I have a friend who’s an artist and he’s some times taken a view which I don’t agree with very well. He’ll hold up a flower and say, “look how beautiful it is,” and I’ll agree, I think. And he says, “you see, I as an artist can see how beautiful this is, but you as a scientist, oh, take this all apart and it becomes a dull thing.” And I think he’s kind of nutty.First of all, the beauty that he sees is available to other people and to me, too, I believe, although I might not be quite as refined aesthetically as he is. But I can appreciate the beauty of a flower.

At the same time, I see much more about the flower that he sees. I could imagine the cells in there, the complicated actions inside which also have a beauty. I mean, it’s not just beauty at this dimension of one centimeter: there is also beauty at a smaller dimension, the inner structure…also the processes.

The fact that the colors in the flower are evolved in order to attract insects to pollinate it is interesting – it means that insects can see the color.

It adds a question – does this aesthetic sense also exist in the lower forms that are…why is it aesthetic, all kinds of interesting questions which a science knowledge only adds to the excitement and mystery and the awe of a flower.

It only adds. I don’t understand how it subtracts.

Taken from Richard Feynman:  What Do You Care What Other People Think?

One of the primary influences in my outlook on life, besides the movie Duck Soup, was the TV show Connections by James Burke from 1978. I was 21 when it was broadcast; I remember the impact of that series more than any science related book or show.

The show took various scientific advances and demonstrated how seemingly unrelated events were actually interconnected and how these unexpected connections led to the wonders of modern society. Burke took the usual linearity of events that is taught as history and went on what seemed like endless tangents to get to an end result.

“Burke begins each episode with a particular event or innovation in the past (usually Ancient or Medieval times) and traces the path from that event through a series of seemingly unrelated connections to a fundamental and essential aspect of the modern world. For example, the program traces the invention of plastics from the development of the fluyt, a type of Dutch cargo ship (Wikipedia).”

The show gave me, for the first time, an understanding of the complexity of scientific advances and history. Connections resulted in one of the few epiphanies in my life (5), and have informed my approach to medicine and science. Understanding and looking for connections, both obvious and hidden, leads to understanding in medicine and often to finding unusual etiologies for diseases.

An example from my practice: an elderly female with acute bloody diarrhea. Cultures of the stool grew Aeromonas hydrophilia, a fresh water organism. Chatting with her led to the discovery that each day she drank a tittle of holy water. She had brought home a jug of the water from a shrine, which was in Mexico. We cultured the water and it grew Aeromonas. Turns out that holy water is a common source for Aeromonas (6). It’s a long way from a Mexican shine to American diarrhea, but if you look for connections you can find them.

The are many connections in medicine: through time, through space, and through scale (1). Anyone who has spent any time listening to me pontificate at the hospital knows that not only do I think Infectious Disease is the coolest specialty in medicine, it is the only specialty in medicine that encompasses not only all of medicine but all of human experience (2).

Let’s wander through an example of the connections in an ID case.

A patient presents with what looks like a boil on the leg.

It’s probably methicillin resistant Staphylococcus aureus, the dread MRSA (7). MRSA is rampant in the USA, with a new strain of MRSA, the USA 300 strain, that has become the predominant strain in the US this century. In my neck of the woods, 65% of community acquired Staph infections are MRSA. When I started practice in 1990, only 2% of Staph were MRSA and the infections were virtually always acquired from hospitals and nursing homes. It has been an interesting change.

At the level of the patient, I have to ask, is it MRSA? Are there connections that lead to another diagnosis? A hot tub associated infection? Or a mycobacterium or fungus from the environment? A few quick questions can exclude these possibilities. No environmental or other exposures to lead to other etiologies. No connections. No odd exposures to make me think it’s not MRSA, and I am going to lance the boil and send it for culture to make sure. But it will take 48 hours to get the culture back.

Again, connections at the level of the patient: any needle use or skin conditions that increase or decrease the likelihood it is Staph? Nope.

Step up to connections in the patient’s local environment: family who might be carriers of Staph? Pets? Hobbies? Is he a wrestler? Fresh from prison? Any connections to the local environment that leads to an exposure to Staph? No connections.

Step up to the city, the US, the world. What is the carriage rate for Staph (it’s about 1 in 3)? What is the MRSA rate (about 1.5% as of 2004). Rates are increasing for uncertain reasons. It has always been thought that antibiotic resistant strains are less fit in an antibiotic free environment. Why is the MRSA increasing? It should be less fit unless there are compensatory mutations that make up for the decreased fitness of being antibiotic resistant. Doesn’t appear to be a connection at the larger level. Certainly some diseases are increasing from global warming such as dengue and malaria, while others are decreasing, such as RSV. MRSA doesn’t appear to have a connection with global climate change.

Back to the patient.

Nothing in the environment or the US to worry about with a connection to this patient.

Is there a reason this patient has an MRSA infection? Bad luck? Probably. Nothing by history to suggest there is a reason to suspect an immune defect I can diagnose.

That being said, there is increasing data to suggest a wide variety of polymorphisms in a variety of systems are associated with increased or decreased susceptibility to infections.

Polymorphisms are the natural variations in the genes that code for proteins.

Your DNA codes for a tyrosine where I code for a glycine. As a result of a simple amino acid substitution in protein, you may have a increased likelihood of dying or getting an infection.

There is a wing of the immune system that in humans is called the toll like receptors. The toll receptors were first discovered in fruit flies (8) but have subsequently been found in virtually every living animal and are one of the oldest parts of the immune system.

While the toll like receptors cannot be boosted, they can certainly have mutations, and these mutations, these variations, are polymorphisms.

If you have one variant in your DNA, then there may be an increased risk for infection. There are many toll mutations that lead to increased risks for a variety of infections. There is no firm connection as of yet with MRSA and a toll like receptor mutation, but there is a suggestion that TLR2 Arg753Gln polymorphism (that toll like receptor 2 arginine substitution at location 753) may increase risk for Staph infections (3).

And there are other mutations that are connected with Staph infections. Perhaps the patient is colonized with Staph and get boils due to other variations in the immune system.

Variations in interleukin, C reactive protein and complement factor H are all associated with Staphylococcus colonization and boils:

“The IL4 −524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was over represented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were over represented (4)”

Translated: variations in common proteins can lead to increased susceptibility to MRSA.

So even without classic risks for S. aureus, the answer for why one patient gets disease and why it runs in the family may be bad luck. Or it may be in the genes. It may be that the fault, dear Brutus, lies not in our stars, but in ourselves.

There are also the connections at the level of the organism. Staphylococcus aureus makes dozens of proteins whose sole purpose, apparently, is to kill us. The current MRSA frequently has a protein called the Panton Valentine leukocidin (PVL) that dissolves human cells. The presence of the PVL in part is why the current MRSA is such a problem. It liquifies the local tissues, dissolving the immune system and surrounding tissues into the bloody pus so commonly found in the boils when they are lanced. PVL may be one of the compensatory changes that allow MRSA to prosper.

PVL is but one of many toxins, many of which enhance the virulence of S. aureus. I have often wondered what the real function of some bacterial toxins is. What good is botulism toxin? I can’t see how it promotes the spread of the organism in humans. Many virulence factors are probably epiphenomena of their real function, what ever that may be. What is the connection to bacterial evolution of these toxins? I don’t know.

Then there is the level of antibiotic resistance. Is the infection located where I can deliver an antibiotic? Is it resistant to what I am going to choose? I have knowledge of current resistance patterns in my community, but it is a moving target.

Doxycycline is effective, as is trimethoprim-sulfamethsoxazole. The problem with both agents is the development of resistance is easy, and the pus environment is potentially antagonistic for tmp-sulfa. The only other oral agent is linazolid, but it costs 50 dollars a pill, so a 10 day course often runs 1200 dollars or more. With 1 in 5 people with no health care, that brings into play the biopolitical connection between the ability to provide health care and the ability of the patient to pay. A quick check: no insurance (9).

I could use intravenous vancomycin, but the use of vancomycin not only drives vancomycin resistance in Staph, but leads to increased incidence of vancomycin resistant enterococcus. In the few cases of vancomycin resistant S. aureus, the resistance genes have jumped from enterococcus to Staph. If I go with vancomycin, I be will be contributing, in my own small way, to local and world wide resistance to vancomycin (10).

There are also the multitudinous ways organisms become resistant to antibiotics and how those resistance genes can jump, again by a variety of means, from organism to organism and then world wide. The local ecology can increase the development of resistance in one bacteria; that resistance can jump to other species, and then spread.

The penicillin resistance of S. pneumoniae, for example, occurred when a few strains acquired resistance genes from other bacteria and then spread across the world, taking with it resistance to many of the common and inexpensive antibiotics.

Think globally, act locally. It is ID in action.

To understand ID is to understand evolution and ecology. ID is applied evolution of people and pathogens. There may be, oh, I don’t know, say a neurosurgeon somewhere that doesn’t understand the connections of evolution with infectious diseases, but I would be shocked if there was an ID doc who was an evolution denier. I wonder if there has been enough genetic change in the MRSA of today to say it is a different species as the S. aureus of 30 years ago. A rough estimation makes 30 years of bacterial replication the same as 6 million years of human replication. Humans have had a reasonable number of changes in 6 million years. I wonder what has occurred to S. aureus. The connections between evolution and the ecology that drive antibiotic resistance provide deep understanding of the treatment of infectious diseases.

If the patient is unlucky enough to require IV antibiotics, I have to wonder what the best therapy is, and I know that the MIC to vancomycin, the mean inhibitory concentration, the amount of antibiotic it takes to stop growth, is increasing for Staph. While it used to be 0.5, increasingly I am seeing 1 or 2 for an MIC. As the MIC increases, due to simple amino acid substitutions in the cell wall, the efficacy of vancomycin decreases. Even susceptible organisms may not be, and if I push the vancomycin, I may be increasing the toxicity, No good deed ever goes unpunished. And I will not wander into the swamp of drug drug interactions.

Is he sick enough for IV, but not hospitalization? Payment and coordination of care and the lack of a health care system again enter into the picture.

And should I treat his fever? (No). The evolution of fever is topic for another time.

In the end, the boil is lanced, the patient is sent home on doxycycline and he and his family are decolonized. If he is lucky, that will be the end of it.

So many connections, and I only covered a few of them:

The biology, anatomy, physiology of the infection.
The chemistry and epidemiology of the infection.
The chemistry of the antibiotics.
The history, evolution and ecology of organisms and the host.
The finances of the the medical industrial complex.

Up and down scale, space and time. Every time with every patient.

How does this relate to the topics on this blog?

I understand medicine from the level of the individual molecules interacting to cause disease to the world as it alters the risks of infection. From the atom to the bacteria to the human to the city to the planet, extending back to the beginning of human evolution.

I have, dare I say it (dare, dare) a holistic approach. A real holistic approach. The panoply of medicine as I see it is rich with understanding from connections from the level of the human DNA to global climate change and many things in between. It is what makes Infectious Diseases just so damn cool.

Where in all this understanding does acupuncture, as one example, fit? How do the alternative practices connect with the known world? They don’t. Homeopathy, acupuncture, chiropractic, energy therapies exist in their own isolated universe with no connection to natural reality.

There is no chi, there are no genes that code for meridians. There are no polymorphisms that render one patient susceptible to acupuncture and another not. Acupuncture has no connections to anatomy, physiology, chemistry, genetics, evolution, physics, biochemistry, developmental biology etc etc. What do they add to the understanding of the world at any level beyond the psychology of deception? Or any other alt med? Alt med is like a god of the gaps, but there are no gaps, at least no gaps that need to be filled with any of the interventions studied by the NCCAM.

Alt med’s are intellectual dead ends that add nothing to understanding of biology or history or ecology or evolution or anatomy or anything. They have no connections.

I know, I know, I know. I am a closed minded reductionist. There is more in heaven and earth than is dreamt of in my philosophy. Right?

Unlike alt med, in science and medicine I see connections, endless, amazing, incredible, connections. A beauty and understanding of the world that is absent in alt med.

“I am among those who think that science has great beauty. A scientist in his laboratory is not only a technician: he is also a child placed before natural phenomena which impress him like a fairy tale.”

Marie Curie (1867 – 1934)

Marie would not find beauty in alt med.

References and Snotty Comments


2) For the record, not only is Infectious disease the best part of medicine, and ID docs the smartest docs the following are also superior: Mac OS, French Bordeaux’s, Oregon IPA’s and ESB’s, and my wife and sons. Just saying.

(3) A novel polymorphism in the toll-like receptor 2 gene and its potential association with Staphylococcal infection. Infection and Immunity.
2000, vol. 68, no11, pp. 6398-6401.

(4) The Journal of Infectious Diseases 2008;197:1244–1253.
Host Polymorphisms in Interleukin 4, Complement Factor H, and C-Reactive Protein Associated with Nasal Carriage of Staphylococcus aureus and Occurrence of Boils.

(4) Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis.2008-Feb; vol 46 (issue 4) : pp 584-93

(5) The other being a meal at St. Estephe’s in Manhattan Beach, California, my first gourmet meal; more memorable, I am afraid to say, than my first kiss.

(6) Holy water fonts are reservoirs of pathogenic bacteria
Environmental Microbiology 4 (10) , 617–620 I suppose that Louis Pasteur went to hell, otherwise he would have insured that holy water was pasteurized water.

(7) M-R-S-A, not mursa.

(8) “Their name derives from Christiane Nüsslein-Volhard’s 1985 exclamation, “Das war ja toll!” The exclamation, which translates as “That’s weird!”, was in reference to the underdeveloped posterior portion of a fruit fly larva.” Wikipedia.

(9) Health care in the US is second to none. Its because we rank 27th. One does get what one pays for.

(10) In infectious disease, its use it and lose it.

Posted in: Science and Medicine

Leave a Comment (33) ↓

33 thoughts on “Connections

  1. apteryx says:

    A very elegant piece, Mark, but you somewhat spoil it by asserting at the end that there is no place in health care, not just for any “sCAM,” but for any traditional practice whatsoever that your profession has not already adopted or co-opted.

    You write: “There are no polymorphism’s [sic] that render one patient susceptible to acupuncture and another not.” How do you know that? Many people respond to acupuncture better than to “other placebos” or conventional treatments; others do not. If you are insistent that their pain relief is solely due to a super-placebo effect, that it’s all in their heads, and that what’s in their heads is a meat machine whose circuits are laid out in accordance with genetic dictates,those premises could well lead you to the hypothesis that genetic differences will affect who responds. Nobody has looked, have they? You admit that there are no proven polymorphisms affecting MRSA susceptibility, yet you are sure they will be found.

    You also write: “Alt med is like a god of the gaps, but there are no gaps, at least no gaps that need to be filled with any of the interventions studied by the NCCAM.” This belittles the experience of people who receive pain relief from acupuncture, after getting no relief or unacceptable side effects from conventional treatments. Such people will not be pleased to hear that your inability to relieve their suffering is either not a gap in conventional medicine, or not a gap that “needs to be filled”! Also, if you deliberately included botanicals, which are studied in NCCAM-funded research, you are showing ignorance; there are botanicals that have been well demonstrated to have bioactivity profiles not offered by any pharmaceutical on the market, and I can’t imagine why any believer in science would not want those activities to be studied and put to use whenever possible. And when they are studied, new things are learned about chemistry, biology, and yes, evolution.

  2. randytoad says:

    Don’t know if you intended to attribute it or not, but the first couple of paragraphs (about the appreciation of a flower) are nearly a direct quote of Richard Feynman from one of his books (I think it’s Surely You’re Joking Mr. Feynman). The way it’s written, it appears as if you are relating your own own experience. And though it may be a common sentiment, Feynman’s use of language (e.g. the use of the phrase “kind of nutty”) make his words pretty easy to spot.

  3. dhawk says:

    Shouldn’t the first six paragraphs be attributed to Feynman?

  4. wisnij says:

    Whenever some woo sneers at science for being “cold” or “impersonal”, I always think of Feynman’s example of the flower.

  5. Zetetic says:

    “How do the alternative practices connect with the known world? They don’t. Homeopathy, acupuncture, chiropractic, energy therapies exist in their own isolated universe with no connection to natural reality.”

    I’m surprised the altie-woo folks haven’t jumped in here yet with that call out! Well put.

    BTW – I particularly like WASHINTON IPAs & ESBs.

  6. The opening paragraphs are taken from Feynman. Mark did include the attribution but I screwed up when I edited his post and put it up for him. This was simply an editing error.

    It is correct now with the attribution in place.

  7. Spiv says:

    as to Dr Feynman, I really have to disagree (I’m an artist in addition to that rocket science thing, so I figure I’m pretty qualified to argue on either behalf). Years of studying the fine arts show something very similar to the effects you work so hard to eliminate from your research: the human mind is incredibly good at fooling itself. Thus, so is the eye attached to it. Most people really see perhaps 5% of what they look at, using that highly tuned interpretation ability evolution has so gifted us with. Basically we’re good at noticing a tiger moving in the bushes, but not so good at telling how many stripes it has, how they twist and roll over the body, and how that shifts the appearence of muscle underneath the fur and skin.

    You definitely get better at picking all that out with training, and being fooled less and less. Anyone who doesn’t believe me, have at drawing a human body. Medical professionals definitely get better at it, but you’ll still find yourself with the same set of out-of-scale parts everyone new to drawing seems to accomplish. And no, there’s not some magical articulation in an artist’s hands, I often find myself drawing with the left when it’s convenient.

    That said, of course understanding the inner workings of the thing makes it more appreciable. I can’t imagine any serious artist finding the dissection or study of a thing “dulling” to it. I’ve never met one who believes that, anyway.

  8. Harriet Hall says:

    Dr. Crislip said, “Alt med’s are intellectual dead ends that add nothing to understanding of biology or history or ecology or evolution or anatomy or anything. They have no connections.”

    I see some “connections” for alternative medicine. There are connections with all the other ways humans have managed to fool themselves through the centuries. There are connections with religion, superstition, philosophy, folk beliefs, psychology, human imagination and story-telling. There are connections with the origins of medicine, before it adopted the scientific method. There are connections with all the moms who have kissed it to make it better.

    But these are not productive connections. As Dr. Crislip says, they don’t contribute to progressively building a body of knowledge. I suppose they “could” contribute to progress indirectly if we really tried to dig into why so many people are attracted to alt med and used the knowledge we gained to improve scientific medical care and public education.

  9. pec says:

    Of course a scientist can see the beauty of a flower, or any aspect of nature. Trying to understand nature’s amazing intricacy can be a form of worship, as it was to Einstein, for example.

    But if a scientist happens to also be a materialist, they are likely to see nature as nothing but piles of junk thrown together by accident over long periods of time.

    Science is an art, and real scientists are creative artists. Materialism is an obsolete ideology based on profound misunderstandings.

    If some artists don’t like science it’s only because science and materialism have become artificially joined together in recent decades.

  10. randytoad says:

    “The opening paragraphs are taken from Feynman. Mark did include the attribution but I screwed up when I edited his post and put it up for him. This was simply an editing error.”

    I figured as much. Even if Dr. Crislip had intended to commit plagiary, I figure he’d be smarter than to plagiarize Feynman in a blog primarily read by skeptics.

  11. daedalus2u says:

    Dr Crislip, I very much have a fondness for the Connections program too. I think that once you know “enough”, so that your web of knowledge becomes a “small world network”, that is when the scales fall from your eyes and you understand. That is when you become an “expert”, when you know what parts of your knowledge are connected to which other parts and which are not. The multiple connections reinforce each other and the whole does become stronger than the sum of its parts.

    You are absolutely correct; CAM treatment modalities are dead ends with no connections to reality. CAM practices might potentially have utility in hypothesis generation for research into how human physiology is affected by different placebos. Virtually all the hypotheses “connected” to CAM contradict data that is extremely well known and extremely reliable. The only “take-home” lesson applicable to actual treatment might be that bedside manner matters, but there is plenty of EBM that shows that.

    I have been thinking a lot about MRSA and other antibiotic resistant topical infectious agents too. It directly relates to my work in NO (bet no one saw that connection coming! ;) I have just posted a blog about it which compliments some of what you have written but more in a theoretical sense rather than a clinical sense (don’t try this at home!). I discuss antibiotic resistance a little and some of the things that cause bacteria to develop antibiotic resistance. Many antibiotics induce antibiotic resistance, but so do some disinfectants. For example pine oil induces expression of multiple antibiotic resistance pathways, for example ATP powered efflux transporters.

    A characteristic of most pathogenic bacteria that you did not touch on is how they transition from the non-pathogenic phenotype to the pathogenic phenotype. This transition is triggered by quorum sensing compounds. Essentially small concentrations of bacteria hang out merely staying alive until a critical mass forms, a “quorum”. That triggers expression of virulence factors including biofilm formation, toxins and lytic enzymes. If quorum sensing is suppressed, so is virulence and so is disease. This is the state the bacteria are in when a person is “colonized” but not infected. All it takes for a colonized person to become infected is an increase in the population of that particular bacteria until quorum sensing occurs.

    Both Staphylococcus and Pseudomonas have their biofilm formation suppressed by levels of NO/NOx readily attainable in vivo. A hypothesis I just came up with recently is that suppressing biofilm formation is the reason for the tremendous production of NO by iNOS during sepsis or LPS injection. If the body can generate enough NO to suppress biofilm formation in the vasculature there is a chance of survival. If it can’t, the chances of survival go way down.

    Suppression of quorum sensing is a major and generic method that many eukaryotes use in the “wild” to keep their surfaces clear of biofilms. Many algae have halogen oxidases and make hypochlorite and other oxidants for this exact reason. Myeloperoxidase in humans can make hypochlorite too.

    There is “chemical warfare” between the various bacteria in and on our bodies and some non-pathogens produce compounds that suppress pathogens. That is why often there are secondary infections following antibiotic use. If the antibiotics knock out non-pathogens that are suppressing pathogens by interfering with their quorum sensing, and if the pathogen is resistant to the antibiotic, the resistant infection can occur very quickly.

    I suspect that continued reliance on killing bacteria with chemical agents will become less and less effective as they evolve greater and greater resistance. Eventually pathogens may become resistant to things like pine oil. I think quorum sensing suppression will be a better long term approach because it doesn’t provide an evolutionary pressure to evolve resistance.

  12. Harriet Hall says:

    pec said,

    “But if a scientist happens to also be a materialist, they are likely to see nature as nothing but piles of junk thrown together by accident over long periods of time.”

    That is one of the silliest things you’ve said. No comment necessary.

    “Materialism is an obsolete ideology based on profound misunderstandings.”

    Evidence, please. If you can’t provide evidence, I can just as well say pec’s is an obsolete ideology based on profound misunderstandings. Without evidence, it’s my word against yours.

    “science and materialism have become artificially joined together in recent decades”

    You keep saying this and I keep telling you that’s not true. Materialism is a philosophy; science is not a philosophy and is bound to no school of philosophy – it is a method of learning about how the world works. Science is not “joined” to materialism and would be quite willing to study the immaterial if some way could be found to do that. I’m still waiting for you to explain how that might be done.

  13. Mark Crislip says:

    In my mind, if you say acupuncture relieves pain, you are saying that placing needles into meridians alters the flow of chi and that decreases pain.Thats acupuncture, albeit a narrow definition.

    Otherwise, its just sticking people with needles and sticking people with needles does something.

    People do get needles stuck in them, and people do say they have less pain.

    However, there is no reason to suspect a genetic underpinning to meridians and chi, hence no reason to suspect a polymorphism.

    Pain is a curious thing and the subjective nature of the experience makes determining response to interventions that are hard to blind, such as acupuncture, difficult. The interesting issue of whether patients are better if they say they are better subjectively even it they are not objectively was the topic of an earlier post. I do not, in practice, find these issueclear cut.

    I don’t think there is a placebo effect for any process with objective end points and the subjective endpoints are always harder to interpret, see my podcast on the topic. Most of the response to alt meds is just N Rays redux.

    And you must have using the Bible code algorithm to read the essay, where did botanicals come in?

    My point, or so I thought, was that science leads to understanding, that scams do not.

    Lying, cheating, fooling yourself and others has always been a successful way to get desired outcomes, esp if the outcomes are subjective. It will decrease pain. Unfortunately, I don’t think they are ethical.

    Don’t disrespect the power of a mothers kiss. That crosses the line.

    Washington beers? Puh lease:)

  14. Since Mark brought up Connections (which I too love) I will recommend The Day the Universe Changed, also by Burke.

    My only problem with Burke is that he embraces some post- modernism nonsense. So you have to just ignore that piece.

  15. daedalus2u says:

    Dr Crislip, you are mistaken about the placebo effect for processes with objective endpoints. The archetypal placebo is the mother’s kiss. Mothers instinctively do that because infants and children haven’t learned to invoke the placebo effect themselves.

    The placebo effect is due to the neurogenic production of NO, which causes the transition from the “fight or flight” state to the “rest and relaxation” state. In the “fight or flight” state, the ultimate resource (ATP) is mobilized for immediate consumption in part by turning off ATP consuming pathways with less time urgency. When you are under extreme stress, such as when running from a bear, spending ATP on healing is a luxury you can’t afford. Each molecule of ATP used for healing is a molecule that can’t be used to power the muscles you are using to run from the bear that will kill you if you don’t run as fast and as long as is necessary. ATP supply is what limits how fast and how long you can run. NO is what regulates the ATP level (via sGC), and the ATP level regulates which ATP consuming pathways are turned on and which ones are turned off. This is why people can run themselves to death. ATP consuming pathways that are needed to keep you alive are turned off to divert ATP to voluntary pathways, such as voluntary muscle.

    If your physiology is in a state where ATP is being diverted away from healing because of low NO, then raising NO via any mechanism will increase healing. If your NO status is high enough that the proper level of ATP is being allocated to healing, then a placebo will do nothing.

    The mother’s kiss works because it brings the child down from the “fight or flight” state to the “rest and relaxation” state. Many positive social interactions have the effect of raising NO levels. Negative social interactions have the effect of lowering it.

    I have blogged about the placebo effect and how it is connected to NO physiology.

    In the blog I cite some work where they show that placebos exacerbate nausea and that nocebos (the same inert material but said to make nausea worse) actually make nausea better. The nausea was subjective, but they also measured gut motility by measuring gastric myoelectrical activity which paralleled the reports of nausea. My understanding is that because much of the gut neural activity is nitrergic, increasing the NO level makes it more active causing greater gastric myoelectrical activity.

    The placebo effect from surgery is well known and very powerful. Very difficult for patients and even surgeons to correct for.

    Because all placebos work via the same final common pathway (raising NO levels via neurogenic NO release), raising NO levels by any mechanism should invoke the same physiological effects.

    This is where I think my bacteria could play a role. It could be administered as one would a placebo; “some people find that this does help, some people find it doesn’t. We don’t understand the precise mechanism(s), or have ways of identifying who will be helped and who won’t be helped except by trying it.” I think it would work better than any other placebo because it increases the NO generating ability of an organism via natural mechanisms. The release of ammonia on the skin is an evolved feature to provide substrate to the normally resident biofilm which then generates NO/NOx which is absorbed. I think that is the evolved reason for sweating during shock, for adrenergic sweating, for night sweats and essentially all non-thermal sweating.

  16. ellazimm says:

    Thank you Dr Crislip, I’m going to pass your essay on to some friends who teach Anatomy & Phys.

    My own epiphany came in 1978 but I was watching The Ascent of Man which I would also like to commend to one and all.

  17. apteryx says:

    Mark – You say “In my mind, if you say acupuncture relieves pain, you are saying that placing needles into meridians alters the flow of chi and that decreases pain.”

    Nope. The definition of my words does not depend upon your opinions. That is what an old-fashioned TCM practitioner would have said, to be sure. But if there is no such thing as chi, that does not mean that acupuncture cannot relieve pain by some other mechanism, just as herbal drugs have been proven to act by mechanisms other than the originally postulated “humors.” The belief in chi could be seen as a primitive hypothesis meant to explain observations about human life and health. If the hypothesis is disproven, it does not mean that the observations it was meant to explain do not exist. Western MDs have likewise used plenty of treatments that did some good even though their mechanisms were unknown or wrongly understood.

    If there is no chi, of course there can be no genetic polymorphisms related to chi; that’s a straw man unworthy of you, though, and you dodged the more meaningful question of whether there can be genetic polymorphisms related to placebo response which, you believe, is responsible for acupuncture’s benefits. Incidentally, you say you “don’t think there is a placebo effect for any process with objective end points.” I tend to agree – but does that mean that studies of objective endpoints need not always be placebo-controlled to provide valuable data?

    You also wrote: “And you must have using the Bible code algorithm to read the essay, where did botanicals come in?” How delightfully snarky; I had just been pointing out elsewhere that the real orthodox on this site were generally polite, but I guess there are always exceptions. As I said above, botanicals came in when you wrote “[T]here are no gaps, at least no gaps that need to be filled with any of the interventions studied by the NCCAM.” That most definitely includes botanicals and probiotics, which do seem to fill some gaps that suffering patients would like to have filled.

  18. Flex says:

    Like Mark, and countless others, Connections was a pivotal point in my education. Although I was a bit younger than Mark when I saw it, like eleven. :)

    Watching the show gave me a life-long desire to understand how things fit together and how they relate to the past. This curiosity about the world has been as invaluable in my chosen profession of engineering as it has been in your profession of medicine.

    I am occasionally dumbfounded by meeting people who have lost that curiosity (or possibly never had it). There is a pleasure in finding connections which ranks right up there with the greatest pleasures in the world.

    Of course, there are people who avoid the final step; once a connection is found, it must be tested. Which is one difference between quackery and EBM. I can create connections, even conspiracies, pretty easily. But the greatest pleasure is if the connection if tested and found to be true. Discarding a connection shown to be false is a hard thing to do.

    Thus CAM survives, as does perpetual motion machines, belief in ghosts, ESP, etc.

    I recently re-watched the series (now available on DVD), and while the original is a little dated, in general it holds up well. (Note: I used Netflix, but there are undoubtably a plethora of ways to get ahold of the DVD’s.)

    I haven’t seen any of the other series, but they are also available on DVD now, as well as The Day the Universe Changed, The Ascent of Man, Civilization, and Cosmos. If only I could find The Body in Question.


    p.s. As far as the beer question goes, my experiance is that if the beer has travelled less than 20 miles it’s better. I’ll drink the local brews, worldwide.

  19. overshoot says:

    Mark Crislip:

    I don’t think there is a placebo effect for any process with objective end points and the subjective endpoints are always harder to interpret, see my podcast on the topic.

    I don’t think you meant this to be quite as strong a statement as it is when read literally.

    Manifestly, there are placebo or other psychological influences on human mental state; likewise, mental states have indisputable effects on the body (else I wouldn’t be having much luck getting my fingers to strike the keys entering this text.)

    We can argue the magnitudes and mechanisms of the various influences, but some are just plain obvious. I cite as one example the effect of relaxation on circulation in tense muscles and the (I hope uncontested) effects of mental influences on tension and relaxation. In personal experience terms, I hope I’m not practicing woo when I try to get injured patients to calm themselves and relax; it certainly seems to produce clear improvements in objective signs of well-being such as O2 saturation.

  20. Joe says:

    @ overshoot,
    “Conclusions We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos.”

    oversoot wrote “I’m not practicing woo when I try to get injured patients to calm themselves and relax; it certainly seems to produce clear improvements in objective signs of well-being such as O2 saturation.”

    You have to cite literature on that.

  21. apteryx says:

    Overshoot – No you don’t; we’ll believe your clinical experience over Joe’s lack of experience any day. I have accused him of being a troll, and he hasn’t denied it. Don’t feed the troll!

  22. overshoot says:


    oversoot wrote “I’m not practicing woo when I try to get injured patients to calm themselves and relax; it certainly seems to produce clear improvements in objective signs of well-being such as O2 saturation.”

    You have to cite literature on that.

    You forgot the smileys. On the chance that you were serious, please see previous notes on magnitudes and mechanisms.

  23. Joe says:

    overshoot wrote “You forgot the smileys. On the chance that you were serious, please see previous notes on magnitudes and mechanisms.”

    I don’t find previous notes, let alone “smileys.” What are you suggesting?

  24. Michelle B says:

    Per Harriet’s comment, quoting Pec: …they are likely to see nature as nothing but piles of junk thrown together by accident over long periods of time.

    Sigh. Natural Selection is not accidental. Pec’s ignorance can be easily replaced with knowledge by her checking out:

  25. Mark Crislip says:

    What then is acupuncture? I define the term so we have a common point for discussion. You definition is.…..?

    Pain is a funny thing. I have inflicted lot of it in my career and have, thanks to lot of medical problems, had a lot inflicted upon me.

    I still have issues with any scam as it relates to pain.

    Perception of pain is a complicated response to some stimulus.

    So is taste.

    I know that the same bottle of bordeaux tastes far better in a 2 star restaurant on a summers day in the south of france with friends than it does in a cold jan day alone with some top raman.

    The wine will taste better if the bottle has a higher price tag.

    Many things go into the reaction to the same bottle of wine.

    Or the love you feel towards another person.

    So if someone told me that it was known that acupuncture increased the appreciation of a bottle of wine or the love I feel towards my wife, I would have to respond both yes it does (if you say the wine tastes better, that you love your wife more, who am I to say?) On the other hand I would say it doesn’t. There is no physiologic/anatomic reason to suspect that either the wine or the neuroanatomy of the wine was altered. So the wine tasted the same and your love for your s.o. is unchanged.

    Same with pain. When acupuncture is used outside of meridians, or is shallow, or doesn’t pierce the skin at all, and it has the same result as ‘real’ acupuncture, I conclude that acupuncture doesn’t work in the second instance of a ‘real’ change but it does work in a perceived change.

    Is perception reality? No. Maybe. Yes. Depends. Dont give me that “what the fuck do we know” bullshit, my undergrad degree was in physics. But perception maybe is reality in politics and pain and love and taste. But not in hypertension, stroke, WMD’s, and climate change.

    But if a patient says they are better, the are. If they hear voices I cant, they are still hearing voices. If they see people who are not there, they are still seeing them. If they smell something that I cant, they still smell it. If I stimuate a neuron with an electrical current and they see a dog, or their pain does down, are either responses real? No. yes. Maybe. What goes on inside other craniums is a curious thing. We are all, at some level, brains in a jar of fluid, like in Futurama.

    In the real world I am aware of what and how I say things can alter a patients approach to a disease, and I use these ‘tricks”. I do not, however, lie to patients, which is what most scam does.

    These issue of pain and taste and love are not simple binary issues.

    So does sticking needles in people decrease pain? No maybe yes. Not in the same way nafcillin works for endocarditis. It works more like the trained geologist who looks at the grand canyon and sees evidence for Noah’s flood. Or Blondot seeing N Rays. Or thinking the same bottle of wine tastes better if the price is 90 dollars (

    I’ll let a neurologist tell me if an FMRI effect in the pleasure center changes the taste of the wine, or just the perception of the taste of the wine. And is there a difference. Yes. No. Maybe.

    I do not find the issue of pain as clear cut as other issues in medicine.

    I am glad the comment was found to be delightfully snarky. Ignorant, co opt and belittle are fighten words for me, and, since there is no tone or body language in posts, I think it is important to be thin skinned and always assume that writers are fundamentally malicious and respond accordingly. It is what the intertubes are all about.

    And I do not think there is a placebo effect. at all. actively doing nothing has the same effect as passively doing nothing in most studies where there is both a placebo arm and a observation arm.
    To my mind, a clarification of terms, placebo should lead to a measurable physiologic effect that alters the course of a disease in a way that is different from doing nothing at all. Is a change in perception a change in the process? How many angels can dance on the head of a pin?

    Could there be polymorphisms leading to increased response to a scam.

    I had only been thinking about that issue under the assumption that there is a physical reason for acupuncture to work.

    I am still torn between my old emotional attachment to personality being determined by environment, and my increasing feeling over the years that we are meat puppets, that free will is an illusion, and that all we are and all we do is genetic.

    So if the fantasy prone person, for example, is that way due to some genetic reason, then I suppose there will be polymorphisms that will render some more amenable to the self deception of acupucnture.

    As to botanicals, I can see where there could be inferred from what I wrote, but at the time I was not explicitly considering that issue at the NCCAM. My ability to be clear in these posts is still a big work in progress.

    Off to be crushed by my 11 year old at basketball. I need acupuncture to improve my outside shot.

  26. daedalus2u says:

    There is a serious problem with aggregating studies treating multiple disorders with placebos. Without an underlying understanding of the physiology behind the placebo effect, and the physiology behind the multiple disorders being treated, the placebos could be applied wrongly to the wrong conditions under the wrong “placebo theory”.

    One of the studies I cite in my blog (it is now available open access) on placebos looked at nausea induced by optical means by sitting (motionless) inside a tunnel that was being rotated in 3 groups of subjects. One group received pills said to reduce nausea (positive placebo) the same pills said to cause nausea (nocebo) and the same inert material said to be inert (inert placebo).

    The groups receiving the positive placebo and the inert placebo had had the worst nausea and the group receiving the nocebo had the least nausea (p less than 0.05). This was measured via electrogastrogram.

    The choice of whether to call an inert pill said to make a symptom better or worse a “placebo” or a “nocebo” is semantic. What is a nocebo to the patient (because the patient is told the symptoms might get worse) is a placebo to the administering physician because the physician expects the nausea to be lessened.

    Trials with “placebos” with negative outcomes may occur because the “placebo” was administered wrongly. The administering physician said the inert pills would make the symptom better, when the physician should have said the inert pills would make the symptoms worse.

    I am not saying this post hoc to rationalize why a placebo or a nocebo does or doesn’t work for a particular intervention. The conceptualization I have for the placebo effect is the neurogenic regulation of the allocation of physiological resources between “fight or flight” and “rest and relaxation”. Allocation between immediate consumption and long term maintenance.

    Just as the archetypal placebo is the mother’s kiss it and make it better, the archetypal nocebo is the military leader’s admonishment to kill or be killed. Turning off the “soft” luxury behaviors of rest and turning on the hard and brutal behaviors of extreme life and death stress could save a soldier’s life. Allowing your mother to manipulate your physiological state to turn off stress so you can grow and heal is a survival feature for children. Allowing your military leader to manipulate your physiological state so you can kill instead of be killed is a survival feature for military followers. The pep talk the military leader gives makes the soldiers feel like crap. The military leader knows that more of them will survive if he treats them brutally.

    That is the physiology that the woo peddlers and coaches of athletes tap into.

    The only identified mechanism for virtually all CAM is the placebo effect. Until EBM and SBM come up with better ways to tap into the placebo effect, there remains a niche for CAM. Maximally invoke the placebo effect pharmacologically and there is nothing left for CAM to work with.

  27. apteryx says:

    Mark, you wrote:

    “I think it is important to be thin skinned and always assume that writers are fundamentally malicious and respond accordingly.” Given that you also wrote that you think “we are meat puppets … and that all we are and all we do is genetic,” you would seem to have a rather nasty view of human nature. I would not want to depend for pain relief, as opposed to pain infliction, on a doctor who thought of me as just another meat puppet and inherently malevolent at that. Incidentally, I hope that in practice you also acknowledge the influences of environment and genotype X environment interactions – otherwise, being an MD will not have taught you as much about biology, ecology, and evolution as you seem to think.

    You are, indeed, ignorant of research regarding the placebo effect – sorry for the “fighten words”, Mark, but it’s equally malicious to describe placebo responders as “‘the fantasy prone person” when objective research has shown that anyone can experience the placebo effect; response in one instance does not predict future response. I’m glad to see the consensus developing around here that placebos cannot affect organic processes (e.g., joint space narrowing, cardiac ejection fraction, liver enzyme levels, immune responses), because that means that there can be no more yapping about placebo effects when (placebo-controlled!) studies of botanicals show such effects.

    One final point. Usually, animal studies are regarded as inferior to human studies that generate similar data, because animals’ responses may be different. However, animals ought not to have a placebo effect; they have not been told that they are “supposed to” feel better when someone pesters them with needles. Yet animal studies in several species have clearly demonstrated that acupuncture can alleviate pain, particularly chronic joint pain. I wonder how this can be explained.

  28. weing says:

    You’ve got to talk to the animals.

  29. Mark Crislip says:

    I really have to start using me some :) and ;)

    A pubmed using “acupuncture animals and pain” yielded 235 references.

    The vast majority of acupuncture were ‘electro acupuncture’. Once current is involved, I would not consider it acupuncture, again, my definition, I still await yours

    Studies involving just needles appear to be rare: this is the only one I could find that had an abstract, I am sure I missed some compelling studies where electricity is not invovled and the investigators and pet owners are blinded (guide dogs not included :)). I keep coming back to N Rays.

    This is the only one I could find with 1) no electricity and 2) everyone blinded.

    Double-blind evaluation of implants of gold wire at acupuncture points in the dog as a treatment for osteoarthritis induced by hip dysplasia.Hielm-Bjorkman A, Raekallio M, Kuusela E, Saarto E, Markkola A, Tulamo RM.
    Faculty of Veterinary Medicine, Department of Clinical Sciences, University of Helsinki, Finland.

    Thirty-eight dogs with hip dysplasia were studied to evaluate the use of gold wire implants at acupuncture points around the hip joints. They were assigned at random into two groups of 19. In the treated group, gold wire was inserted through hypodermic needles at electrically found acupuncture points around both hips. In the control group, the areas were prepared in the same way but had only the skin pierced at sites which were not acupuncture points, with a needle of the same size as that used in the treated group. Over a period of six months the dogs were studied repeatedly by two veterinarians and by the dogs’ owners who were unaware of the treatments the dogs had received; they assessed the dogs’ locomotion, hip function and signs of pain. Radiographs were taken at the beginning and end of the study. Although the data collected from both groups by the veterinarians and the owners showed a significant improvement of locomotion and reduction in signs of pain (P=0.036 for the veterinary evaluation and locomotion and P=0.0001 and P=0.0034 for the owners’ evaluation of locomotion and pain, respectively), there were no statistically significant differences between the treated and control groups (P=0.19 and P=0.41, P=0.24, respectively).

  30. Harriet Hall says:

    apteryx said “animals ought not to have a placebo effect”

    Maybe they “ought not” but they clearly DO. The veterinary literature recognizes that.

    “I wonder how this can be explained.” Here’s how:

    (1) They can develop a learned physiologic response to a drug and then respond similarly when a placebo is substituted.
    (2) They respond to attention and care from humans.
    (3) Human owners can experience the placebo effect for their pets by perceiving a response where there really is none.
    (4) Since animals can’t talk, we have to interpret an animal’s behavior as indicating relief of pain; this may not always be accurate.
    (5) Both placebos and acupuncture stimulate endorphin production in the brain. The same endorphins are stimulated by just handling an animal – for instance, a horse’s endorphins are raised by trailering.

  31. daedalus2u says:

    apteryx, there certainly is no consensus developing in the literature that placebos cannot affect physiological processes. There are some who are trying to push that, they are not succeeding. The reference I just cited shows instrumentally measured physiological effects due to placebo. That is inconsistent with the hypothesis that there are no physiological effects from placebos.

    Healing is a much more complicated physiological effect than is nausea, and negatively affecting healing has more then a de minimus effect on health and so procedures where the expectation that there will be negative effects on healing cannot be ethically done.

    Regarding placebo effects on animals; I would certainly expect the physiology that causes the placebo effect in humans to have counterparts in non-human animals. How to invoke those effects reliably is a challenge. In mammals where there is substantial maternal care of young, there likely is the equivalent of the mother’s “kiss it and make it better”. In mammals that hunt in packs, there is likely the equivalent of the military leader’s “kill or be killed” pep talk. Subjecting animals to stress causes adverse physiological effects that impair healing, relieving that stress reverses those physiological effects and improves healing.

    Invoking placebo effects in animals by humans would occur most readily in animals that are highly social and which are highly acclimated to humans and attached to humans in social interactions. Dogs that are pets come to mind, as do horses.

    The study just cited in dogs shows (to me) an effect of both treatments. To me it looks like the placebo effect mediated the effects in all the groups.

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