    We are merely urging caution. It takes only a vaguely tenable theory in the hands of an enthusiast to create a quack cure — of anything, even cancer.

  32. Harriet Hall says:

    I greatly respect daedalus2u’s contributions on other subjects, but I choose not to engage him on the subject of NO. I have to withhold judgment pending better evidence. I think he fully understands that he doesn’t have adequate evidence yet, but his enthusiasm for his subject is too great to restrain.

  33. daedalus2u says:

    I am very aware of the potential for quackery. I control the patents, so as long as they are in force, it can’t be used for quackery. I really don’t want to go that route, but going the other path is very difficult without the resources which I don’t have. I am also acutely aware that if I am right, that every day that this treatment is delayed means more pain, suffering and early death for many people. Many, many, many people.

    One of the major described differences in the skin of people in the rural undeveloped world is that acne is virtually unknown at any age, even during puberty. The ammonia oxidizing bacteria status of people anywhere has not been reported. I don’t have the facilities to look at it on people, I have looked for them on a number of eukaryotes and found it on many individuals of many species.

    The people doing the microbiome have not progressed to testing people in the “wild” yet. They are still foraging for what they think is biodiversity by looking at hundreds of cracks in the pavement of sidewalks (the skin of people in cities who bathe every day) instead of looking at the rain forest (people that never bathe). When I have tried to contact them they do not want to talk to me. :(

    I am not worried about good well-run clinical trials showing negative results. What I am worried about is a false negative due to a badly run trial or because I guess wrong as to the first thing to test this on and don’t get second or third shots. If it works on even a small fraction of the things I think it will work on, it will be hailed as a “wonder drug”. If there is a rational balancing of the risk vs the benefit, even very small benefits will be worth using it for because the risks really are extremely small (I can’t think of any credible ones and neither has anyone else).

    I do appreciate that my evidence is not of publishable quality. I have presented a great deal of it at scientific conferences and no one has been able (or willing) to tell me where it is wrong.

    I really do appreciate the feedback that I get from people here at SBM. The compulsion to only utilize facts and logic is quite refreshing. Most everywhere else science is driven to a large extent by fashion and everyone is so afraid of proposing something outside the box because is might hurt their career. People (and funding agencies) are extremely “risk averse”, which only means not doing something that might look foolish in hindsight. So they fund and work on things that are fashionable. Other people’s ideas can’t be encouraged because that detracts from the PR surrounding their ideas, and it is that PR that will bring the next rounds of funding.

    Right now the fashion is in genes. Genetic research should be done, we need to know what the genes are and how they work, but that will not be the route that solves many of diseases that are the leading causes of morbidity. I am in the process of writing up what will be. ;)

  34. daedalus2u says:

    Dr Benway, it is low NO that accelerates senescence.

    Low NO increases ROS and ROS damage. High NO prevents ROS damage, quenches superoxide and other radicals, and NO activates telomerase and prevents senescence.

    http://jap.physiology.org/cgi/content/full/106/1/333

  35. Dr Benway says:

    Cool, daedalus. But “more NO” or “less NO” might not be as easy as you imagine.

    I remember when I thought of dopamine as one thing and “more dopamine” and “less dopamine” as meaningful states. Now I understand several dopamine systems. Sometimes a little more in one system means a little less in another.

  36. qetzal says:

    Harriet,

    I respect most of deadalus2u’s contributions as well. But I think intellectual honesty demands that we hold one another to the same standards we expect when we criticize CAM.

    How many times has this blog lamented things like the following:

    - a single cause for a wide variety of serious diseases
    - virtual certainty that a novel intervention will be therapeutic for many conditions, despite the near absence of human data
    - insistence that the intervention has zero potential for side effects because it merely restores the body’s natural physiological balance

    Those are not the hallmarks of science-based medicine, as I hope you’ll agree. Yet deadalus2u makes such statements here on a regular basis, and is rarely challenged on them.

    Quite honestly, besides being hypocritical to SBM’s principles, I think it’s a disservice to deadalus2u. I believe he truly has read a huge amount of literature on NO. I believe there’s a real chance that at least some of his ideas may have therapeutic potential. But I also believe that his irrational fervor (or at least, what I see as an irrational fervor) is almost certain to hinder his chances of successfully testing his ideas.

  37. JMB says:

    daedulus,

    You don’t have to go to third world countries to find a large population of people who don’t bathe.

  38. Dr Benway says:

    quetzal, I’ll worry about daedelus when he’s selling something. Right now he’s just hyperfocused and enthusiastic over the possibilities he sees in his research.

    In case you haven’t noticed daedelus is a bit, how you say… neurodiverse. To his credit he is slow to take offense. He doesn’t ragequit in a huff if you question him. He just writes a lot of tl;dr.

    I like him.

  39. daedalus2u says:

    I have a write-up on NO and the physiology behind CFS. If people send me and email I will be happy to send it to them. The best place to send it is to daedalus4u at yahoo dot com. This was the technical background for an Army proposal for basic research on CFS. The reviewers had only good things to say about the proposal, but it was not funded for reasons that were not explained. I think because they had already decided who they wanted to fund.

    I am neurodiverse, I have Asperger’s. I am self-diagnosed after it started getting better after I raised my NO level by applying these bacteria. I didn’t know that I had Asperger’s until after I noticed it started getting better. I only started reading up on autism after I noticed I started getting better and started making the connections to NO physiology. At an autism conference a year ago I was presenting my poster on the connection between NO, functional connectivity and the acute resolution of autism symptoms with fever, and related that I noticed my Asperger’s getting better before I knew I had Asperger’s. An MD in the crowd piped up that “since I have known you, I have noticed your Asperger’s has gotten better”. She is board certified in neurodevelopment. I first met her at an autism conference in 2005 after I had gotten advice from a very very senior NO researcher who had offered to help me, but when I sent him a write-up on the connections between autism and NO, said there were no animal models of autism, his basic research contacts would be no help, I should contact people with clinical experience, which I did.

    In retrospect, Asperger’s does explain my whole life, vulnerability to being bullied, extreme proficiency in science, honors graduate MIT, no GF until I was 28. I have a low NO physiology, which I inherited from my mother. I am pretty sure she has Asperger’s too. She died with advanced Alzheimer’s as did both her parents. I am certain it was her low NO physiology that gave her Alzheimer’s (I can send a write-up on Alzheimer’s too). I was on that tract, with many symptoms of low NO before I raised mine, hypertension, the metabolic syndrome, depression, anxiety, PTSD, allergies. All of those got fabulously better when I raised my NO level. Mostly I only figured out the connection to NO physiology after I noticed the symptoms getting better because it was only then that I started reading about the physiology.

    I appreciate that these are anecdotes, and I would not believe them had I not experienced them myself, and perhaps not even then if the literature had not provided a NO-based physiological explanation. I appreciate that this does not make compelling evidence. But why most people want to take these anecdotes as evidence that my hypothesis is wrong is not something I understand.

  40. I’m in awe that a single blog entry on this site can draw 139 comments. If I get two or three comments on one of my newsletters, I’m lucky.

    I won’t clutter things up further here, but I did want on my website to highlight a fundamental area of disagreement (at least I think it is an area of disagreement).

    P.Mean: Are certain CAM therapies undeserving of further study (created 2010-12-01).

    http://www.pmean.com/10/UndeservingOfFurtherStudy.html

    It’s an interesting discussion.

    Steve Simon, http://www.pmean.com

  41. Steve,

    Part II of this “redux” series will address that very question. It’s already mostly written, and it addresses many of points that you’ve made in your post today, but I’ll try to find time to respond more specifically to some of them (it already mentions the Emily Rosa experiment as part of a more general topic; our views seem to be converging). BTW, have you been a regular Skeptical Inquirer reader long enough to have seen the article linked here?

    KA

  42. Yes, I did read that article, and it was probably in the back of my mind when I wrote the comment “There’s an argument to be made that NCCAM research to date has been pretty much a bust.”

    I also found your comments about conflict of interest thought provoking. I do not believe that holding a grant constitutes a conflict of interest (with a very few exceptions), but others do. There’s an article by Dale Hammerschmidt with the provocative title: “When commitments and interests conflict. ‘There’s probably no greater conflict of interest than an NIH grant’.” (http://www.ncbi.nlm.nih.gov/pubmed/7602234) but I disagree with this strongly.

    The problem is that the people in the world who have SERIOUS conflicts of interest would like it if it were perceived that EVERYONE has a conflict of interest. Then they could pretend that all these conflicts were of equal concern and they would be allowed back at the table. There would be no faster way to get to this goal than to say that any researcher with a research grant has a conflict of interest.

    It is nice that your article is available freely on the web. I wish more of the Skeptical Inquirer and Skeptic magazine articles were that way.

    Steve Simon, http://www.pmean.com

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