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The challenge of rational medicine’s journey from patient- to pathogen-specific

Recently, the New England Journal of Medicine (NEJM) released their 200th anniversary article titled, “Therapeutic Evolution and the Challenge of Rational Medicine,” by Greene et al. [1].  This article gives us a walkthrough of how medicine has evolved in the past 200 years: specifically, from patient-centered in approximately the first century and a half, to pathogen-centered in the last fifty or so years. Traditionally, western doctors had an in-depth knowledge of herbs — and a wide range of (often bizarre) treatments, ranging from the application of the “Devil’s dung” plant to the practice of bloodletting, i.e. “breathing a vein,” to assist in the curing of a disease. While some of these treatments are arguably questionable, specifically the well-versed knowledge of traditional western doctors focused more on the human perspective, and, as a result, may have been a vital ingredient to the overall well-being of the patient. This component appears lost today — where our healers are efficaciously oriented toward targeting a specific pathogen, with very specific aims. This compartmentalization of focus (generating doctors with specific knowledge about specific subjects) leaves patients with any other possible ailments or concerns to hang in the dark. While the light of the brilliant doctor who shines in his specific field of focus may isolate and treat the primary cause of a disease, the flashlight he is shining with on the patient may just as well blind the patient to any other factors just as important that could improve general well-being. The flashlight will of course cast shadows of its own. As the article in NEJM subtly points out, there can be no medicine without both therapeutic enthusiasm and therapeutic skepticism, and skepticism has flourished in the rationale of science ever since the chilling specter emerged from medicines such as thalidomide, Diethylstilbestrol, Vioxx, and Avandia [ibid]. These drugs were developed for specific purposes, i.e. to prevent morning tiredness, to act as an antidiabetic, etc., and while the focus of developing these drugs may have been done through well intention, the outcomes clearly revealed something menacing lurking in the shadows.

“As the locus of disease has narrowed from the afflicted person to the molecular mechanism, and the target of magic bullets has followed suit, physicians have faced regular reminders of the limits of the reductionist approach.” [1]

As we have been endlessly discovering smaller and smaller particles; and smaller and smaller actions that lead to larger reactions, one might wonder if this approach is the best to solely focus on. What may be an additional approach more fitting for our new century?  The Shanghai Center for Systems Biomedicine has released an interesting article titled, “Toward new drugs for the human and non-human cells in people,” by Zhao et al. [2]. This explores the realization that the human body is only sparsely comprised of actual “human” cells. There is in fact a multitude of lifeforms that live within us and work in synergy with our body. For example, our metabolism is aided by lifeforms such as veillonella, bifidobacteria, and lactobacilli. Zhao et al. explain that humans are “superorganisms” due to the fact that we are 10% human cells and 90% microbes (primarily in the intestines).

“‘Super'” in that sense means ‘above and beyond.’ Scientists thus are viewing people as vast ecosystems in which human, bacterial, fungal and other cells interact with each another.” [2]

Therefore, when microbes significantly affect our genetic actions and reactions through gene regulation; i.e. on and off switching, this directly affects our immune response — and thus affects how diseases or disorders manifest. Due to this complexity, scientists realize how the reductionist approach can certainly fail — as all individuals will have a different response to treatment. We are complex beings and thus require complex interventions, and that certainly does not mean we should delve further to find even smaller particles or specialize ourselves even more. We should, on the contrary, seek a more holistic approach. For example, our own nutrition, diets, medications, mental state and physical activity (or lack thereof) completely affect the manifestation of our microbe populations within our bodies — and thus completely affect which genes are expressed and which are not. There is nature just as much as there is nurture.  The so called “functional metagenomics” proposed by Zhao et al. [2] for developing new medicines that affect our microbes (and I say “our” for simplicity, because these organisms work together with us) are showing promise through traditional Chinese medicine  (TCM) — an archaic yet thriving art of medicine that continues to prosper and grow in popularity even among the general scientific community as time passes. In the case of gene-environment reactions, most chronic conditions are involved. Here, Zhao et al. claim the gut microbiome is vital and TCM is tailored to target both the host as well as the synergistic microbes — thus being a holistic medicine, as treatments are not specifically tailored such as the conventional drug approach, which targets in an isolated fashion typical receptors within the “druggable genome.”

It appears that for the next age — moving on from an efficacious, isolated approach in primary care — we are not going back to a patient-centered approach which began in traditional western rational science, but rather a “super organismic” track that attempts to integrate as many human and non-human factors as possible.


1. Jeremy A. Greene, M.D., Ph.D., David S. Jones, M.D., Ph.D., and Scott H. Podolsky. M.D. Therapeutic Evolution and the Challenge of Rational Medicine. N Engl J Med 2012; 367:1077-1082. September 20, 2012. DOI: 10.1056/NEJMp1113570

2. Zhao L, Nicholson JK, Lu A, Wang Z, Tang H, Holmes E, Shen J, Zhang X, Li JV,  Lindon JC. Targeting the human genome-microbiome axis for drug discovery: inspirations from global systems biology and traditional Chinese medicine. J Proteome Res. 2012 Jul 6;11(7):3509-19. Epub 2012 Jun 5.