Western medicine researchers are increasingly focusing their attention on the development of drugs from traditional Chinese medicinal herbs. This is frequently achieved by identifying the active ingredients and their pharmacological actions. Yet the scientific evaluation of such herbs sometimes fails to replicate their clinical efficacy. How can this be explained and how can Chinese medicine research be improved?
Although the principle of homeostasis has been a cornerstone of western physiology for more than a century, the enormous complexity of biological systems has often driven pharmaceutical research towards trying to identify and influence single targets that make the difference between health and disease. This approach has yielded many potent drugs, especially for the treatment of acute conditions such as infectious diseases, but also revealed major drawbacks.
In fact, it involves trying to influence a system by interacting with a single protein that is often part of a complex pathway, and involved in a cascade of reactions and feedback loops. The reality is that most diseases are multi-factorial which means that treating a single target provides a partial treatment, and no cure in the majority of cases. In the case of chronic diseases, serious side effects can occur particularly in the long term. Although this awareness is not new, it has been very difficult to find alternative routes given the complexity of the living system, which is almost impossible to reveal.
The therapeutic principles and goals of traditional Chinese medicine (TCM) are different from those in western medicine. In western medicine, drugs are developed to antagonise pathological targets or eliminate pathogenetic factors, whereas in TCM the therapy is aimed at a specific response which reflects changes on multi-system and multi-organ levels. This is an approach unique to TCM that also distinguishes it from most other folk medicines in the world which usually treat symptoms or diseases.
TCM does not focus solely on the disease defined by specific pathological changes, but instead concentrates on the overall functional state of the patient.
In western medicine, a disease is thought to develop as a result of one of more crucial pathogenic factors, whereas in TCM a disease is a common product of both pathogenetic factors and maladjustments in the body. The diagnosis proposed by TCM focuses more on the body’s response to pathogenetic factors than the pathological mechanisms.
The number of potential different stimulants (eg. microorganisms, environmental changes) is enormous but the number of reaction types elicited by the body (eg. fever, cough) is limited. The absence of knowledge about the pathological changes that occur inside the body does not hinder diagnosis by TCM. In TCM diagnosis, all of the visible signs and symptoms of patients are analysed to identify the type of internal maladjustments. This systematic classification of functional states, or patterns of disharmony, is called syndrome differentiation and forms the foundation of all TCM diagnosis and treatment.
Because the ‘target’ of TCM treatment is the pattern that reflects multi-system changes, benefits produced by herbal medication include not only the regulation of several crucial targets but, more importantly, the modulation of other associated general changes that delay the healing process. The huge number of active ingredients in one formula makes it suitable for multi-target actions. For example, TCM heat-clearing herbs are often used to treat infection but their pharmacological mechanisms are not limited to antibiotic actions.
Microorganisms are not the only important factors involved in infection. In addition to the presence of fever and local inflammation and infection, toxins and their induced cytokines and mediators such as interleukin 1 and histamine can excite the CNS and sympathetic-adrenomedullary system, increase the levels of metabolites of proteins and sugars and capillary permeability, and cause the dysfunction of blood coagulation and the digestive system.
In turn, these effects could do harm to the body, such as inhibit immune function and cause arteriolar constriction, leading to a disturbance of the microcirculation. Antibiotics alone would not be able to solve all these problems.
In another example, TCM cold-dissipating herbs can promote thermogenesis and diaphoresis, dilate constricted superficial blood vessels, and even excite the HPA axis. Thermogenesis helps the body to stimulate the defense system: dilation of blood vessels and sweating can increase heat loss to keep the body’s temperature balanced. These herbs do not aim to inhibit the thermogenic centre or kill the pathogens, although they might contain some anti-organism ingredients. No medicine could be more efficient than improving the self-healing mechanism of the body, which are formed during evolution.
Except in the presence of a genetic defect in self-regulation, drugs should not be designed to replace or interfere with the self-healing process of the body. The role of the drug in TCM is merely to either improve the body’s regulatory mechanisms or remove factors that impair the self-healing ability of the body. It should also be pointed out that chemical compounds such as those used in ‘cocktail’ therapies for AIDS, although multi-targeted, are conceptually and methodologically different from TCM therapy because their design is still based on internal pathological targets and not the general response of the body.
Although different diseases have common pathological mechanisms, the mechanism of one disease might not be identical in different people. Another aspect challenging the validation of the efficacy of herbal medicine is individualised therapy.
Individualised therapy in TCM originated from the ancient physicians’ concern with constitutional differences and different reactions to one pathogenetic factor among individuals. Even when treating the same pathological change (eg. myocardial ischemia), TCM practitioners still give individualised therapy based on the symptoms and the patient’s constitution. The different mechanisms that cause ischemia validate the scientific basis of such individualised treatment.
Preliminary work supports the viewpoint that the efficacy and toxicity of herbs are associated with syndromes in TCM (ie, pharmacokinetics of a formula correlated with the specific pattern). The idea behind pattern-based individualised medication is in accordance with the future point that pharmacogenetics hopes to reach.
The western pharmaceutical industry often tends to approach Chinese medicine from a non-holistic perspective, by searching for single bioactive compounds. This is the standard approach used for exploring natural products. However, this approach for bioactivity screening removes the important basis of multiple component intervention, including synergy, being the basis of TCM’s holistic approach.
Synergy is an aspect that will be lost in a target driven, single lead discovery programme with TCM. For example, the US National Cancer Institute and US Department of Agriculture screened 35,000 samples from different tissues from 12,000 plant species and only three new drugs were discovered. Nevertheless, the ancient Oriental pharmacopoeias contain thousands of therapeutic formulations, indicating that the biological activity of these preparations might result from the synergy of active compounds rather than from a single chemical entity.
For example, the antimicrobial activity of the alkaloid berberine is 100 times enhanced by 5′ MHC, a compound found in the same plant as the alkaloid but has no antimicrobial effect itself.
Even the antiproliferative activity of pomegranate juice extract is enhanced by both peel and seed extracts.
Another example from nature comes from the traditional use of bark of Salix to treat pain and headaches. Interestingly, acetylsalicylate (aspirin) is not found in the bark. The bark contains salicin which is hydrolysed to saligenin and finally oxidised to yield salicylic acid in the gut. The medicinal plant itself doesn’t contain an active compound in this case, but a pro-drug, which would be very unlikely to be selected by conventional screening methods.
The nascent use of systems biology and metabolomics can study the effect of complex mixtures such as those used in traditional Chinese medicines as well as the foods we eat. It offers a more holistic approach to the study of complex biological systems such as plants and humans which cannot be adequately described by a reductionist approach. These techniques are promising but also represent one of the most complex challenges today in life sciences research.
In TCM more than 80% of the constituents of preparations are derived from plants. Like any other organism, plants are constantly interacting with their changing, and often harsh, environment during the several phases of their life cycle. Many plant secondary metabolites have biological effects because these compounds confer many benefits to the plant such as chemical protection against invading pathogens and predators, or the attraction of pollinators. Plants can make several thousands of these secondary metabolites. This has resulted in a natural treasure house with highly diverse and often very potent compounds with a wide diversity of application in human health. It is also a strong argument for the protection of the biodiversity of our natural environment, upon which we depend for our health and our medicines.
Plants must also be regarded as living systems and not merely a collection of compounds to be harvested and extracted.
The production of plant secondary metabolites is highly dynamic and responsive to their environment. For example, harvesting ginkgo leaves after a light period dramatically increases both the ginkgolide and bilobalide content. Not only the quantity but also the qualitative composition of the secondary metabolites is affected by the time of harvesting.
In many studies of the activity of medicinal plants, and in particular clinical studies, the plant material was not properly defined, making the results very doubtful and difficult to evaluate. Researchers studying plant metabolites would be well rewarded with the additional study of plants themselves.
China’s experience has shown that methodologically it is not appropriate to apply reductionism to TCM research.
It may be relatively cheap and convenient to trial single herbs and their active constituents, but we can now understand why the result will fall short of the true potential and efficacy of TCM.
It is evident that as western medicine begins to explore the benefits of complementary medicines such as TCM, it must also take the further step of learning the therapeutic wisdom with which to understand its methodology and evaluate its efficacy. All life belongs to a system and we will never truly understand it unless we begin to study the sum of the parts.
Ed: a large part of this article is paraphrased from the excellent paper by Wen-Yue Jiang. We encourage interested readers to pursue the original article referenced below which contains even more detail.
Jiang WY. Therapeutic wisdom in traditional Chinese medicine: a perspective from modern science. Trends in Pharmacological Sciences. 2005:26(11);558-563. [PDF]
Wang M, Lamers R-JAN, Korthout HAAJ, van Nesselrooij JHJ, Witkamp RF, van der Heijden R, Voshol PJ, Havekes LM, Verpoorte R, van der Greef J. Metabolomics in the context of systems biology: bridging traditional Chinese medicine and molecular pharmacology. Phytotherapy Research. 2005:19;173–182. doi: 10.1002/ptr.1624 [PDF]