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Molecular Cell Biology and Interventional Proteogenomics
 Part Three: New Implications for Naturopathic Medical Education, Clinical Practice and Naturogenomics
By Alex Vasquez, ND, DC, Editor, Naturopathy Digest
AVasquez@NaturopathyDigest.com
Nothing will stop the advancement of genomic medicine, and perhaps nothing should. At its best, genomic medicine simply is the clinical application of genomics and the data and insights gleaned from the rapidly advancing basic science of molecular biology.
What remains to be seen is the extent to which this information is either utilized to advance patient care or the extent to which it's exploited for pharmacoeconomic profitability1 and subsequent indirect and direct suppression of naturopathic medicine and hindrance of patient care.2
Medical journals, medical associations, and the medical profession as a group (minor exceptions noted) can be expected to acquiesce to the dictums of the pharmaceutical industry since this private industry controls much of the research and many of the major medical journals (according to the recent editors of the New England Journal of Medicine,3 British Medical Journal,4 and The Lancet5). The general population of patients is likewise influenced by the pharmaceutical industry via direct-to-consumer advertising, which represents the vast majority of their "health education" in the form of drug advertisements that entice wanton and additive drug consumption.6 As naturopathic physicians are the only doctorate-level clinicians educated to use nutrition, lifestyle and treatment of the underlying problem before turning to drugs, it seems probable that if any "balance" to the clinical application of genomics is to be realized, then it might have to come from the ND perspectives. If this is true, then we must at least consider the following two questions:
- Is there a counterbalancing scientific basis supporting the use of botanical, nutritional and other "naturopathic" interventions for diseases attributed to genomic defects and adverse patterns of gene expression?
- Are naturopathic students in general, and the profession as a whole, aware of and current with the modern state of the art in molecular cell biology,7 which includes the basic science of gene expression and the means by which a potentially healthy geneotype is transformed into a disease-ridden phenotype?
The answer to the first question in general is "yes" but it must be applied on a disease-by-disease and case-by-case basis. Generally, most of our nutritional/botanical/naturopathic therapeutics have an effect on gene expression as part of the mechanism by which their clinical benefits are realized. One important and common example I reviewed previously8 is the downregulation of NF-kappaB activity effected by the use of routine therapeutics such as vitamin D,9 lipoic acid,10 green tea,11 rosemary,12 grape seed extract,13 resveratrol,14 caffeic-acid-phenethyl-ester (CAPE) from bee propolis,15 indole-3-carbinol,16 N-acetyl-L-cysteine,17 selenium18 and zinc.19 The scope and length limitations of this current article prohibit me from adding more examples, but it should suffice to say that the majority of nutrients, botanicals and other natural interventions are effective in small or large part due to their effects on gene expression. This leads us to the second question: Are naturopathic students in general, and the profession as a whole, aware of and current with the modern state of the art in molecular cell biology?
I propose here that, although it should not supersede the importance of clinical outcome studies, the science of molecular biology needs to take a more preeminent role in naturopathic education for the following reasons. First, like it or not, molecular biology will be the language of the next edition of The King's English, published in journals and underwritten by the pharmacomedical consortium. For the sake of interprofessional communication and keeping pace with current and future research literature, NDs need to be fluent not only in the basics of transcription and translation, but in the details of how these processes are effected by spliceosomes and (vitamin-induced) histone modification and modulated by transcription factors, only one of which is NF-kapppaB. Second, for our own sake, in order to have a more complete understanding of the mechanisms by which our treatments work, we need to delve deeper into the science that details these effects. Third, as the naturopathic profession continues to take on larger and more important roles in national health care, it's no longer sufficient to simply say, "It works;" we have to be able to accurately describe mechanisms of effectiveness if we are to be on scientific par with our propharmaceutical counterparts.
Every time you make a dietary recommendation for a patient, you are changing his or her genetic expression and inclination or aversion to disease;20 the modulation of genetic expression via natural/naturopathic interventions, what I have termed "naturogenomics", is inclusive of nutrigenomics21 but differentiated from pharmacogenomics. The recent finding that chronic neuropathic pain changes gene expression22,23 opens the door to new horizons for the chiropractic profession and all of us who use manual, nutritional and botanical medicine in the alleviation of pain and inflammation, but these and other opportunities will only be available to the profession as a whole if the profession as a whole works to integrate this and other data on genetic expression and its modulation into our current research projects, educational standards and clinical protocols. Properly utilized, molecular biology and the insights gleaned from genomic testing hold scientific and clinical and therefore political promise for the naturopathic profession.
References
- See the following citations for examples: Roses AD. 2025: the practice of neurology: back from the future. Arch Neurol 2001 Nov;58(11):1766-7; Angell M. The Truth About the Drug Companies: How They Deceive Us and What to Do About It. Random House; August 2004; Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005 May;2(5):e138. Epub 2005 May 17. Click to view it online; "...despite lush advertisements from companies with obvious vested interests, and authoritative testimonials from biased investigators who presumably believe in their own work to the point of straining credulity and denying common sense... (translate: economic improvement, not biological superiority)." Stevens CW, Glatstein E. Beware the Medical-Industrial Complex. Oncologist 1996;1(4):IV-V. Click to download PDF.
- See the following citations for examples: Wilk CA. Medicine, Monopolies, and Malice: How the Medical Establishment Tried to Destroy Chiropractic. Garden City Park: Avery, 1996; Carter JP. Racketeering in Medicine: The Suppression of Alternatives. Norfolk: Hampton Roads Pub; 1993; Morley J, Rosner AL, Redwood D. A case study of misrepresentation of the scientific literature: recent reviews of chiropractic. J Altern Complement Med. 2001 Feb;7(1):65-78; Micozzi MS. Double standards and double jeopardy for CAM research. J Altern Complement Med. 2001 Feb;7(1):13-4; Terrett AG. Misuse of the literature by medical authors in discussing spinal manipulative therapy injury. J Manipulative Physiol Ther. 1995 May;18(4):203-10.
- Angell M. The Truth about the Drug Companies: How They Deceive Us and What to Do About It. Random House; August 2004.
- Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005 May;2(5):e138. Epub 2005 May 17. Click to view it online.
- Op cit: "Journals have devolved into information laundering operations for the pharmaceutical industry." Horton R. The Dawn of McScience. New York Rev Books. 2004;51(4):7–9. Click to view it online.
- "...many ads may be targeted specifically at women and older viewers. Our findings suggest that Americans who watch average amounts of television may be exposed to more than 30 hours of direct-to-consumer drug advertisements each year, far surpassing their exposure to other forms of health communication." Brownfield ED, Bernhardt JM, Phan JL, Williams MV, Parker RM. Direct-to-consumer drug advertisements on network television: an exploration of quantity, frequency, and placement. J Health Commun. 2004 Nov-Dec;9(6):491-7.
- Cooper and Hausman: The Cell: A Molecular Approach, Fourth Edition. ISBN 9780878932191, www.sinauer.com/detail.php?id=2191. See also www.sinauer.com/cooper/4e/ for samples and animations.
- Vasquez A. Reducing Pain and Inflammation Naturally - Part 4: Nutritional and Botanical Inhibition of NF-kappaB, the Major Intracellular Amplifier of the Inflammatory Cascade. A Practical Clinical Strategy Exemplifying Anti-Inflammatory Nutrigenomics. Nutritional Perspectives 2005; July: 5-12. Click to view it online.
- "1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2-D3), the active metabolite of vitamin D, can inhibit NF-kappaB activity in human MRC-5 fibroblasts, targeting DNA binding of NF-kappaB but not translocation of its subunits p50 and p65." Harant H, Wolff B, Lindley IJ. 1Alpha, 25-dihydroxyvitamin D3 decreases DNA binding of nuclear factor-kappaB in human fibroblasts. FEBS Lett. 1998 Oct 9;436(3):329-34.
- "ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced NF-kappaB activity in these cells in a dose-dependent manner." Lee HA, Hughes DA.Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10.
- "In conclusion, EGCG is an effective inhibitor of IKK activity. This may explain, at least in part, some of the reported anti-inflammatory and anti-cancer effects of green tea." Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ, Varilek GW. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol. 2001 Sep;60(3):528-33.
- "These results suggest that carnosol suppresses the NO production and iNOS gene expression by inhibiting NF-kappaB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action." Lo AH, Liang YC, Lin-Shiau SY, Ho CT, Lin JK. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis. 2002 Jun;23(6):983-91.
- "Constitutive and TNFalpha-induced NF-kappaB DNA binding activity was inhibited by GSE at doses > or =50 microg/ml and treatments for > or =12 h." Dhanalakshmi S, Agarwal R, Agarwal C. Inhibition of NF-kappaB pathway in grape seed extract-induced apoptotic death of human prostate carcinoma DU145 cells. Int J Oncol. 2003 Sep;23(3):721-7.
- "Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappaB and AP-1 and the associated kinases." Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000 Jun 15;164(12):6509-19.
- "Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory component of propolis (honeybee resin). CAPE is reportedly a specific inhibitor of nuclear factor-kappaB (NF-kappaB)." Fitzpatrick LR, Wang J, Le T. Caffeic acid phenethyl ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan polysaccharide-induced colitis in rats. J Pharmacol Exp Ther. 2001 Dec;299(3):915-20.
- Takada Y, Andreeff M, Aggarwal BB. Indole-3-carbinol suppresses NF-{kappa}B and I{kappa}B{alpha} kinase activation causing inhibition of expression of NF-{kappa}B-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood. 2005 Apr 5; [Epub ahead of print].
- Paterson RL, Galley HF, Webster NR. The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis. Crit Care Med. 2003 Nov;31(11):2574-8.
- Faure P, Ramon O, Favier A, Halimi S. Selenium supplementation decreases nuclear factor-kappa B activity in peripheral blood mononuclear cells from type 2 diabetic patients. Eur J Clin Invest. 2004;34(7):475-81.
- Uzzo RG, Leavis P, Hatch W, Gabai VL, Dulin N, Zvartau N, Kolenko VM. Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. Clin Cancer Res. 2002;8(11):3579-83.
- Trujillo E, Davis C, Milner J. Nutrigenomics, proteomics, metabolomics and the practice of dietetics. J Am Diet Assoc. 2006 Mar;106(3):403-13.
- Kaput J, Rodriguez RL. Nutritional genomics: the next frontier in the postgenomic era. Physiol Genomics. 2004 Jan 15;16(2):166-77.
- Rodriguez Parkitna J, et al. Comparison of gene expression profiles in neuropathic and inflammatory pain. J Physiol Pharmacol. 2006 Sep;57(3):401-14.
- Wang H, Sun H, Della Penna K, Benz RJ, Xu J, Gerhold DL, Holder DJ, Koblan KS. Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases. Neuroscience. 2002;114(3):529-46.
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