The Gerson Institute of Ayurvedic Medicine

Scott Gerson, M.D., Ph.D. (Ayurveda) Medical Director, Jupiter Medical Center Dept. of Integrative Medicine Division of Education and Research

Jupiter Medical Center at The Calcagnini Center for Mindfulness
1210 S. Old Dixie Highway, Jupiter, Florida 33458, Suite M-117.2

 

Lake Mary Clinic and Panchakarma Facility: at 635 Primera Blvd. Lake Mary, Florida 32746

 

 Telephone: (561) 263-MIND (6463); option #2 or (561) 510-3833

Using Systems Biology and Pharmacoayugenomics to Re-Design Ayurvedic Research in the Twenty-First Century

Ayurveda is a holistic system of healthcare that utilizes multiple interacting therapies and interventions which are individualized and uniquely designed for each person. Precisely because Ayurvedic therapies are not standardized and depend on multi-component interactions and synergies, the randomized clinical trial (RCT)—which is the gold standard of modern medicine—is an inappropriate tool to evaluate Ayurvedic treatments. Recently, within Ayurvedic research circles efforts are being made to develop a research approach which accounts for the interaction between the various Ayurvedic treatment components without sacrificing scientific rigor. This trend involves assessments of the Ayurvedic treatment of specific diseases which focuses on a more comprehensive outcome rather than on the specific effects of isolated elements. These new “system” studies recognize the dynamic connection between the individual and the environment and, further, understand that a system can acquire new properties which are independent and unpredictable from knowledge of the individual elements.

Similarly, to correctly evaluate Ayurvedic medicines, we need to redesign the reductionist way in which they are currently studied. The same” systems approach” which is being applied to disease outcome is now also starting to be used to evaluate Ayurvedic herbal and herbomineral medicinal substances. Just as an Ayurvedic treatment protocol consists of multiple interacting elements, even the simplest Ayurvedic medicine—the root of Ashwagandha—consists of more than three hundred biologically active molecules which constitute a “system”.

Western medicine depends on science to create and assess therapeutic substances—mainly drugs— at the molecular level, where they are viewed as isolated molecules. In India and throughout Asia, while scientific method is certainly respected, equal respect is given to the art of healing. Both art and science should cooperate to help eradicate illness and relieve suffering.

In addition, Western medicine arrives at their diagnoses through the processes of "lumping and splitting". What this means is that initially Western doctors try to identify similarities among various condition and then proceed to "lump" them all together under a common name, i.e. hypertension, diabetes, ulcerative colitis, etc. The other approach involves the "splitting" of a condition into different types. For example, under schizophrenia, we find the diagnostic subcategories of paranoid, delusional, catatonic, schizoaffective, childhood, and others. Ayurveda finds neither of these approaches acceptable and instead recognizes that the art of medicine begins with the appreciation that any condition occurring in a specific individual is a unique condition which defies categorization.

The art of medicine is reflected in the way that Ayurvedic physicians arrive at a diagnosis. Drawing simultaneously upon both rational and intuitive knowledge, vaidyas identify multiple signs and symptoms across the whole spectrum of body and mind and then consider them as a constellation or pattern that is unique to each person. Prescription, therapy and dosage are tailored to each patient and initial treatments are often modified as the course of treatment progresses. Such complexity and variability has been difficult, if not impossible, to assess through the current standard method of placebo-controlled randomized controlled clinical trials (RCTs). Therefore, there is an urgent need to design a form of rigorous yet appropriate clinical trial that can assess the safety and efficacy of traditional Ayurvedic medicines, while respecting inter-individual uniqueness and variability.

RCTs are the gold standard for assessing new medicines. Within an RCT, a person will be randomly assigned to a group that receives one of the treatment options or a placebo. Typically, each group should contain the same distribution of relevant demographics, such as age, sex and ethnicity, among others.

RCTs can be classified into two subtypes depending on what they seek to prove. Explanatory RCTs (ERCTs) are primarily used to evaluate the efficacy of a pharmaceutical drug or medicinal herb under highly controlled conditions that do not necessarily reflect real life ( i.e., does the herb lower cholesterol?). Pragmatic RCTs (PRCTs) assess the effectiveness of a treatment in real-life everyday situations, meaning that a less-than-strict adherence to the treatment regimen is acceptable. Besides that difference, both subtypes of RCT share the same basic methods: randomization of subjects into treatment and control groups; blinding all participants as to which group subjects are in; the need for follow up; and accounting for drop-outs and withdrawals. ERCTs can produce more precise assessments of a pharmaceutical agent, although the trial design often deviates significantly from daily routine. PRCTs, on the other hand, generate weaker evidence but better reflect the practical circumstances of patients as they go about their daily lives (i.e. does the herb lower cholesterol when an individual eats, works, exercises, lives in his usual manner).The conclusions reached from any RCT applies to an “average patient” that does not truly exist. Designing a trial which assumes average patients with identical genotypes leads to erroneous conclusions for tailoring treatment for a given individual. Without prior consideration of the underlying genetics, patients in a particular trial group might receive a drug that is ineffective for their genotype — or worse still, dangerous. Now that we know that a person's genetic variation affects response to treatment, science must adapt and abort the “one-size-fits-all” study design.

Knowledge that dysregulated genes and proteins underlie the pathogenesis of many diseases has led to the development of pharmacogenomics: targeted molecular or genotype-based therapies that improve treatment and reduce adverse effects. As relates to Ayurvedic medicines I have coined the term “pharmacoayugenomics”. However, RCTs have failed to evolve at the same pace as the emerging understanding of individual pharmacogenomics. For example, osteoporosis is the most common metabolic bone disorder worldwide. At least 15 genes (e.g., ESR1, LRP5, SOST, OPG, RANK and RANKL) have been confirmed as osteoporosis susceptibility genes, and another 30 have been highlighted as promising susceptibility genes.

Estrogen-replacement therapy (EST) represents one of the therapeutic options for osteoporosis in postmenopausal women. The Women's Health Initiative RCT has shown that the daily use of oral conjugated equine estrogens (0.625 mg) with or without medroxyprogesterone acetate (2.5 mg) significantly reduces the postmenopausal risk of fracture in all skeletal sites. However, not all subjects respond to ERT with equal efficiency, many very poorly, and some 8% are non-responders. Estrogen functions through binding of two different estrogen receptors (ESRs), ESR1 and ESR2, with ESR1 being more important in bone. People who are homozygous for an inactivating mutation in the ESR1 gene exhibit severe estrogen resistance. Multiple large-scale studies have firmly established that ESR1 is a true osteoporosis gene. No amount of estrogen replacement will correct or prevent osteoporosis in individuals with dysfunctional ESR1. Yet doctors persist in prescribing EST for women regardless of the high percentage of treatment failures. However, new treatment options are now emerging which take into account individuals with this particular genotype. The principles noted here are a good example of modern personalized medicine.

Personalized medicine emphasizes the individualization of healthcare, with interventions being adapted to each individual. Genetic, metabolic and other personal idiosyncrasies are used to optimize every patient's promotive, preventive and therapeutic regimen. Traditionally, western medicine has only considered (usually in a marginalized way) a patient's family history, social circumstances, environment and behaviors in tailoring individual care. The physician’s thought process generally focuses on “what drug to give for what disease”.

Until now, Western medicine has based its standards of care on studies of large cohorts. However, large cohort studies do not take into account the genetic variability of individuals within a population. Personalized medicine is trying to find an objective basis for recognizing such individual differences. Recently-developed methods of high-throughput screening allow researchers to rapidly conduct literally millions of chemical, genetic or pharmacological tests. This process permits rapid identification of active compounds, antibodies or genes which modulate a particular biomolecular pathway. This data is being used by pharmaceutical companies as starting points for new drug design aimed at a particular isolated biochemical process. However, a much more intriguing use of high-throughput cellular data is its use to provide a platform for better understanding multi-site cellular networks related to immune-mediated, infectious and inflammatory diseases.

Similarities Between Personalized Medicine and Ayurvedic Medicine

Integrating the principles of personalized medicine into RCTs leads to personalized explanatory RCTs (PERCTs) and personalized pragmatic RCTs (PPRCTs). These types of trials select patients according to their genotype, rather than the normal methods based on shared clinical diagnostic and biological characteristics. Moreover, this concept of personalized medicine has similarities with the individualized diagnostic and treatment methods of traditional Ayurvedic medicine which bases treatments on individual constitutional type (prakriti), the status of one’s metabolism (agni) and many other individualized considerations. Therefore, it is reasonable to assume that any clinical trial designed for personalized medicine should be adaptable for testing Ayurvedic medicine protocols.

The diagnostic principles of Ayurvedic and Western medicine can be bridged by systems biology, which is a trend in biomedical research to examine complex systems in their entirety, rather than take a more traditional reductionist, molecular viewpoint. An emerging concept in the scientific literature describes an ability to adapt and self-manage in the face of social, physical and emotional challenges. This concept of health has been highly developed in Ayurvedic medicine which further includes spiritual insight in its definition of health.

Systems Biology

In recent decades, the Western reductionist target-oriented medical model has experienced more and more failures. In particular, the once unassailable concept of “one disease -one target” is faltering. We are in the beginning of a paradigm shift towards more personalized medicine tailored to individual patients, including the use of multiple therapeutic agents and the consideration of genomic, nutritional, psychological and lifestyle factors when deciding the best course of treatment. This shift in strategy has been most obvious in the prevention and management of chronic diseases such as diabetes, autoimmune and cardiovascular disease. The rational foundation for such a transition in medical practice can be seen in systems biology.

Systems science aims to understand both the connectivity and interdependency of individual components within a dynamic and non-linear system, as well as the properties that emerge at certain organizational levels. The relation to quantum mechanics is clear. While you don't need quantum mechanics to figure out the structure of plant chemicals, gene regulation, or protein folding, or what a protein does in a cell, you may need it to fully understand how it does it. Photosynthesis, for instance, involves absorption of light by matter - which is a quantum mechanical process, and gene regulation involves events like the transfer of electrons, which is also a quantum mechanical process. The more you “zoom in”, the more quantum mechanical Life becomes but once you “zoom out” and reach the “biochemical” realm, quantum mechanical effects are no longer evident or required.

Systems biology is particularly useful when it comes to describing homeostasis — the regulation of a system's internal milieu to maintain a stable condition. This echoes the central theme of Ayurveda: to maintain the unique balanced state of the tridosha in each individual before disease occurs. However, Ayurveda also recognizes that stability is not always maintained and sometimes progresses beyond the preliminary stages of samprapti (i.e., sanchaya, prakopa, prasara).

In this case, the ability to cope with more dramatically changing environments and greater stress is encompassed in the modern principle of allostasis — the physiological or behavioral changes required to achieve stability in a biological system which has been disrupted.

Systems biology can also provide insight into the multi-target pharmacology of herbal formulae. Deocaris, Widodo, Wadhwa, Gerson, et. al. demonstrated that interaction between components of the crude leaf extract of Ashwagandha (Withania somnifera, Dunal.) lead to a greater synergy of cell killing effects than any of its five individual active components (withanone, withaferin A, and three uncharacterized fractions). The network-web map showed that the crude extract from LASH occupied the central “hub” position interconnecting all the pathways representing its individual components. How the crude herbal extract does this should help researchers pinpoint novel ways to treat metabolic disorders, immune and degenerative diseases, and even cancers.

Figure 1. A Flock of Starlings behave as a system.

 

A flock of starlings relying on connectivity, dynamics and communication, elegantly embodies the features inherent in Ayurvedic medicine. Herding behavior seen in many species is another fascinating example. Just as the plight of one single bird does not accurately represent the direction or status of the flock, the activity of one biochemical value does not represent the health of the human being.

The concepts and practices of systems biology align very closely with those of Ayurvedic medicine. Ayurveda views human beings using concepts based on the relationship between many physical and mental characteristics, signs and symptoms, obtained through questioning, listening, palpation, visual inspection, smelling and even tasting. In addition, there is a significant intuitive component to diagnosis. In contrast, Western medicine has mainly used single biomarkers to describe disease states, for example diagnosing type 2 diabetes by measuring glucose levels. But there is a growing realization in the West that single biomarkers are not enough. A better approach is to look at patterns of biomarker responses to a challenge. These data will provide insight into the resilience of allostatic mechanisms, and hence into a person's health, an approach not unlike the tenets of Ayurveda.

In addition to giving Western medicine a basis for adopting some concepts of Ayurveda, systems biology is also pushing the convergence from the other direction. Increasingly, Ayurveda uses modern biochemical measurements and tools to refine or augment diagnostic descriptions. This is starting to facilitate the translation of Ayurvedic concepts into Western concepts based on biochemical, pathway or regulatory processes.

Ayurvedic researchers are also beginning to connect Ayurvedic diagnoses and treatments with genomic signatures which may eventually be applied in PERCTs and PPRCTs.

Guggul (Commiphora mukul), an extract from the resin-producing Guggul tree, has been used for thousands of years by Ayurveda doctors in India to treat obesity and high cholesterol levels, but a recent PRCT of the guggul extract “guggulipid” at the University of Pennsylvania[1] failed to confirm its efficacy. “Guggulipid” used in this study was a purified form of guggulsterone, an isolated molecule purported to be the active principle. While there was an overall improvement of LDL-C (low density lipoprotein-cholesterol) /HDL-C (high-density lipoprotein-cholesterol) ratio in 18% of participants, neither the standard dose nor a high dose of standardized guggulipid showed any beneficial effects for 82%. The majority of participants were Caucasian. In fact, guggulipid increased levels of directly measured LDL-C by significant amounts and tended to depress levels of HDL-C. The 18% positive response rate to guggulipid was significantly lower than what has previously been described in Indian populations, in whom the response rate ranges from 60 percent to 80 percent. Not only was guggulipid ineffective in lowering cholesterol levels, it seemed to cause a hypersensitivity in a subset of patients. Unfortunately, critics used this study to further invalidate Ayurveda as a viable health care system. Constructive critics of the study pointed out several methodological errors including: (i) the use of a purified extract instead of the crude guggul resin, (ii) the guggul resin must be aged to achieve efficacy, (iii) guggul resin is always traditionally compounded with other plant materials and rarely used alone, (iv) the guggul resin was not processed in the prescribed manner to remove impurities.

However, the most important take-away message from this ill-conceived study, is that not all hypercholesterolemic individuals have the same genomic profile at the root of their condition. Guggul confers its benefits at a specific set of as yet undetermined genomic and epigenomic loci, including as an antagonist of the farnesoid X receptor--a nuclear hormone receptor that regulates the conversion of cholesterol to bile acids; bile acid synthesis plays a critical role in the maintenance of human cholesterol homeostasis. FXR antagonism causes up-regulation of cholesterol 7α-hydroxylase and a reduction in cholesterol as it’s converted into bile acid. FXR is expressed from a single gene locus in humans (chromosome 12q23.1). Internal splicing causes FXR to be expressed as 4 different isoforms that are not equivalent in term of gene transactivation and eventual biologic activity. Therefore, even optimally prepared guggul given under the best conditions will not be effective in correcting dyslipidemia in many individuals. It is also worth noting that treatment of this type of hypercholesterolemia with statin drug (HMG-CoA reductase inhibitors) will not alleviate elevated serum cholesterol which is due to a defect in hepatic conversion of cholesterol into bile acids.

Molecular structure of Guggulsterone

pregna-4,17-diene-3,16-dione

Also known as: Guggulsterone, Guggulsterones Z, (Z)-Guggulsterone, Z-Guggulsterone, E-Guggulsterone Molecular Formula: C21H28O2 Molecular Weight: 312.44582

Another example of systems biology is a study conducted at the SU BioMedicine, Utrechtseweg, Netherlands in Zeist, the Netherlands, that attempts to unify Eastern and Western diagnostic principles. Rheumatoid arthritis patients, selected according to American College of Rheumatology criteria, were subsequently categorized by experienced Traditional Chinese Medicine physicians into either 'heat' or 'cold' patterns — based on their own criteria: joint appearance and qualities, level and features of pain, response to weather, accompanying symptoms (i.e. fever, thirst, nocturia, dizziness) and tongue and pulse interpretation. A systems biology investigation of the two groups found statistically significant differences between them in the expression of genes related to apoptosis and metabolite profiles[2]. In the RA Heat group caspase 8 activated apoptosis seems to be stimulated while in the RA Cold group apoptosis seems to be suppressed through the Nrf2 pathway.

For Ayurvedic approaches to become integrated into modern medicine, we need to consider alternative inclusion and exclusion criteria and designs for RCTs. We also need to review how outcomes are assessed. Both Western-style modern allopathic medicine and authentic holistic Ayurvedic medicine aim to restore—as well as prevent and maintain—patients to health and can be developed together into an integrated form of personalized medicine. Systems biology is a paradigm to understand the integration of all levels of biological organization from molecules to the biosphere. Such a non-reductionist perspective captures the uniqueness and complexity of herbal action within a living cell. Redesigning clinical trials with a systems biology methodology will accelerate the blending of allopathic and Ayurvedic healing, for the benefit of humankind.



[1]Szapary, SO, Wolfe, ML, et. al., Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial, JAMA, 2003 Aug 13; 290(6):765-72.

 

[2] van Wietmarschen, H. et al. J. Clin. Rheumatol. 15, 330337 (2009).