4
Science

Science is nothing but trained and organized common sense.

—Thomas H. Huxley


The keynote address for the session on science was delivered by Dr. Dean Ornish. Ornish surveyed the key fields related to integrative medicine, providing examples of the effectiveness of integrative interventions in improving patients’ health. The panel discussion was moderated by Dr. Bruce McEwen of the Rockefeller University, with panelists offering their perspectives and priorities surrounding the development and advancement of the evidence base for integrative medicine.

Topics reviewed focused on the complex interplay of biology, behavior, psychosocial factors, and environment shaping health and disease. Often, as Ornish pointed out, these interactions can produce synergistic results—for good or ill. This very complexity calls for a systems approach in health care and in health sciences research that could evaluate multiple variables interacting in dynamic ways. As several panelists, including Dr. Lawrence Green, noted, this is a significant shortcoming of randomized trial methodology, which tests one variable at a time and is not designed to evaluate multifaceted preventive approaches, such as the lifestyle interventions described by Ornish. New, more appropriate assessment methods are under development. They range from improved effectiveness trials at the community level to studies of immune system biomarkers at the molecular level, to an array of study methods being used at the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM), described by Dr. Josephine Briggs.

Advances in genomic sciences are increasingly illuminating the contribution of genes to health and disease, explained Dr. Richard Lifton. New, more effective treatments may result that can be tailored to a person’s genetic profile—a possibility that will greatly facilitate personal-



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4 Science Science is nothing but trained and organized common sense. —Thomas H. Huxley The keynote address for the session on science was delivered by Dr. Dean Ornish. Ornish surveyed the key fields related to integrative medi- cine, providing examples of the effectiveness of integrative interventions in improving patients’ health. The panel discussion was moderated by Dr. Bruce McEwen of the Rockefeller University, with panelists offering their perspectives and priorities surrounding the development and ad- vancement of the evidence base for integrative medicine. Topics reviewed focused on the complex interplay of biology, be- havior, psychosocial factors, and environment shaping health and dis- ease. Often, as Ornish pointed out, these interactions can produce synergistic results—for good or ill. This very complexity calls for a sys- tems approach in health care and in health sciences research that could evaluate multiple variables interacting in dynamic ways. As several pan- elists, including Dr. Lawrence Green, noted, this is a significant short- coming of randomized trial methodology, which tests one variable at a time and is not designed to evaluate multifaceted preventive approaches, such as the lifestyle interventions described by Ornish. New, more ap- propriate assessment methods are under development. They range from improved effectiveness trials at the community level to studies of im- mune system biomarkers at the molecular level, to an array of study methods being used at the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM), de- scribed by Dr. Josephine Briggs. Advances in genomic sciences are increasingly illuminating the con- tribution of genes to health and disease, explained Dr. Richard Lifton. New, more effective treatments may result that can be tailored to a per- son’s genetic profile—a possibility that will greatly facilitate personal- 77

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78 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC ized medicine and person-centered care. However, as several panelists pointed out, “we are more than our genes,” and it is the epigenetic influ- ences—the interactions of genes with other factors—that shape health and illness. Dr. Mitchell Gaynor reported on numerous studies indicating the influence of diet and other environmental factors on the expression of genes and, consequently, their effects on health. Psychosocial factors including stress, loneliness, and depression, all mediated by the brain, were described by McEwen and Dr. Esther Stern- berg as strong contributors to health and disease. As the brain responds to stress, hormones are released that can, for example, interfere with the immune response and metabolic processes and damage the cardiovascu- lar system. Something as simple as having a support group, a wide social network, or a nurturing belief system helps people manage stress and recover from illness, Ornish and Sternberg said. People with high levels of stress can be found throughout society. Dr. Nancy Adler noted that people in lower socioeconomic strata are particularly vulnerable to the effects of stress, which is reflected in their lower health status and pre- mature aging at the cellular level. Panelists said that lifestyle choices are important not only because unhealthy choices contribute to many of the leading causes of mortality, but also because healthy choices hold the potential to outperform com- monly prescribed drugs, increase brain function, and affect the expres- sion of genes. As individuals around the world begin to adopt an “American” lifestyle, especially our diet, the challenges of preventive medicine are becoming global, Ornish said. SCIENCE KEYNOTE ADDRESS Dean Ornish, Preventive Medicine Research Institute and University of California, San Francisco The good physician treats the disease; the great physician treats the patient who has the disease. —Sir William Osler Ornish is a scientist and clinician who has spent much of the last three decades conducting clinical studies in what is now called integra- tive medicine. He described integrative medicine, or “prospective medi-

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79 SCIENCE cine,” as predictive, preventive, personalized, and participatory (Sny- derman and Williams, 2003; Weston and Hood, 2004). While it provides the best conventional care, its principal focus is on the preventive main- tenance of health by attention to all components of lifestyle, including diet, exercise, stress management, and emotional well-being. Lifestyle choices offer many opportunities to improve health, as these decisions are made multiple times throughout every day. Integrative medicine may also be perceived as “functional medicine,” which focuses on the under- lying pathways of chronic disease, such as inflammation, genetics, and metabolism (Bland, 2008; Hyman, 2007). Integrative medicine takes a systems approach to improving patient health, and analyses of its effec- tiveness also must examine systemic, synergistic effects. Integrative medicine contrasts with that of conventional medicine, where, Ornish said, clinicians spend a great deal of time mopping up the floor around an overflowing sink instead of just turning off the faucet. Evidence in integrative medicine accumulates, not through studies involving one independent variable and one dependent variable, but rather through studies of the effects of multiple factors working together in systematic ways. Similar to the components of a light bulb, the whole is greater than the sum of the parts. Ornish gave an example of the synergy of integrative medicine that is demonstrated in a study of curcumin—a component of the spice tur- meric, an ingredient in Indian curries. Curcumin, he noted, is known to have anti-inflammatory and antitumor properties, suppressing the onco- gene MDM2; further, as a free radical scavenger, it inhibits oxidative DNA damage and may help prevent Alzheimer’s disease. Researchers have hypothesized that India’s substantially lower incidence of Alz- heimer’s disease might be associated with curcumin ingestion because it suppresses inflammation that, in turn, leads to amyloid deposits in the brain that lead to Alzheimer’s disease. Initial studies of curcumin alone failed to show any beneficial effect. However, he reported, when it is combined with black pepper, as it often is in local cuisine and in Ay- urvedic medicine, there was about a 20-fold increase in curcumin’s bioavailability, demonstrating a synergistic effect of the spices (Shoba et al., 1998). Similarly, other studies show that a diet rich in fruit and vegetables protects against heart disease and some forms of cancer, although vita- mins alone usually do not. For example, foods containing beta-carotene and other carotinoids have various health benefits, most likely owing to their antioxidant effect. Yet, in some circumstances, beta-carotene die-

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80 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC tary supplements appear to have a pro-oxidant effect and actually in- crease the risk of lung cancer among smokers. Smoking causes inflam- mation in the lungs, a condition that increases free radicals that can damage DNA. In a recent study, beta-carotene supplements were shown to further increase free radicals in a smoker’s airways (van Helden et al., 2009). This increase occurs because supplemental beta-carotene inhibits an enzyme called myeloperoxidase and increases the formation of hy- droxyl free radicals, leading to increased inflammation and oxidative stress. Thus, dietary beta-carotene inhibits inflammation whereas sup- plements can increase it; studying beta-carotene in isolation (supple- ments) can miss the benefit of beta-carotene in foods and result in misleading information. The third example Ornish gave of synergy in integrative medicine research was a 1989 study in which a group of women was treated with chemotherapy, radiation, and surgery for metastatic breast cancer. One study cohort, randomly assigned to a support group that met 1 hour a week, exhibited a 5-year survival rate twice as high as that of control subjects who did not participate in a support group (Spiegel et al., 1989). “If a new drug had been shown to do that, it would be malpractice not to prescribe it,” Ornish said. However, more recent studies failed to repli- cate this result. The possible explanation for this result came in 2007, in research re- porting that there was no overall survival in support group participants, but there was a survival advantage for women with estrogen receptor (ER)-negative breast cancer (Spiegel et al., 2007). Apparently, hormonal therapy improved so much after 1989 in ER-positive breast cancer (but not ER-negative breast cancer) that it washed out the contribution of support groups for those who were ER-positive, while the benefit of sup- port groups still occurs among ER-negative women. Among ER-negative women, those who participated in the support group still had survival rates 25 percent greater than those who did not (Spiegel et al., 2007). Without looking at the larger context—the system—this effect would have been missed. Integrative Medicine and Pathways of Disease Awareness, in Ornish’s view, is the first step in healing. One prop- erty of science is its power to raise awareness. Science can help us un- derstand that what we do, how we feel, and what happens to us are all

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81 SCIENCE interconnected. Clinical research in various aspects of integrative medi- cine have produced dramatic evidence of the effects of lifestyle on health status and suggested the importance of taking a systems approach and considering factors other than those traditionally held responsible for causing not only chronic disorders but also infections diseases. Health and disease are much more multidimensional than once thought—for example, not everyone who is infected with a virus gets sick. Psychosocial factors significantly affect this varying susceptibility. For example, HIV-positive patients who were depressed were twice as likely to develop AIDS, and to die of it, than were HIV-infected patients without depression (Burack et al., 1993; Mayne et al., 1996). Depression prompted a significantly more rapid health decline, measured by cell death and reduced lymphocyte counts. Similarly, volunteers infected with a rhinovirus were less likely to develop head colds if they had ex- tensive social supports (Cohen et al., 1997). Subjects with at least six interpersonal relationships—manifested in phone calls or visits—were only one-fourth as likely to develop cold symptoms. Reactions to stress are a well-recognized factor in immune function and can be either health protecting or health damaging. Stress generally suppresses immune function, while relaxation and meditation enhance it. Thus, there can be synergy between meditation and allopathic interven- tions. For example, psoriasis patients’ skin cleared much faster (60 per- cent after 50 days) if they received standard photochemotherapy and listened to mindfulness-based stress management tapes; lesions of pa- tients who did not use the tapes were only 20 percent clear after 50 days (Bernhard et al., 1988). Integrative Medicine and Lifestyle Change Many people mistakenly believe that only a new drug or a new and expensive technology can succeed against disease. Ornish and his team use high-tech, state-of-the-art measurement techniques to show the bene- fits of low-tech, low-cost, and, in some cases, ancient interventions and forms of disease prevention. Comprehensive lifestyle changes— including changing what we eat, how we respond to stress, moderate ex- ercise, and greater love and intimacy—can yield remarkable improve- ments in health. Equally as important, these improvements are experienced within a short timeframe, which helps individuals feel better and facilitates the sustainability of their lifestyle modifications.

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82 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC Early in his career, Ornish conducted several studies to evaluate the effects of lifestyle on heart disease. In the first study, 10 heart disease patients who undertook comprehensive lifestyle changes for only 1 month experienced a 90 percent reduction in angina as well as improved blood flow (myocardial perfusion) to their hearts, the first study showing that coronary heart disease may be reversed by changing lifestyle (Ornish et al., 1979). In the second study, a randomized controlled trial, a similar set of patients experienced a 91 percent reduction in angina and a signifi- cant increase in the heart’s ability to pump blood, while the control group experienced a decrease (Ornish et al., 1983). In later randomized trials, patients who made comprehensive lifestyle changes showed a significant reduction in coronary artery blockages (atherosclerosis) as measured by quantitative coronary arteriography after 1 year and an even greater re- versal of heart disease after 5 years, whereas the randomized control group showed a worsening of coronary atherosclerosis after 1 year (Or- nish et al., 1990) and greater worsening after 5 years (Ornish et al., 1998), as shown in Figure 4-1. Cardiac PET scans revealed that 99 per- cent of patients who made these lifestyle changes were able to stop or reverse the progression of their heart disease (Gould et al., 1995). In a subsequent study, comprehensive lifestyle changes appeared to significantly slow, stop, or reverse the progression of early-stage prostate cancer, the first time that an integrative medicine intervention was shown to affect the progression of any form of cancer in a randomized con- trolled trial (Ornish et al., 2005). In both the cardiac and prostate cancer studies, the more people changed their lifestyle, the more benefit they received in a dose–response effect. If borne out, this finding is empower- ing, as the degree of improvement may be more a function of adherence than age or disease severity. Lifestyle changes can even outperform drugs in the secondary pre- vention of disease. In diabetes, lifestyle modifications functioned better than metformin in preventing the adverse effects of diabetes, including damage to the eyes, nerves, and kidneys (Knowler et al., 2002). One’s own body, Ornish suggested, may be able to regulate blood sugar levels more consistently than drugs, in these conditions. The idea that taking a pill is easy but changing lifestyle is difficult, if not impossible, is not supported by the evidence, said Ornish. Studies show that two-thirds of patients prescribed statin drugs are not taking them only 4 months later because these drugs do not make people feel

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83 SCIENCE 60 ✝ 55 51.9 50 Diameter stenosis, % Control ✽ 45 42.3 41.3 40.7 40 38.5 37.3 35 Treatment 30 Baseline 1 year 5 years FIGURE 4-1 Mean percentage diameter stenosis in treatment and control groups at baseline, 1 year, and 5 years. NOTES: Mean percentage diameter stenosis in treatment and control groups at baseline, 1 year, and 5 years. Error bars represent SEM; asterisk, P = .02 by between-group 2-tailed test; dagger, P = .001 by between-group 2-tailed test. SOURCE: Ornish et al., 1998. Reproduced from JAMA 280(23):2001-2007 (De- cember 16, 1998), with permission. Copyright 1998 American Medical Associa- tion. All rights reserved. better (Ornish, 2009). In contrast, Ornish said that comprehensive life- style changes are dynamic, and often cause people to feel so much better, so quickly, that it reframes the reason for changing lifestyle from risk factor reduction (which is boring) or fear of dying (which is too frighten- ing) to joy of living. Ornish noted that moderate changes in lifestyle create only moderate benefits. For example, people who are diagnosed with hypercholes- terolemia are often asked to make moderate changes in diet, but these relatively small changes cause negligible reductions in LDL cholesterol. Conversely, those who made more intensive changes in diet and lifestyle

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84 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC experienced a 40 percent average reduction in LDL cholesterol, compa- rable to what can be achieved with statin drugs without the costs ($18 billion for Lipitor last year) and potential side effects (e.g., muscle and liver damage) (Ornish et al., 1998). Effects of Lifestyle Changes on Brain Function and Gene Expression Ornish provided several examples of how lifestyle changes can im- prove brain function. Evidence exists that healthy diets, effective man- agement of stress, moderate exercise, and being in loving relationships can produce growth in neurons, through the newly appreciated phenome- non of neuroplasticity. Consuming such foods as chocolate, blueberries, and tea, as well as alcohol in moderate amounts, can cause neurogenesis, whereas saturated fats, sugar, nicotine, and excessive consumption of alcohol can speed up the death of brain cells. Interestingly, he said, can- nabinoids may increase neurogenesis, but opiates and cocaine decrease it. Depression and chronic feelings of stress reduce hippocampal volume and therefore impair memory (Campbell et al., 2004; Conrad, 2006; Sheline et al., 2003). In contrast, increased exercise has been associated with an increase in hippocampal volume within only a few months, as demonstrated in Figure 4-2 (Erickson and Kramer, 2009). Increases in brain size in the hippocampus and frontal cortex have been also associ- ated with cognitive therapy, stress management, and psychotherapy (de Lange et al., 2008). Changes in lifestyle affect gene expression—as nurture, in some cases, trumps nature. The Gene Expression Modulation by Intervention with Nutrition and Lifestyle (GEMINAL) studies found beneficial effects in 501 genes within 3 months after comprehensive lifestyle changes, in- cluding meditation. Changes in gene expression included the down- regulating of genes that promote heart disease or cancer and up- regulation of tumor-suppressing genes (Dusek et al., 2008; Ornish et al., 2008a). Ornish reiterated that genes are not destiny, and that genomics can be an important platform in studying the effects of integrative medi- cine. Lifestyle change also has been shown to affect telomere length, which plays a role in aging and longevity. The effect of stress on te- lomere length was demonstrated in a study of women who felt highly stressed, as long-time caregivers of children with autism or birth defects.

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85 SCIENCE 4500 4450 4400 Volume (mm3) 4350 4300 Control group 4250 Exercise group 4200 4150 Time 1 Time 2 Time 3 FIGURE 4-2 Hippocampus volume change. SOURCE: Reproduced from British Journal of Sports Medicine, K.I. Erick- son and A. F. Kramer, 43(1):22-24, 2009 with permission from BMJ Pub- lishing Group Ltd. These women exhibited lower levels of telomerase, the enzyme that re- pairs and lengthens damaged telomeres (Epel et al., 2004). The women’s perception of stress was highly correlated with shorter telomeres. In con- trast, comprehensive lifestyle changes led to almost 30 percent increases in telomerase, and thus telomere length, within 3 months, as shown in Figure 4-3 (Ornish et al., 2008b). Ornish commented that this was the first study showing that any intervention can increase telomerase, another example that integrative medicine interventions are not only as good as pharmaceutical interventions but often better, much less expensive, and that the only side effects are good ones.

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86 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC 2.4 p=0.031 (two-tailed) 2.3 Telomerase activity (natural logarithm) 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 Baseline 3 months FIGURE 4-3 Increase in telomerase activity from baseline to 3 months. SOURCE: Reprinted from Lancet Oncology, Vol. 9, Ornish, D., J. Lin, J. Daubenmier, G. Weidner, E. Epel, C. Kemp, M. J. Magbanua, R. Marlin, L. Yglecias, P. R. Carroll, and E. H. Blackburn, Increased telomerase activity and comprehensive lifestyle changes: A pilot study, Pages 1048-1057, Copyright 2008, with permission from Elsevier. A globalization of chronic diseases such as heart disease, diabetes, and cancer is occurring, as other countries are starting to eat like us, live like us, and die like us—a trend that is almost completely preventable, said Ornish. Through lifestyle change, preventive medicine can reap benefits on a global scale. Ornish also pointed out that the choices we make in our personal lives affect our planet as well. For example, some suspect that more global warming is caused by livestock consumption (due to methane production) than from all forms of transportation com- bined. Limitations of Conventional Medicine and Traditional Research Diet and lifestyle changes that have already proved effective could prevent 95 percent of heart disease (Yusuf et al., 2004), Ornish said. However, a series of randomized controlled trials has shown that the usual course of treatment that consists of angioplasty and bypass surgery

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87 SCIENCE and costs the nation more than $100 billion annually—does not prevent heart attacks or prolong life for the great majority of patients who receive them (Boden et al., 2007). An evidence-based approach to health care is necessary, he said, and should be applied across the board to conven- tional and integrative interventions alike. Instead, the dominant approach tilts toward reimbursement-based medicine rather than evidence-based medicine. Conventional methodologies available for gathering evidence on in- tegrative medicine are often limited. Randomized controlled trials (RCTs) may work well for controlling bias in drug trials and are consid- ered the gold standard for evaluating new treatments. However, lifestyle interventions and systems approaches often introduce uncontrollable sources of bias, making RCTs a less suitable evaluation method for com- plex lifestyle interventions. The randomization of participants can be challenging in lifestyle interventions. All participants must go through a series of baseline tests and agree to commit to make lifestyle changes if they are assigned to the experimental group. However, participants who are then randomized to the control group may become disappointed or even angry about the assignment, because they believe the intervention may have been beneficial to them, and they often drop out of the study as a result. Unlike a drug study, in which access to a new drug can be lim- ited to experimental group participants, researchers cannot prevent the control group from making positive lifestyle changes on their own, which will confound the study’s results. The study of integrative medicine cannot easily be limited to the study of only one independent variable and one dependent variable, noted Ornish. For example, if the intervention consists of exercise, addi- tional independent variables may be involved, such as increased social interaction with others who are exercising with the participant. Such in- teractions provide encouragement and support, and reinforce the individ- ual’s sense of meaning, self-efficacy, and purpose. People who begin to exercise regularly are also likely to improve their diets. These additional variables can complicate the interpretation of study results. New research methods are being devised to better assess integrative medicine interventions. One alternative, developed by Marvin Zelen, consists of a randomized invitational design. In this approach, partici- pants are assigned to a study group before being interviewed, so that the intervention is not described in detail to those assigned to the control group, and they do not have to commit to participate in the intervention before randomization. Members of the control group are asked only to

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100 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC sion or HIV, and the role of common variants of PLPLA3 in increasing the risk of nonalcohol-related fatty liver disease in Hispanic Americans. The path from gene identification to therapy is difficult and unpre- dictable. To further advance the science base for integrative medicine, Lifton perceived a need for at least five resources: (1) a robust scientific enterprise, where investigators with subject-matter expertise proceed from gene discovery to finding plausible points for therapeutic interven- tion; (2) far broader interactions between academia, where the scientific strength in biology resides, and the pharmaceutical industry, where talent in medicinal chemistry prevails; (3) enterprising ways to manage con- flicts of interest; (4) well-designed clinical trials to define best practices; and (5) improved delivery systems to ensure that the public ultimately benefits from this substantial investment in science. Lifton offered two complementary visions of the future. In one, pa- tients are treated with drugs targeted to individual abnormalities, based on their genomic data. That will likely be the case for disorders in which differences among patients are large, such as in certain cancers. In the other vision, disease pathways and key nodes along those pathways will be identified, allowing for the development of population-based interven- tions. Examples of the latter approach could be used to address both be- havioral and environmental factors, such as reducing salt intake in order to control blood pressure and reducing cholesterol levels in order to pre- vent heart disease. Lifton said that realizing both visions require a fun- damental, science-based understanding of the causes of disease. Environmental Epigenetics Mitchell L. Gaynor, Weill-Cornell Medical Center and Gaynor Integrative Oncology Gaynor introduced the discussion of environmental epigenetics by noting that one in three Americans, at some point in his or her life, is go- ing to hear the words, “You have cancer.” The question at hand is to what extent one’s chances of acquiring cancer or other diseases are the result of one’s genetic endowment or other, more controllable factors? The answer is a combination of the two—while the genes one is born with cannot be controlled, how those genes are expressed can be. Gaynor illustrated this point by describing nutritional genomic and toxicoge- nomic studies that use mouse models. In these studies, toxicogenomics examines how various toxins can increase tumor-promoter genes and decrease tumor-suppressor genes. Conversely, nutritional genomics uses

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101 SCIENCE nutrients to reduce cancer risk by increasing expression of tumor- suppressing genes. Agouti mice are typically born with a pale yellow coat and an ele- vated risk of developing diabetes, obesity, and eventually, cancer. How- ever, pregnant female agouti mice that are fed a methyl-rich mixture of nutrients including folic acid, B12, choline, and betaine (found in beets) produced “pseudoagouti” offspring. These mice are born with brown coats and no elevated risk of obesity, diabetes, or cancer (Waterland and Jirtle, 2003). Researchers have found that the mother’s diet during preg- nancy changes gene expression in the offspring, a positive change that is transmitted to subsequent generations. Researchers have obtained the same overall result after administering a different nutrient, the soy extract genistein (Dolinoy et al., 2006). While the earlier diet provided additional methyl groups enabling the DNA methylation that caused the change in gene expression, the gen- istein affected histone formation, which also facilitated the methylation process. Endocrine disruptors exist in plastic products, cosmetics, and pesti- cides and are stored in the body for decades. When pregnant mice were exposed to either of two endocrine disruptors, vinclozolin (a fungicide used on grapes and other fruits) and methoxychlor (a pesticide now used instead of DDT), 90 percent of their male offspring had a 70 percent de- crease in sperm cells. This defect in the epigenome was inherited through four generations (Reik et al., 2001). It may be no coincidence that 11 percent of Americans have problems with fertility, Gaynor said. Bisphenol A (BPA) is another possible example. Agouti mice that were exposed to BPA and then fed either genistein or a diet rich in methyl groups produced pseudoagouti offspring. The nutritional supple- ment protected these mice from the BPA-induced heritable changes (Dolinoy et al., 2007). The incidence of breast cancer in American women has tripled, from one in 22 in 1960, to one in eight today. A geneticist at the University of Washington has found that women born with the BRCA1 or BRCA2 mu- tation before 1940 had a 24 percent risk of breast cancer, whereas such women born after 1940, as endocrine disruptors have become more prevalent in the environment, have a 67 percent risk. Simultaneously, the risk of ovarian cancer doubled for BRCA1 carriers, and increased 23 percent for BRCA2 carriers (King et al., 2003). These large increases in cancer risk suggest a significant gene–environment interaction, said Gaynor.

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102 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC Women in societies that consume a great deal of soy, such as Japan, have one-seventh the incidence of fatal breast cancer as American women. Asian men living in Asian countries have one-thirtieth the inci- dence of fatal prostate cancers as American men. Gaynor suggested a close relationship between environmental public policy and personalized medicine, saying that often “The environment outside us is the same as the environment inside us.” Intervention Evaluation and Outcomes Measures Lawrence W. Green, University of California, San Francisco Green indicated that he approaches integrative medicine from the opposite end of the biopsychosocial spectrum than the previous panelists. Namely, he approaches it from the standpoint of public health. He noted progress has been made in public health since the development of the disease prevention and health promotion initiative in the late 1970s under Surgeon General Julius B. Richmond, Dr. Michael McGinnis, and others. Drawing from this experience, he contended that, in order to achieve more evidence-based practice, we need more practice-based evidence. Patient-centered medicine, which is a hallmark of integrative care, challenges the supremacy of RCTs in evidence-based medicine, said Green. This challenge was acknowledged in 1999 in the preface to the second edition of a book by Archie L. Cochrane, whose previous contri- butions earned him the sobriquet of “father of evidence-based medicine,” and it appropriately may be termed the “post-Cochrane challenge” (Cochrane, 1999). A Venn diagram illustrates this challenge, as shown in Figure 4-9. There is a large circle of information (labeled C) that is potentially useful to patients in their decision making. This sphere overlaps a smaller sphere (B) of information that is potentially evidence based. The overlap is small, consisting of information that is both potentially useful to pa- tients and potentially evidence based. Only a tiny sector of this overlap contains information already grounded in good evidence (labeled A), usually resulting from RCTs. Ten years after Cochrane offered this con- struct, researchers are finally recognizing the need to apply alternative designs and to develop new study designs to obtain a large body of evi- dence that will also be useful to patients, said Green. Difficult to under- take, and tethered to conditions that may be far removed from patients’ true circumstances and desires, RCTs provide information of only lim- ited value or utility for prevention.

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103 SCIENCE Information of Area where there is currently good importance to patient evidence-based information which is of choice which is not even importance to patients in making choices potentially of evidence-based type, e.g., information about the process of delivery of health care C A B Information of importance to patient choice which is potentially of evidence-based type A. Information which is currently based on good evidence B. Information for which good-quality evidence-based information could be available in due course C. Information which is potentially of importance to patients in making health care choices FIGURE 4-9 Evidence-based medicine and integrative, patient-centered medicine. SOURCE: Hope, T. 1997. Evidence-based patient choice and the doctor-patient relationship. In But will it work, doctor? London: Kings Fund. Reprinted, with permission from Tony Hope, The Ethox Center. Research in integrative and person-centered medicine can shift the spotlight from the mediating variables that focus on the mechanisms of change to the moderating variables that focus on the characteristics of individual people and the context in which they live. Moderating vari- ables are reflected in the types of questions a clinician asks patients in order to learn about their identity, values, lifestyle, and life conditions. Green offered two strategic suggestions for meeting the post- Cochrane challenge. The first is to shape interventions in clinical re- search around moderating variables. Second, he emphasized the value of strategically blending theory and practical experience with evidence. An obsessive emphasis on best evidence has tended to crowd out good ob- servational and theoretical considerations, he said. Theory permits us to generalize evidence to other populations, settings, and circumstances. This is especially useful when, as is almost always the case, replication

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104 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC of evidence may be too cumbersome, Green noted. Theory can help pro- vide solutions to problems, so long as investigators draw on theories eclectically and do not start with a theory and then look for problems on which to test it. In the aphorism of computer scientist Jan van de Snep- scheut, “Theory and practice are the same thing in theory, but they are not the same thing in practice.” The same could be said of best evidence and practice. Modalities in Complementary and Alternative Medicine Josephine P. Briggs, National Center for Complementary and Alternative Medicine Briggs expressed the National Center for Complementary and Alter- native Medicine’s (NCCAM) commitment to integrative health care. NCCAM’s mission is to build the evidence base for complementary and alternative medicine interventions. The NIH core principles that govern this mission include rigorous peer review, investigator-initiated science, and partnerships. NCCAM’s annual budget of approximately $122 mil- lion constitutes only about 4.1 percent of all NIH expenditures. However, she reported that the center’s programs generate a significant share of interest and excitement. All of NCCAM’s large programs are operated through partnerships; partners include other NIH institutes and centers, other federal agencies, such as the Agency for Healthcare Research and Quality (AHRQ), and private-sector organizations. The programs occupy four spheres: basic science, translational re- search, efficacy studies, and effectiveness research, as shown in Figure 4-10. Basic science consumes roughly half of NCCAM’s resources. Cur- rent investigations in this area are evaluating the neuroscience of medita- tion, the biology of the placebo effect or expectancy effect, the neurobiological correlates of acupuncture, and neuroplasticity. An NCCAM-funded study in neuroplasticity, for example, demonstrated that a stroke patient imagining moving an arm affected by stroke increased movement and function in the affected arm. This may support the hy- pothesis that mental practice helps build neurocircuits for moving that arm (Page et al., 2007).

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105 SCIENCE Basic Translational Efficacy Effectiveness science research studies research FIGURE 4-10 NCCAM’s mission: Building the evidence base for integrative medicine. Other basic science research includes investigation of natural foods and other natural products; epigenetics, including effects of stress on gene expression; and the role of prebiotics and probiotics in health. Al- though the basic science portfolio is thriving, NCCAM’s limited funding means that these studies have the lowest grant application funding rates. Efficacy studies make up about 12 percent of NCCAM’s budget, in- cluding its signature RCTs of natural products and dietary supplements. For example, these investigations so far have found: no impact of Echi- nacea on the severity or frequency of head colds; positive substantial impacts of fish oil and omega-3 fatty acids on cardiovascular risk factors; and mostly negative results for ginkgo biloba, glucosamine and chondro- itin, and St.-John’s-wort. The results of these studies tend to affect con- sumer use of the products; for example, St.-John’s-wort, which was widely used in 2002, is no longer among the top 20 nonvitamin, nonmin- eral, natural products used by adults, as reported by the 2007 National Health Interview Survey. Sometimes these types of studies lead to addi- tional research. Further analysis of St.-John’s-wort revealed that the ac- tive ingredient hypericin may not be the only active ingredient, as was initially expected. It is now thought that hyperforin, another compound in St.-John’s-wort, may also be an important active ingredient. Improved methodologies will be needed to evaluate complex com- plementary and alternative interventions in real-world settings. Effec- tiveness research, which is an expanding area of activity for NCCAM, is particularly ripe for new study designs. For example, use of sham inter- ventions in acupuncture studies may describe certain effects but fails to show whether acupuncture is more effective than standard care. Despite some assertions to the contrary, rigorous scientific studies can substantiate practices used in complementary and alternative medi-

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106 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC cine. To illustrate, in the management of chronic lower back pain, a peer- reviewed study supports the use of yoga (Sherman et al., 2005), a sys- tematic (or Cochrane-type) review supports the use of manipulative ex- ercise (Slade and Keating, 2007), and an authoritative clinical guideline includes recommendations to consider acupuncture, massage, spinal ma- nipulation, and yoga among other approaches for patients who do not improve with self-care options (Chou and Huffman, 2007). Now in its 10th year, NCCAM is embarking on a strategic planning process. Briggs solicited input from stakeholders and summit participants in this endeavor. Panel Discussion Members of the panel responded to questions from audience mem- bers in a discussion that was moderated by McEwen. Selected points of discussion follow. Socioeconomic Status, the Environment, and Research In response to a question on how research on integrative medicine can better involve lower-socioeconomic status (SES) populations, Adler observed that one attribute of low-SES groups is that they tend not to be well organized. Greater involvement of these patients may require going to where they are, through community-based research. Green agreed and noted that the NIH, Centers for Disease Control and Prevention (CDC), and the AHRQ are all supporting community-based participatory re- search. Green noted that one disadvantage of this approach is the need for an investigator to spend adequate time building trust in the commu- nity, but an advantage is that the community can help frame high-value research questions. An audience member took issue with the notion that minority populations are reluctant to participate in research projects; his organization’s research has shown that the main factor in nonparticipa- tion is that people were simply not asked to do so. Several panelists responded to a related question regarding the lack of research on the effects of environmental risk factors and toxins on low-SES communities, where risks are often prevalent. Gaynor observed that African American women face an increased incidence of breast can- cer as a result of increased exposure to endocrine-disrupting chemicals,

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107 SCIENCE which are found in many hair care products and cosmetics. He called for studying the relationships between endocrine disruptors and not only cancer, but also diabetes and obesity. Adler added that this point ties in with community-based research, as members of focus groups composed of inner-city residents have expressed concern about the health effects of toxins, dumpsites, and other local environmental hazards. Lifton noted that measuring the environment can be difficult. However, advances in measuring environmental effects on the body through evaluation of gene expression can be useful in recognizing harmful environmental agents. Sternberg suggested that proteomics can also be useful in analyzing bio- logical changes that result from exposures. Balancing High-Tech Interventions with Lifestyle and Environmental Changes Panel members responded to the question of how to balance high- tech medical interventions and diagnostics with the broader impact of lifestyle and environmental health changes. Sternberg said that technol- ogy should be used as an advantage in advancing integrative medicine. She noted that high-tech methods can be used to assess the effects and health outcomes of lifestyle changes. Adler commented that skyrocketing health care costs create incentives to seek relatively inexpensive, low- tech interventions. Lifton mentioned the possibility of greater investment in disease prevention strategies, such as through changes in Medicare reimbursement. Shifting the Paradigm Panelists were asked to discuss how alternatives to RCTs could be developed. Green cited growing interest in this topic, as a result of the recent economic stimulus legislation, which contained support for com- parative effectiveness research. He mentioned that large clinical trials often produce weak results; in the early 1980s, for example, the Multiple Risk Factor Intervention Trials (“MR. FIT”), a multi-intervention RCT, sought to reduce coronary heart disease in high-risk men. When no statis- tical difference in coronary deaths was found between the experimental and control groups, researchers sought to undertake subgroup analyses. Biostatisticians objected to analyzing the subgroups because they were

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108 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC not randomized, and subgroup analysis fell immediately into disrepute. Green suggested that subgroup analysis nevertheless offers the greatest potential to understand variations in moderating variables. Briggs agreed with Green, indicating that RCT methods, developed in order to determine the efficacy of drugs, may not be sufficient to ex- amine other types of interventions. Nor are they suited to assess the ef- fectiveness of interventions in the real world, given all of the forms of heterogeneity in the U.S. population. Green urged that the different dis- ciplines along the biopsychosocial spectrum resist the centrifugal force that pulls them into silos, and instead develop more transdisciplinary re- search approaches. Gaynor commented that, in matters of protecting public health, the threshold for public policy interventions should be the precautionary principle, rather than 100 percent proof of effectiveness. The last half century could have been better spent in a war on carcinogenesis than in the war on cancer, he suggested. For example, much time was lost in ac- cepting the tobacco industry’s persistent claim that cigarettes were not proven to cause cancer. Adler added that a market model is lacking for making disease prevention profitable, and a better alignment of incen- tives is needed. PRIORITY ASSESSMENT GROUP REPORT 2 Advancing the Science Base Lifton provided the report for the priority assessment group on ad- vancing the science base. This summary includes the priorities discussed and was presented by the assessment group to the plenary session for its discussion and consideration; these priorities do not represent a consen- sus or recommendations from the summit. The assessment group began with a discussion of one challenge that had resonated throughout the summit—one of definitions. The group noted that a difference exists between integrative medicine and an inte- grated system. The former involves the care of individual patients, while 2 See Chapter 1 for a description of the priority assessment groups. Participants of this assessment group included Bruce McEwen (moderator), Richard Lifton (rapporteur), Donald Abrams, Kenneth Brigham, Margaret Chesney, Gary Deng, Wayne Jonas, Lixing Lao, Patrick Mansky, Rustum Roy, and Alan Trachtenberg.

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109 SCIENCE the latter extends from basic science discovery all the way through the mechanisms of delivery and organization of care and to broad public health interventions. In building the evidence base for integrative medicine, a pivotal task is establishing causal vectors. Genetics and genomics, in particular, have the capacity to demonstrate causation; within the next 3 to 5 years, these disciplines may revolutionize the understanding of some of the funda- mental causes of health and wellness. In advancing this area of science, one participant noted the importance of recognizing biological variations among individuals when it comes to assessing effectiveness research on interventions. Certain areas of biomedicine are not yet accorded sufficient attention among researchers, despite their importance and prevalence in popula- tion health. Areas that the group identified as requiring additional re- search and understanding were fatigue, the link between beliefs and biology, and the science of achieving behavior change. Fatigue is very prevalent in chronically ill patients, but scientists have not yet developed an understanding of its biologic foundations, nor is there funding support for research in this area. One disease where fatigue has received consid- erable attention is breast cancer. Findings in the area of fatigue should also be extended to increase the understanding of the role it plays in other conditions and diseases. An increased understanding of the link between beliefs and biology, as described by Sternberg and others throughout the summit, and the ef- fects of belief on physiology and human health are fundamental areas that the group suggested warrant additional research. Progress is also needed in the development of evidence-based inter- ventions for effective behavior change. Behavior change is a key strategy for preventing a very large number of diseases, but strategies for accom- plishing it lack a great deal of empirical evidence. Additional research is required to improve the understanding of the various components of be- havior change, including the effects of motivation, group support, and education. During the discussion with the audience, participants offered additional insight into ways to advance the science of behavior change. One participant suggested research involving a qualitative perspective— that is, asking individuals about their experiences and what meaning they attribute to behavioral change—may be a promising line of inquiry. An- other suggestion was to apply the stages-of-change model used in psy- chology, which adjusts interventions to the individual’s progress along the continuum from precontemplation to action.

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110 INTEGRATIVE MEDICINE AND THE HEALTH OF THE PUBLIC To advance the science base of integrative medicine, including the priority areas identified for additional research, the assessment group determined that the most important set of key actors is research funders, including the NIH and private foundations. The role of funders in re- search is vital to providing incentives for shifts in research approaches. The group also noted that, while the biomedical research workforce has a strong basis, it requires more training in integrative human biology, be- havior, and physiology. This additional training would show researchers how their work can apply to individual patients. One audience member reiterated this point and noted the importance of exposing doctorate-level bioscience students to the physicians and patients who ultimately use and benefit from their research.