The Yin and Yang of traditional Chinese and Western medicine

The success of Western Scientific approaches to medicine, over the last 150 years, can be measured by substantial increases in life expectancy, reductions in infant mortality and the virtual elimination of many infectious diseases accompanied by development of effective management practices for noncommunicable diseases. However, major challenges remain in the form of infectious diseases that evolve resistance to pharmaceuticals rapidly, new diseases, particularly those caused by viruses and effective long‐term treatments for chronic, noncommunicable diseases. Traditional Chinese Medicine (TCM) can offer complementary treatments based on personalised interventions, informed by knowledge accumulated from empirical observations gathered over centuries of practice, that address the impact of disease on the whole body.


| INTRODUCTION
Traditional medical practices, particularly Traditional Chinese Medicine (TCM) have often been portrayed as philosophically distinct from Western Scientific Medicine (WSM), fuelled by the absence of hard evidence for efficacy of traditional practices involving the WSM gold standard; randomized, double-blind, placebo-controlled clinical trials. Additionally, western pharmaceutical companies have often declined to develop therapies based on traditional medicines, because of the lack of opportunities for patenting. However, views of TCM as "unreliable, fanciful, false, and irrelevant" 1 were refuted effectively by the award of the Nobel Prize for medicine in 2015 to three scientists for identifying natural products for treatment of human diseases caused by parasites, one of whom was Youyou Tu, who led the team that identified artemisinin from Artemisia annua (Qinghao), an effective treatment for the malarial parasite Plasmodium falciparum.
Despite the excitement surrounding the award of the 2015 Nobel Prize, there remains considerable scepticism surrounding TCM, typically because of the absence of data that meet US Food and Drug Administration standards for efficacy and lack of side effects. Ironically, TCM is the product of accumulated clinical observations gathered over centuries of practice.
Of course, there are fundamental differences between the philosophies of TCM and WSM as well as the ways in which they are applied. Although these differences have often led to the dismissal of TCM, based on criteria established for WSM, the two approaches may, like Yin and Yang (阴和阳), be complementary, interconnected and interdependent in terms of disease outcomes and consequently may offer hope in the form of combination therapies that allow more effective management and treatment of the most challenging of human diseases.
WSM takes a technocentric approach. Disease is seen as something "going wrong" with the body. Starting in earnest more than 150 years ago methods based on surgery and drugs have been used to repair the body and get things working again. WSM is evidence-based and its methodology is fundamentally analytical and reductive.
In contrast, TCM is an empirical discipline developed over more than 2000 years. Consequently, TCM is a product of accumulated observations gathered over centuries of practice. It looks at the behaviour of the human body as a whole during the course of a disease. TCM defines a healthy individual as having balance within themselves and with their natural environment. A diseased condition represents a deviation from that balance and the role of TCM is to restore balance.
One of the most important and fundamental theories of TCM is prevention of disease; prevention before disease onset, prevention from exacerbation of disease and prevention of recurrence. 2 Prevention is increasingly being emphasised by modern western medicine, and advocated by the WHO in its annual reports since 1996. 3 In TCM, prescriptions are personalized, according to the physical condition and personal habits of the patient and the FU ET AL.
| 3183 development of the disease, reflecting an emphasis on individualised treatment, more recently also adopted by western medicine.
The advances that have come from WSM have improved the quality of human life enormously, particularly in reducing infant mortality and because of this success, WSM has become the predominant medical system in the world. Even in China surveys suggest that less than 30% of the population use TCM and, when they do, their use is predominantly as a complement to WSM, although use is also very dependent on the age of the patient, their geographic location and the nature of the complaint. 4 However, the methodology of western medicine does not always address disease completely, for three main reasons.
(1) No two individuals are the same, and ideally medication should be individualized.
(2) The human body is an open, large, and complex system and cannot be understood by analysing subsystems in isolation.
(3) The human body's role in pathogenesis is often forgotten in WSM. Diseases consist of two components, the cause of the disease (infection, cancer etc.) and the body's responses to the cause of the disease.
In this mini-review we consider TCM treatments for three diseases, (two infectious and one chronic) of current relevance to societies globally and compare these to WSM treatments. The benefits of TCM are specific to each example, due to the different mechanisms of action of traditional interventions, but collectively they support arguments for the wider adoption of combined therapies. We assess the benefits of harnessing the complementarity of TCM and WSM approaches, and how western approaches to understanding how TCM works may augment the benefits of combined therapies.

| MALARIA
Malaria is caused by Plasmodium falciparum infection and has probably been around for more than 50,000 years. 5 Despite substantial scientific progress in the modern era, malaria remains a worldwide problem and causes hundreds of thousands of deaths every year. 6 In 2018, an estimated 228 million cases occurred worldwide and caused approximately 405,000 deaths, among which, two thirds were deaths of children under 5 years old. 7 Natural medicines from plants have made significant contributions to the treatment of malaria, including quinine from Cinchona ledgeriana and artemisinin (qinghaosu) from Artemisia annua (Qinghao).
In China, qinghao has been recommended traditionally for the treatment of malaria, reported originally in Zhouhou Beiji Fang (The Handbook of Prescriptions for Emergencies, 肘後備急方) edited by Ge Hong in the 4th Centuary AD. Following structural identification and the report on the use of artemisinin to treat malaria 8 ( Figure 1), many research groups systematically purified and analyzed artemisinin using WSM strategies. Due to the rapidity with which it can clear the parasite from the human body and reduce fever, artemisinin became the frontline drug for treatment of malaria from the late 1990s until 2012, 9 but the production of combination therapies and the development of resistance to artemisinin particularly in South East Asia, saw the World Health Organisation then advise against use of artemisinin alone. Currently, artemisinin-based combination therapies comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs, including quinine derivatives, which are recommended for the treatment of uncomplicated malaria by the World Health Organization. 10,11 Consequently, the success of artemisinin has been built on both TCM and, more recently, refinement by WSM.
Several western scientific strategies have been adopted to increase the activity and production of artemisinin.
To increase the efficacy of artemisinin, its solubility in oil and water has been improved through the development of several artemisinin derivatives, including dihydroartemisinin, artemether, and artesunate, which have been shown to have enhanced anti-malarial activities. 12,13 In practice, artemisinin is usually extracted from A. annua leaves and used for further modification.
Consequently, a major limitation on production has been the low content of artemisinin in A. annua leaves.
Many accessions of A. annua contain artemisinin below 0.2% and cannot be used for commercial production. 14 F I G U R E 1 Cover page of the 1979 article from the Qinghaosu Antimalarial Coordinating Research Group that described the use of artemisinin to treat malaria 8 FU ET AL.

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To maintain a stable supply of artemisinin, different western production strategies have been employed.
Chemical synthesis began shortly after the discovery of artemisinin and the total synthesis of artemisinin from (-)-isoeugenol was first reported in 1983. 15 At the same time, conversion of artemisinic acid to artemisinin was reported providing the theoretical ground-work for semi-synthetic production. 16,17 The need for high levels of investment, and low yields have limited chemical synthesis for industrial-scale applications. 18 The pursuit of high artemisinin varieties of A. annua by plant breeders has also been ongoing since artemisinin was first discovered. Massive breeding programs have created high content varieties. 19,20 Varieties with artemisinin contents of over 1% have been cultivated by farmers in China and now represent the major source for the world supply of artemisinin 14 (Figure 2). More advanced approaches including metabolic engineering by breeding, marker-assisted selection and mutation breeding have also been used to select higher content varieties, with many now awaiting field trials and regulatory approval. 14 Production of artemisinin in other plant chassis has been reported but the maximum production attainable, so far, has been 120 mg kg −1 fresh weight of tobacco leaves, which translates to a yield of 0.12% from the leaves. 21 When the costs for transformation, plant cultivation and regulatory approval are also taken into consideration, it seems unlikely that this production route will be competitive, economically.
Identification of the partial biosynthetic pathway of artemisinin from acyl CoA to artemisinic acid 22-26 offered the opportunity for engineering artemisinic acid production in yeast by introducing the A. annua genes encoding the enzymes of the pathway, blocking competing pathways and building synthetic metabolons to improve flux. 23,27 Although the best strains can now achieve yields of 25 g L −1 , 23 in combination with semi-synthetic conversion of artemisic acid to artemisinin, this route is still more expensive (350-400 US$ per kg) than growing A. annua plants and extracting artemisinin from the leaves directly (<250 US$ per kg) and production in yeast has been limited since 2015. 28 Consequently, economics still dictates that the most cost-effective means of producing artemisinin is the traditional way from leaves of A. annua plants. Thus, the most effective treatment for malaria was identified from TCM and is still produced in a close-to-traditional fashion (  Table 1 for the definition of TCM terms). TCM formulas have been recommended for mild and moderate cases of COVID-19 infection as well as for convalescence ( Figure 3). Combinations of TCM formulas and Chinese patented medicines have been recommended for treating severe and critical cases. Qingfei Paidu Decoction (清肺排毒汤) was recommended for mild, moderate, and severe cases, and could also be used for critical patients, according to their specific conditions ( Figure 4).
The basic formula of Qingfei Paidu Decoction, which includes 20 herbs and one chemical constituent, is shown in Table 2. Analysis suggests it contains 45% flavonoids (including 4′-deoxyflavones from roots of Scutellaria baicalensis [Huang Qin]), 15% glycosides, 10% carboxylic acids and 5% saponins. A component of particular importance is the Ma Xing Shi Gan decoction (麻杏石甘汤), of which glycyrrhizic acid, a saponin from liquorice roots ( Figure 5) appears to play a pivotal role in supressing pulmonary inflammation and the cytokinin storm that accompanies COVID-19 infection. 33 Glycyrrhizic acid has been recognised for a long time as an effective antiinflammatory and an antioxidant, although at high doses it may also show toxicity. Consequently its delivery within a therapeutic window is important for its efficacy and its composition in the Ma Xing Shi Gan decoction seems to fit well within this dosage window. The ephedrine (Ma Huang) in the Qingfei Paidu Decoction inhibits platelet aggregation and may serve to supress blood clotting in severe cases of COVID-19 infection ( Figure 6). 33 TCM showed considerable power in the prevention and treatment of SARS in 2003. 34,40 This demonstrated the efficacy of TCM against infectious diseases. However, integration of TCM and WSM has shown even better outcomes in the treatment of COVID-19 than WSM alone. 30,41 Compared to WSM, integrated medicine had a better overall response rate, higher cure rate, lower severity of illness rate, lower mortality rate, and shorter FU ET AL.
| 3187 hospital stays in the treatment of COVID-19. The integrated approach also improved the disappearance rate of symptoms including fever, fatigue, coughing and expectoration and reduced the duration of fever and fatigue.
Outcomes from an example of 51 moderate cases treated by the Chinese patented medicine, Lianhua Qingwen Granule, combined with conventional treatment as the treatment group and 51 moderate cases with only conventional treatment as the control group 42 are shown in Table 3.
T A B L E 1 Glossary of TCM terms used 35,36 Yin (阴) A term from ancient Chinese philosophy referring to things or natures which are cold, downward, inert, dim, internal, material, declining, and inhibitory.

Yang (阳)
Things or natures opposite to yin.

Yin and Yang
A concept of dualism, describing how opposite or contrary forces may actually be complementary, interconnected, and interdependent in the natural world.

Qi (气)
Flowing refined nutritive materials in the body or functional activities of the body.

Ying (营)
One substance from the digested food which circulates to nourish the body.

Blazing of both qi and ying (气营两燔)
A disease characterized by high fever, dysphoria, thirst, epistaxis, irregular or fast pulse, etc.

Cold (寒)
An exogenous pathogenic factor which hinders the dispersion of yang and obstructs the activities of qi and blood. It's also a term used to describe decreased functioning of an organ system which presents as any of the following: body aches, chills, poor circulation, fatigue, lack of appetite, loose stools or diarrhea, poor digestion, pain in the joints. It pertains to all "hypo" conditions such as hypoadrenalism, hypoglycemia and hypothyroidism.

Damp (湿)
A pathogenic factor, whose nature is heavy, sticky and greasy, obstructing the activities of qi and spleen. It's also a term describing excessive fluids in the body with symptoms of abdominal bloating, loss of appetite, nausea, vomiting, lack of thirst, sluggishness, and stiff, aching, or sore joints

Cold-damp (寒湿)
A pathogenic factor causing obstruction of yang and blood activities, pain of skin, less flexibility of joints, etc.

Heat (热)
A pathogenic factor with the same nature as fire or a symptom characterized as excess yang.

Damp-heat (湿热)
Combination of damp and heat, causing diseases to the spleen, liver, large intestine, bladder, skin, such as jaundice, hepatitis, urinary problems, or eczema due to damp-heat.

Decoction (汤剂)
A medicinal soup or tea obtained by brewing herbs in boiling water and then removing the herbs from the mixture.

Deficiency (虚, 虚症)
Any weakness or insufficiency of qi, blood, yin, yang or essence.    Table 4. There were two deaths (14.29%) in the WSM group, but no deaths in the group receiving integrated TCM and WSM ( TCM injections in addition to WSM treatments. Outcomes for the integrated medicine group were better than those for the WSM group (Table 5).
There  Toll-like receptors, T cell receptors, and other signaling pathways involved in immune responses. 47 These indicated Xuebijing Injection functions mainly in protecting vital organs through modulating inflammation triggered by the immune response to the virus. Molecular docking showed good affinity of the main components of Xuebijing Injection with ACE2 and SARS-CoV-2 3CL hydrolase, supporting the antiviral effects of the Xuebijing injection. 47 The multiple components of TCM decoctions, formulas and injections offer advantages in treatment targeting multiple pathways affected by the virus, and their impact on these broad targets may result in benefits through synergy in treating the disease, explaining the efficacy of TCM as a complement to WSM in COVID-19 treatment.
Due to the effectiveness of Integrated Traditional Chinese and Western Medicine, integrated medicine has been used widely for the treatment of COVID-19 in China. More than 90% of the confirmed COVID-19 cases received TCM treatment. 48 Although these data are very recent, the use of integrated traditional Chinese and western medicine would appear to be particularly effective in the treatment of COVID-19 and recommended for more widespread adoption, since COVID-19 infection remains severe around the world.

| TYPE 2 DIABETES
Type 2 diabetes (T2D) is a chronic disease involving raised glucose levels in the blood as a result of reduced sensitivity to insulin (insulin resistance) and/or inadequate insulin production. Elevated blood glucose levels can cause serious complications including damage to eyes, kidneys, heart, blood vessels, and nerves, leading to retinopathy and sight loss, kidney failure, heart failure and increased risk of cardiovascular disease as well as amputations. There were an estimated 463 million cases of diabetes worldwide in 2019, 90% of which were T2D.
Because of its association with obesity, the number of people in the world suffering from T2D is predicted to rise to 700 million by 2045. 49 The basic treatments for T2D are management through education and maintenance of a healthy lifestyle; adopting a healthy diet (low in refined fats and sugars), undertaking suitable physical exercise, cessation of smoking, control of alcohol intake and, most importantly, control of body weight. 50,51 Indeed, recent reports suggest that adopting a healthy diet including decreased intake of added sugars and processed foods, swapping out refined grains for whole grains, increasing fiber intake, increasing intake of fruit and vegetables, avoiding processed red meat and eating healthier fats in the form of oils such as olive oil, walnut oil, flax seed oil and oils from marine fish can improve outcomes and life expectancy of patients with T2D. One example is based on results from the DIRECT project where 149 prediabetic individuals undertook antidiabetic and antihypertensive drug withdrawal, total diet replacement (825-853 kcal/day formula diet for 3-5 months), then stepped food reintroduction (2-8 weeks), and structured support for long-term weight loss maintenance, compared to 149 prediabetic individuals treated with best practice care according to the National Health Service (UK) guidelines as the control group. At 12 months, almost half of participants in the treatment group had achieved remission to a nondiabetic state and were off antidiabetic drugs. 52 However, when adoption of a healthier lifestyle is not enough for the control of blood glucose levels, pharmacologic treatment is needed. In WSM, metformin is recommended universally as the frontline drug in pharmacological therapy. When metformin is insufficient, as tends to happen over time from first diagnosis, a combination of metformin and other glucose-lowering drugs is used for dual or triple therapy, including sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-dependent glucose transporters 2, glucagon-like peptide 1 (GLP-1) receptor agonists, and alpha-glucosidase inhibitors. When such combined therapies are ineffective for the control of hyperglycemia, insulin injections become necessary, usually slow-release insulin. Beyond the control of blood glucose levels, the blood pressure and blood lipid levels of T2D patients also need to be managed. 50,51 TCM has been used to treat diabetes for thousands of years with relatively good efficacy. 53,54 Diabetes-related symptoms were referred to as "Xiaoke" (消渴, meaning consumptive thirst) disease in ancient China.
Four pathological stages of T2D have been defined by the International TCM guidelines for diagnostic and treatment principles of T2D: the stagnation stage, the heat stage, the deficiency stage and the injuring stage, corresponding to the prediabetic or early stage of diabetes, the stage of diabetic attack, the diabetic deterioration stage (the most common stage), and end stage of diabetes (chronic complications). 55  Decoction with metformin can improve the control of blood glucose levels and the metabolism of blood lipids for improved theraputic effects on phlegm-heat in T2D patients.
In the treatment for T2D patients with obesity, a combination of Xiaoshi Zhuyun Decoction (消食助运方) and liraglutide (a GLP-1 receptor agonist) injection was applied in a treatment group, and liraglutide injection alone was used in the control group. 65 After 3 months, improvements in plasma FPG, 2-h PG, and HbA1c levels, and T2D syndrome scores were observed in the treatment group compared to the control group. Adverse reaction rates were lower in the treatment group than in the control group, indicating that the combination of Xiaoshi Zhuyun Decoction and liraglutide had better effects in the treatment of T2D patients with obesity than the monotherapy of liraglutide. The integrated treatment also reduced adverse reactions to liraglutide.
In treatment of T2D patients the effects of Buzhong Shengqing Xieyinhuo compound prescription (补中升清泻 阴火复方) combined with insulin injections have been assessed. 66 Buzhong Shengqing Xieyinhuo compound prescription and premixed insulin were given to the treatment group, while a placebo and premixed insulin were given to the control group. After treatment for 12 weeks, plasma FPG, 2-h PG, HbA1c, TG, and LDL-C levels were all lower in the treatment group than those in the control group. The degree of hypoglycemia resulting from overactivity of the injected insulin was also lower in the treatment group than the control group. Fasting insulin levels, the insulin acuity index, and the homeostatic model assessment index for β cell function were all higher in the treatment group than in the control group. Therefore, a combination of Buzhong Shengqing Xieyinhuo compound prescription and insulin could improve the control of blood glucose levels, lipid metabolism, reduce the risk of hypoglycemia, and help in the recovery of β cell function in treatment of more advanced T2D patients. In conclusion, these examples suggest strongly that the integration of TCM and WSM treatments can improve the management and control of T2D.

| OUTLOOK
There is mounting evidence that treating human diseases, both infectious and noncommunicable, with therapies that integrate western medicine with TCM can substantially improve outcomes, compared to western medicine alone. It is true that we do not yet know many of the mechanisms by which TCM affects disease and recovery from disease, but this does not mean that we should ignore the benefits of traditional medicine, particularly when integrated with western medicine. Acupuncture carried a stigma similar to that bourn by TCM in the West in the 1970s, before the discovery that acupuncture needles could stimulate the release of β-endorphins and reduce pain. Now use of acupuncture to treat pain is far more widely endorsed.
Although current scientific studies have not established all the mechanisms underlying the beneficial effects of TCM, the methodologies of WSM can shed light on some of the existing problems in the use of TCM. TCM emphasises specific medical materials, which are more widely known as "Daodi" (道地) in Chinese. Genuine or "daodi" medical material is material which has been grown in a specific geographical region and screened for efficacy in accordance with long-term traditional medical practice, usually associated with unique cultivation conditions. 67,68 These guidelines are reasonable from the perspective of plant science, because most of the bioactive compounds used in TCM are specialised metabolites, and the accumulation of these compounds can be influenced hugely by the environment and cultivation management practices. Therefore, quality control of medical herbs has been a significant issue in the application of TCM, and failures in QC can lead to inefficacy and sometimes, toxicity. To address QC issues, DNA barcoding and chemical fingerprinting are now being used to facilitate compound identification, traceability, and standardisation of medicinal herbs. [69][70][71][72] More recently, machine learning has been shown to be very effective in facilitating compound identification. 73,74 In addition, the introduction of conventional breeding as well as marker-assisted selection and clonal propagation, has improved quality control and availability of medicinal herbs, especially those derived from endangered species. 75,76 Similarly, once the mechanisms of action of TCM are better defined, together with greater quality control of prescriptions, it is highly likely that the benefits of TCM will become more widely accepted. Because TCM is an empirical discipline, it is not necessary to believe in its efficacy, to derive benefits. However, if the benefits of integrated TCM and WSM are to be disseminated more widely, there will be an inevitable increase in the demand for TCM practitioners as well as the herbs that are used to make the decoctions, formulas, capsules, granules, and patented medicines.
Consequently far more research is required into the bioactives in TCM prescriptions, their synergies, their dosage windows, any side effects and their mechanisms of action in the human body. Greater research and understanding will lead to more widespread adoption and acceptance of TCM. Further development of Chinese patent medicines, and their integration with WSM will undoubtedly lead to better health outcomes and lower cost burdens on health services across the world.