Applying systems biology to validate prescientific quackery is tooth fairy science

Although I did not coin it, I frequently use the term “quackademic medicine” because, unfortunately, there’s a lot of quackademic medicine around. Although regular readers know what the term means, i always feel obligated to briefly explain what quackademic medicine is, for the benefit of any newbie who might happen upon this blog. Basically, it is a term used to describe an increasingly common and alarming phenomenon, the infiltration of rank quackery and pseudoscience into medical academia. You might think it impossible or unbelievable, but it’s anything but. Beginning around a quarter of a century ago, alternative medicine started finding its way into medical schools and academic medical centers, first in the form of “complementary and alternative medicine” (CAM) and then later renamed “integrative medicine.” The intent of renaming it “integrative medicine” was to portray the idea of “integrating” the “best of both worlds” (alternative medicine and conventional medicine) as though they were equals, but in reality all integrative medicine does is to integrate quackery with real medicine; that is, when it isn’t busy co-opting perfectly science-based modalities, such as exercise, nutrition, and lifestyle changes, as somehow being “alternative” and “integrated” into medicine.

One of the most pernicious effects of quackademic medicine is not just how it places the imprimatur of real medicine on sheer quackery like acupuncture, much of traditional Chinese medicine (TCM), reflexology, naturopathy, homeopathy, and the like. That’s bad enough. What’s just as bad, though, is how it distorts research, wastes money, and encourages research into treatments that are so implausible that it is unethical to subject man or beast to them in the name of science. I’ve listed many examples before, the first example coming to mind being the clinical trials of homeopathy for infectious childhood diarrhea in Third World countries, acupuncture for menopausal hot flashes, or acupuncture for in vitro fertilization. Then there are the many experiments subjecting rodents to various quackery, such as this one torturing rats in the name of pseudoscience by shocking them with electroacupuncture.

A while ago, I noted that the open access journal, PLoS One seemed to have a penchant for publishing horrible studies of quackery, such as one purporting to identify anatomic correlates of acupuncture meridians and functional MRI (fMRI) studies of laser acupuncture. Of course, it’s not just PLoS one, but a lot of journals, even journals within the Nature stable of journals, such as Scientific Reports. I’m referring to an article that its authors, Sun et al, entitled To Unveil the Molecular Mechanisms of Qi and Blood through Systems Biology-Based Investigation into Si-Jun-Zi-Tang and Si-Wu-Tang formulae. It might better have been entitled Disguising pharmacognosy research using crude plant extracts as evidence for qi and the five element theory of medicine.

Basically, this study uses various bioinformatics databases of compounds and their molecular targets in the cell, does a bunch of analyses that use the known effects of various ingredients in the TCM compounds to predict what molecular signaling pathways they affect. They used TCMID Cytoscape thusly:

Since the TCM formulae are normally composed of several medicinal herbs, and each herb normally has many ingredients, and each ingredient has a lot of targets, a formula is a complex biologic active network. Fortunately, along with the rapid development of life science and computer science, a variety of computational tools and bioinformatic database have been developed to facilitate the analysis of a large number of genes associated with complex ingredients of TCM formulae2, which provide opportunities to predict potential pharmacological actions of TCM formulae and clarify complex molecular mechanisms of formulae and theories of TCM. Based on primary biomolecular databases, e.g. Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www.kegg.jp)3, HPRD4, PDB5, TTD6, OMIM7, Drug-Bank8, STITCH9 and ChEMBL10, a lot of TCM-related databases have been developed, such as TCMID11, HIT12, TCM Database@Taiwan13, TCMGeneDIT14, TCM-ID15, TCMSP16 and CHMIS-C17. These TCM-related databases complement each other to provide information on complex interactions of TCM-active ingredient-gene-disease2. Among these TCM-related databases, TCMID (http://www.megabionet.org/tcmid/) contains 3,791 diseases, 47,000 prescriptions, 8,159 herbs, 6,828 drugs, 25,210 compounds and 17,521 related targets, which facilitates the study of interactions between formula, ingredient, gene and disease to uncover the molecular biological mechanisms of TCM. Meanwhile, there are several network analysis tools for biological functionality of TCM-related network analysis, such as Cytoscape18,19. More than 150 specialized plugins integrated in Cytoscape can be used to import and map existing interaction data cataloged in public databases2, such as ClueGO20, BioGrid Plugin21 and MiMI22. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways to create functionally organized GO/pathway term network and analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms.

I’ll translate. Basically, it is now possible to use biomolecular databaes, databases of molecular targets and their interactions with various molecules, and sophisticated bioinformatics tools like Cytoscape to import and map known interaction data from public databases and use network analyses to model and identify likely signaling pathways affected by the molecules. This list can be shaped and narrowed down by other databases cataloguing targets and signaling pathways known to be involved with specific diseases and conditions. All of this has become fairly standard in drug development, both in pharma and academia. It’s basically science.

But what are these sophisticated bioinformatics techniques being used for in this study. Here’s where it goes off the deep end. Now, I frequently refer to studies like this as “tooth fairy science.” It’s a term coined by Harriet Hall to describe science purporting to measure the properties of a phenomenon whose existence has not been established. Basically, you can study how much money the tooth fairy leaves each night, but you haven’t established the existence of the tooth fairy. Similarly, you can study the “effects” of homeopathy, but you haven’t established that homeopathy is anything more than water. Believe it or not, this isn’t tooth fairy science, as you will see. However, it is something almost as bad.

First, take a look at this figure to see how Sun et al set up their experiment (click to embiggen):

Systems biology of TCM

Yes, on the left, there is “Qi deficiency” on the left and “blood deficiency” on the right. Both are TCM diagnoses, not diagnoses that have anything to do with biology or medical reality, given that qi is a term to describe the “life energy.” I sometimes wonder if qi deficiency is caused by excessive use by the alien healing machine in Babylon 5 to heal others (that’s a joke only real Babylon 5 geeks will get). Be that as it may, on the one side, you have a diagnosis based on a prescientific concept of how the body works in an ancient Eastern medical system resembling ancient European humoral theory treated with an herbal remedy called Si-Jun-Zi-Tang (SJZT) based on that same prescientific understanding. On the other side you have a different diagnosis based on a prescientific concept of how the body works in an ancient Eastern medical system resembling ancient European humoral theory treated with another herbal remedy called Si-Wu-Tang (SWT) based on that same prescientific understanding. Each is then run through TCMID Cytoscape to find what is described as an herb-ingredient gene network. The two are compared using ClueGO KEGG analysis of predicted targets of SWT and SJZT. It’s not important that you understand what that is other than that it’s a computer analysis. You then get fancy network analysis charts like this, in which red nodes represent terms of SWT; green nodes represent terms (pathways) of SJZT; grey nodes represent common terms of the two formulae (again, click to embiggen):

A systems biology map of woo masquerading as pharmacognosy. A systems biology map of woo masquerading as pharmacognosy.

It’s not important that you know exactly what this chart means. All it shows is basically how the two herbs affect different signaling pathways. Basically, this is nothing but pharmacognosy (natural products pharmacology) using very “dirty” natural products (raw herbs with active compounds not isolated or otherwise purified). The authors then use this to try to convince you that the pharmacognosy investigations performed in this paper somehow validate the prescientific mystical beliefs of TCM, but only after first trying to convince you that TCM foresaw how modern medicine would work:

Combination therapy is the major feature of TCM, which is increasingly recognized by modern western medicine, such as cocktail therapy for HIV27 and the opinion shifting from targeting a single disease-causing molecule to the pursuit of combination therapies that comprise more than one active ingredient28. According to the symptoms of patients, different kinds of Chinese medicines are combined to form formulae to improve clinical efficacy1. such as SWT and SJZT have been used to rectify blood deficiency and Qi deficiency respectively for about 1,000 years.

This is, of course, utter nonsense. First, it invokes the false dichotomy of “Eastern” versus “Western” medicine. There is no such thing. There is scientific medicine, which knows no “East” or “West.” There is also quackery, which, unfortunately, also knows no “East” or “West.” (After all, homeopathy is “Western” medicine, having been invented, as it was, in Germany by Samuel Hahnemann over 200 years ago.) That’s just a pet peeve of mine, though. Scientific medicine has always used combination therapy, whether antibiotics to try to eliminate an infection before resistance evolves, the many, many multidrug combinations used in the chemotherapy of cancer, or even something as mundane as treating hypertension with more than one drug. There is nothing unusual or new about this. While it is true that scientific medicine did at one time tend to look for single genes that could be targeted, my perception is that the reason that changed was not so much a revelation that those ancient Chinese were right after all but rather as a result of the increasingly sophisticated technology that permits the study of gene networks and changes in the expression of every gene in the genome simultaneously instead of the levels of individual genes. TCM advocates would have you believe that TCM was there first, looking at individuals in a “holistic fashion,” but that’s just nonsense. TCM came by its beliefs because humans didn’t know any better and didn’t have the tools at the time to know better.

I used to call the co-opting of modern genomic techniques as “woo-omics,” to go along with genomics, metabolomics, and all the other “omics” in modern medical science, and TCM is not alone in this. This study is a perfect example of woo-omics or woo systems analysis. It’s perfectly fine as pharmacognosy, although most scientists in drug development would not be too thrilled with the use of crude extracts, but it is no evidence that the precepts of TCM have anything to do with reality. None of this stops the authors from arguing just that:

Blood deficiency normally manifests anaemia, vertigo, heart palpitations and menstrual discomfort. The SWT formula has effects on stimulating hematopoiesis in bone marrow, anti-coagulant, vasodilatation and sedative, so it can be used to treat anemia, bone formation dysmenorrhea and other estrogen-related diseases. Qi deficiency normally manifests lack of strength, body function decline and decreased disease resistance, and so on. The SZJT formula has effects on regulating granulocyte macrophage colony-stimulating factor secretion, enhancing phagocytosis of macrophages, recovering cAMP signal pathway and recovery of intestinal microflora. However, the mechanisms of the pharmacological action of SWT and SJZT have not yet been clarified.

And:

In conclusion, SWT with the functions of influencing amino acid and carbohydrate metabolism is significant different from SJZT with the actions of influencing neuroendocrine system by affecting excitatory synapses (serotonergic synapse) to regulate thyroid hormone, ovarian steroidogenesis, prolactin and oxytocin secrction and can regulate corrective hormones secretion and promoting vascular smooth muscle contraction. The common effects of SWT and SJZT are regulating the functional activities of the hypothalamic pituitary adrenal and gonadal axis by affect inhibitory synapses (GABAergic synapse) to stimulate estrogen and steroid hormones secretion and strengthening the ability of anti-infection. All the differences and common pathways also reflect the characteristics of blood deficiency and Qi deficiency, and the molecular mechanism of blood and Qi of TCM.

Molecular mechanism. You keep using that term. I do not think it means what you think it means.

Seriously, their argument boils down to being able to vaguely relate some of the molecular pathways apparently affected by SWT and SJZT to the TCM diagnoses of qi deficiency and blood deficiency and using that vague relation to claim that the precepts of TCM are valid and that this study has provided evidence in support of those precepts. This is a feature, not a bug, of studies like this, and this is not the first such study. Not by a long shot.

Hmmm. Maybe I was wrong. Maybe this is tooth fairy science, after all. Strike that. There's no "maybe" about it.

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Computer scientists would call this GIGO, as they put in a bunch of nonsense and used computational methods to map it to a different but equally nonsensical realm.

By Chris Hickie (not verified) on 26 Oct 2016 #permalink

Chris@1: Just about every kind of woo is a form of GIGO: you assume that some "theory" of medicine is accurate, regardless of whether there is any evidence or even plausibility for it, and turn the crank to get nonsensical results.

As for the East-West false dichotomy, I suspect that is a literal translation of metaphoric Chinese. The Chinese didn't have a word for the kind of science-based medicine that those foreigners from countries bordering the Great Western Sea (i.e., the Atlantic Ocean) were practicing, so they used the character for "west" (xi) to describe it. Thus the indigenous folk medicine traditions would for contrast be labeled zhong ("Chinese")[1] medicine. Westerners translating from the Chinese would generally not know these nuances, so they would pick up the notion that science-based medicine was "Western" medicine.

[1]This character can also mean "center", which is why China (Zhongguo) is sometimes called the Middle Kingdom.

By Eric Lund (not verified) on 26 Oct 2016 #permalink

Yep, GIGO, Garbage In, Garbage Out.

Yes, I do indeed have an energy metabolism - chemical energy. Glucose and oxygen and all. All of the pins and needles in the world won't adjust any such flow, it might however make that which carries the glucose and oxygen leak out, assuming a large enough gauge was used (as I do have acupuncture needles (got them on a closeout and used them as microwave antenna probes in a basement experiment (which worked very, very well)), suffice it to say, they're a tiny gauge, useless for any valid purpose beyond intercepting microwaves).

As for unrefined herbals, I do know of some drug researchers who did enjoy just that, largely from remote areas and a few actually became marketable drugs or lead directly to a novel marketable drug.
Their challenge, finding what the active compound was, figure out what it was, figure out how it worked, then see if replication would work or perhaps, a modification of the compound would create a superior drug.
Most of the time, the results were... Disappointing.
But, we do have statins for a very good reason, studying the effects of some of the compounds released by some relatively common molds.
The difference between their activities and the woo outlined here, the woo is based upon disproved prescientific nonsense, the latter, upon biochemistry.

As for unrefined herbals, I do know of some drug researchers who did enjoy just that

Not sure if this is what you intended, but it gives me an image of researchers smoking ... something. Which can vary widely in potency: anything from Tampico ditch weed to BC Bud. (Not that I know the difference between them firsthand.)

By Eric Lund (not verified) on 26 Oct 2016 #permalink

""But, we do have statins

But because many red yeast rice supplements did have monacolin, the Food and Drug Administration (FDA) considered them to be drugs. Manufacturers were supposed to remove any red yeast rice products with monacolin from the market. As a result, many of the red yeast rice products you can buy may not contain monacolin. Unfortunately, there is no way to tell whether a product contains moacolin because it is not listed on the label.

http://umm.edu/health/medical/altmed/supplement/red-yeast-rice

Herbs that the FDA deem medicinal are taken away from the people -- Synthetic compounds are derived from them such that, for many, the former relief is put behind an insurmountable prescription and pay wall.

I am sure that there are plenty of dubious articles like this one in respectable journals, but we don't have the woo clue to identify them.

By Daniel Corcos (not verified) on 26 Oct 2016 #permalink

I followed Gilbert's link and found that the author appears to be

Steven D. Ehrlich, NMD, Solutions Acupuncture, a private practice specializing in complementary and alternative medicine, Phoenix, AZ.

Surprise, surprise. A woo practitioner pushes woo. Of course the FDA is not allowed to do what Gilbert (via this link) claims it did as long as red yeast rice is sold as a supplement.

Also of note: two of the alleged references cited on the page are conference presentations from 1999. On a web page with a last revision date of 2015. I can't speak for the medical field generally, but the leading journals in my field tend not to allow citations to unpublished sources--you can get away with a conference presentation in the last year or two because the corresponding paper may not have been published yet, but I'd raise eyebrows at a sixteen-year-old conference presentation, let alone two, on a reference list.

Also, I haven't seen the qualification "NMD" before. By chance, does it stand for "Not a Medical Doctor"?

By Eric Lund (not verified) on 26 Oct 2016 #permalink

'Also, I haven’t seen the qualification “NMD” before. By chance, does it stand for “Not a Medical Doctor”?'
Short answer - yes.
Long answer - Doctor of Naturopathic Medicine, so still yes.

By Derek Freyberg (not verified) on 26 Oct 2016 #permalink

The point of these studies is not to demonstrate that the initial TCM explanation of a formula's mechanism of action is correct; it is to demonstrate that it has conventional bioactivities that can explain benefits demonstrated in clinical trials and human experience. The precursors of Western drugs were considered to work by affecting "humors", which are no more real than qi. We do not declare that allopathy is therefore pre-Scientific and worthless across the board no matter how many clinical trials - and nowadays mechanisms of action - pile up. But your revanchism arises from an effectively religious belief, not a small-r rational one - what evidence would you accept that a formula invented by ancient Chinese physicians was effective? - and so there is nothing that can be said to change your mind. Fortunately, most potential readers can think for themselves.

Of course, we still run into the occasional bright individual who recalls the handful of classes of drugs in use today whose mechanism of action is either unclear or unknown.
The advantage of evidence based medicine is, eventually, the mechanism of action is found and fully documented. That isn't true with woo based medicine, which rely upon non-extant things like the immeasurable Qi, thereby keeping alive the "mystery" that science already solved.

By Wzrd1 (not verified) on 26 Oct 2016 #permalink

In reply to by jane (not verified)

We do not declare that allopathy....

TCM is "allopathic," Jane. Do consult the Rectification of Names.

I can't stand AZ naturoquacks

By Chris Hickie (not verified) on 26 Oct 2016 #permalink

"what evidence would you accept that a formula invented by ancient Chinese physicians was effective?"*

How about reproducible evidence from quality clinical trials?

"But your revanchism arises from an effectively religious belief"

Yet another example of "your science is just religion har har har"

Do come up with something new, jane.

*this reminds me of the old TV ad where the dry cleaner claims his results are due to an "ancient Chinese secret", which of course turns out to be the American Wonder Product he is covertly using.

By Dangerous Bacon (not verified) on 26 Oct 2016 #permalink

I found the layout of that diagram to be reminiscent of the Underpants Gnomes' business plan in "South Park".

By palindrom (not verified) on 26 Oct 2016 #permalink

what evidence would you accept that a formula invented by ancient Chinese physicians was effective?

The same standard that applies for any novel drug: evidence in the form of proper clinical trials that it is safe and effective. At that point it becomes science-based medicine rather than alternative medicine.

This has happened at least once. Last year's Nobel Prize winner in Medicine, building off TCM treatments for malaria, found an active ingredient, artemisinin, which was then shown to be safe and effective as a malaria treatment. But it was laborious work: of the hundreds of potential active ingredients, only one was found to be effective.

As Orac points out in the original post, pharmacognosy can be useful. But it is typically only the first step in identifying potential new drugs. After that comes the hard work of verifying that the drug actually works.

By Eric Lund (not verified) on 26 Oct 2016 #permalink

found an active ingredient, artemisinin, which was then shown to be safe and effective as a malaria treatment.

Great. Wormwood will now become schedule I in due time.

clinical trials of homeopathy for infectious childhood diarrhea in Third World countries,

Maybe I've spent too much time in Third World countries, but this makes me feel stabby.

By shay simmons (not verified) on 26 Oct 2016 #permalink

Great. Wormwood will now become schedule I in due time.

Does this mean absinthe on prescription?

By herr doktor bimler (not verified) on 26 Oct 2016 #permalink

Well, they do say, absinthe makes the fart grow louder, erm, heart grow fonder. My bad. ;)

By Wzrd1 (not verified) on 29 Oct 2016 #permalink

In reply to by herr doktor bimler (not verified)

Jane @9:
The point of these studies is not to demonstrate that the initial TCM explanation of a formula’s mechanism of action is correct

Perhaps this explanation of the study's intention would be better directed to its authors, as they are the ones who are getting it wrong -- e.g. their conclusion that they have demonstrated the validity of TCM categories and curative mechanisms:

the characteristics of blood deficiency and Qi deficiency, and the molecular mechanism of blood and Qi of TCM.

By herr doktor bimler (not verified) on 26 Oct 2016 #permalink

# 18 HDB

Does this mean absinthe on prescription?

No, devil worship. See C.S Lewis and The Screwtape Letters .

However one can buy a goat to sacrifice without a prescription and usually more cheaply. Probably not covered by most insurance plans though.

By jrkrideau (not verified) on 26 Oct 2016 #permalink

@hdb,

Perhaps Demon Srewtape has found a new patient for his nephew to minister to.

Although the target might be too easy to be worth the effort.

By squirrelelite (not verified) on 26 Oct 2016 #permalink

However one can buy a goat to sacrifice without a prescription and usually more cheaply. Probably not covered by most insurance plans though.

Just don't let the ASPCA catch you.

By shay simmons (not verified) on 27 Oct 2016 #permalink

Just don’t let the ASPCA catch you [sacrificing goats]

They can complain all they want to, but if it's a religious ritual, that's all they can do. The Supreme Court held in Church of the Lukumi Babalu Aye v. City of Hialeah that a city ordinance forbidding the "unnecessar[y]" killing of "an animal in a public or private ritual or ceremony not for the primary purpose of food consumption" was unconstitutional. So one can legally practice Santería if one so chooses.

By Eric Lund (not verified) on 27 Oct 2016 #permalink

Got the Babylon 5 reference. That machine lead to the death of my favorite character on the show, but did save my second favorite.

An obscure Babylon 5 reference! Marry me, Orac!*
I can just imagine you standing at the podium, declaring "Who am I? I am (Orac), M. D.... I am the right hand of medicine and the boot that is going to kick your sorry woo-peddling ass all the way back to the fringes, sweetheart! I am science incarnate, and the last academic presenter that you will ever see. God sent me."

*Don't take this proposal seriously, since I am already married, although you are kind of cute.

By Old Rockin' Dave (not verified) on 27 Oct 2016 #permalink

Derek, I have it on good authority (namely my own) that NMD stands for Not Much of a Doctor.
kiiri, I would have to say that Ivanova was tied for best character with Londo Mollari. Least favorite were Delenn, Lennier, and the Minbari in general. Totally insufferable, with all those damned rituals, prophecies, caste boundaries, and what not. Come to think of it, there was a culture with an overload of mystical (insert name of large Minbari draft animal)sh*t going on.

By Old Rockin' Dave (not verified) on 27 Oct 2016 #permalink