History of NCCIH Botanical Research Funding

The National Center for Complementary and Alternative Medicine (NCCAM) was established in 1998 by Public Law 105-277 for the purpose of supporting research, training, and the dissemination of information on a diverse collection of health practices considered to be outside of mainstream medicine. Importantly, in that legislation, the Center’s director was also given the charge to study the integration of these modalities with the practice of conventional medicine. During the last 20 years, national surveys have consistently shown that most Americans use dietary supplements or other complementary health approaches in conjunction with (i.e., integrative) rather than in lieu of (i.e., alternative) conventional care.¹ In December 2014, NCCAM’s name was changed to the National Center for Complementary and Integrative Health (NCCIH*) by Public Law 113-235. Notably, although the name changed, the mission has remained the same, and the new name now more accurately reflects the research NCCIH supports.

While NCCIH’s overall mission has remained unchanged for the past 17 years, its research priorities have evolved. When the Center was first established, its natural products research portfolio was organized into two main areas. The first was a set of large, NCCIH-initiated phase III clinical trials testing the efficacy of a number of botanical products for a variety of different conditions (Table 1). These trials included studies of St. John’s wort extract for depression, echinacea extract and herb for upper respiratory tract and rhinovirus infections, ginkgo extract for memory and dementia, saw palmetto extract for benign prostatic hyperplasia, and milk thistle extract for hepatitis C. (See Table 2 for more information about the botanicals mentioned in this article.) The second area of the natural products research funding supported a wide variety of research initiated by academic investigators. This research, spanning in vitro, in vivo, and clinical projects, involved a diverse collection of natural products for an equally disparate set of conditions. The reason for supporting such an assortment of projects stemmed from a realization that research in this field was still in its infancy and there were so many products with such limited evidence that the Center did not have sufficient data upon which to base decisions regarding a particular research focus.

Over time, the natural product clinical studies were completed and the findings published. For the most part, the results failed to support the hypothesized benefits of the botanical products. However, once the studies were published, their designs were criticized by some for failing to use what critics considered the optimal product formulation and/or dose. Furthermore, for most of the products, the mechanisms of action by which they exerted their hypothesized activity was unclear, making it difficult to make definitive statements about the biological activity of the products even at the conclusion of the studies. Consequently, the Center chose not to initiate additional large clinical studies for natural products unless the mechanistic underpinnings of their hypothesized activity were clearly established.

Without the large investment in NCCIH-targeted clinical studies, the academic investigator-initiated portion of the Center’s research portfolio began to account for an increasing percentage of its budget. Because of the diffuseness of that portfolio, it became difficult to articulate clear priority areas or adequately describe a research niche NCCIH supports that did not overlap with other parts of the National Institutes of Health (NIH).

Establishing Research Priorities

Recently, the Center has undertaken a critical evaluation of its natural products research funding to better understand past and current investments. This included an analysis of the NIH-wide investment in botanical research to determine where resources could have the most impact. The Center also organized a series of workshops, convened an expert panel, and had numerous informal conversations over the past two years to solicit advice and input from experts in the field. NCCIH reached the conclusion that its investments in natural products have supported a large number of groups conducting high-quality research. Because of limited resources, the Center also recognized the need to concentrate efforts into more focused areas that are aligned with NCCIH research interests in order for investments to produce a meaningful impact on this field of science.

Importantly, this led to the decision that NCCIH would consider research focused on disease treatment a low priority. The reasons for this were twofold. First, many other branches of NIH focus specifically on individual diseases (e.g., National Cancer Institute, National Institute of Neurological Disorders and Stroke [NINDS], National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], etc.). Second, surveys consistently show that for those people who take dietary supplements, their primary reason for doing so is not for disease management but for general health promotion.^2-4

What has emerged from this intensive effort is a reshaped natural products research agenda that focuses NCCIH funding into a handful of scientific areas that are closely aligned with its research priorities; these areas are not well represented at other parts of NIH, and they offer the potential to yield impactful research that will advance the field. The first major research focus is on improved methodology across all aspects of natural products research. The second major focus is on exploration of the ways in which natural products, either as complex mixtures or as isolated ingredients, interact with biological systems.

Methodology

There is a sense among some in the research community that the techniques and methodologies employed to conduct natural products research have remained largely unchanged for the last 20-30 years. Compared to the rapid advances in the biological sciences as a whole, progress in natural products research has not kept pace. As a result, natural products researchers continually struggle with the same bottlenecks. Therefore, to make major advances, improved methods are needed across the board, including those related to chemical characterization, biological characterization, and biological manipulation.

There is continued reliance on traditional chromatographic methods to fractionate and purify the milligram quantities of natural products needed for NMR (nuclear magnetic resonance)- and MS (mass spectrometry)-based dereplication and structure elucidation. This generally requires relatively large amounts of material and time. Improvements in chemical characterization will allow for improved quality control procedures in the dietary supplement industry while also providing a means to more rapidly determine if a particular extract contains interesting compounds worth pursuing. Efforts are currently underway using bioinformatics to compare the chemical profiles, based on NMR or MS spectra, of large numbers of extracts to ascertain similarities and differences among them. Depending on the context, an “outlier” may represent a batch of product that does not meet established specifications, or it may represent a promising lead for new natural product discovery.

Improvements in biological characterization will allow for a more comprehensive approach to identifying bioactive compounds and describing their overall biological activities. The existing paradigm is to assay isolated natural products in highly specific mechanism-based assays. However, it is well known that complex mixtures may contain multiple active compounds and that individual natural products often have pleiotropic effects mediated by activity at numerous targets. For example, curcumin, a component of turmeric, has been reported to modulate dozens of different genes and proteins. Conversely, a combination of berberine and specific flavonoids in goldenseal has been shown to act synergistically through different mechanisms to produce the antibacterial activity present in this plant. By moving toward more phenotypic assays (e.g., whole-cell or animal rather than single-enzyme), it will be possible to identify bioactive compounds without stipulating a priori the mechanism of action. Furthermore, this will make it possible to capture activity when more than one compound is responsible for the phenotypic response or when multiple mechanisms of action are involved.

Improvements in biological manipulation have the potential to drastically expand the pool of accessible natural products in two ways. First, they will allow access to the vast number of unculturable microorganisms that represent perhaps more than 95% of the microorganisms on earth, thus increasing the likelihood of discovering novel compounds.^5,6 The second way is by uncoupling the relationship between natural products and their sources. Researchers are just beginning to develop techniques that allow the biosynthetic machinery of natural product production to be transferred from the original producing organism into a more sustainable host. This approach has the potential to protect valuable natural resources while also providing researchers with a reliable source of natural product compounds.

Interactions

Natural products have the ability to interact with biological systems in a wide variety of ways. Recent advances in the various “omics” technologies now make it possible to capture these interactions in ways that were not imaginable a few years ago. NCCIH has an interest in exploring these interactions in a few selected contexts, including drug interactions, network pharmacology, the microbiome, and genetics/epigenetics.

The American public is prescribed an ever-increasing number of pharmaceutical medications.⁷ About one-third of adults who are taking prescription drugs report also taking one or more dietary supplements.⁸ This suggests there is a widespread risk of natural product/drug interactions. Current literature and publicly available resources provide varying accounts of just how prevalent and significant such interactions may be.^9,10 Many warnings are based on animal studies, case reports, or purely theoretical arguments, which has led to confusion among consumers and healthcare providers. NCCIH has initiated a new program that focuses on providing clear guidance to the research community on best practices for conducting research on natural product/drug interactions. The expectation is that this will ultimately lead to improvements in reporting of such interactions and allow for better healthcare management.

Some natural products have been shown to have a high degree of selectivity and specificity for individual biological targets. More commonly, however, the same natural products are found to modulate multiple targets. When this is extended to a complex mixture as found in medicinal plants, the number of possible interactions is staggering. The term network pharmacology has been coined to describe the sum of these biological interactions. NCCIH is interested in studying the ability of natural products, either individually or collectively, to modulate biological systems through these networks. To do so will require the application of powerful bioinformatics tools to the study of natural products.

Over the last several years, there has been an explosion of interest in the human microbiome. Researchers are only beginning to fully understand the myriad of ways in which the microbiome influences human health. The trillions of microbial cells in the human body are known to metabolize phytochemicals in ways that the human metabolic machinery cannot. NCCIH has a keen interest in better understanding how natural products interact with the human microbiome, including what metabolites are produced, how they are distributed throughout the body, and what activity, if any, they possess. This will involve careful study regarding the intricacies of human/microbiome co-metabolism of natural products to fully understand the biological implications of this interaction.

Recent NCCIH-funded research has shown that individuals with a genotype common in people of African descent metabolize fatty acids differently than individuals with a genotype common in people of European descent; this difference may make the “Western diet” even more unhealthy for those with the genotype of African origin.¹¹ The implications are potentially enormous for the field of personalized nutrition. Similarly, natural products can influence a person’s genome through tailoring modifications known as epigenetics.¹² These changes can have lasting impacts long after consumption of the natural product. As a result, natural products can not only produce short-term pharmacologic responses, but also change individuals’ genotypes and influence their future health and that of their children. NCCIH seeks to better understand how individuals’ genetic backgrounds can influence their biological response to certain natural products and how natural products might modulate health through epigenetic modifications.

Product Integrity Policy

NCCIH’s natural product integrity policy is foundational to all aspects of its natural products research portfolio. This policy was established to ensure that the natural product materials studied through NCCIH funding are rigorously evaluated in terms of their identity and composition. This is critically important to allow for proper interpretation of research results and to maximize the reproducibility of research. The requirements of the NCCIH policy operate on a graduated scale depending on the complexity of the product and its intended use. For herbal extracts, NCCIH asks for information not required for pure compounds. Similarly, additional information is required for human research that is not necessary for cell culture or animal studies.

NCCIH has made efforts to align its policy with relevant US Food and Drug Administration (FDA) guidance. For example, the policy requires documentation that the product was manufactured in accordance with current Good Manufacturing Practices (cGMP) if it was obtained from a commercial source. Also, there is a requirement for independent confirmation of any specifications declared on a certificate of analysis. This is especially important for confirming the identity of plant material, relative concentrations of important marker compounds, and purity of isolated ingredients. Similarly, any investigator proposing clinical research must consult with the FDA to determine if an Investigational New Drug (IND) application is needed for the study. It is important to recognize that this is a regulatory decision that NCCIH cannot adjudicate. This is a source of much confusion on the part of some investigators based on the incorrect assumption that any clinical trial involving a product with GRAS (Generally Recognized As Safe) status does not require an IND. The IND status of a product is predicated on the design of the study and not the nature of the product. For example, if a GRAS product is being investigated for its ability to stabilize blood sugar in diabetics, then, from FDA’s perspective, it is being studied as a drug rather than a dietary supplement and therefore likely will require an IND designation.

Summary

The priority areas outlined herein were chosen because they are well-aligned with the overall mission of NCCIH, fit research gaps not currently addressed by other parts of NIH, and are well-integrated with each other. For example, it is not difficult to imagine how advances in natural products methodology could help better unravel complex interactions or how a better understanding of the ways in which natural products interact with the microbiome could potentially lead to a more complete understanding of the network pharmacology of natural products. The objectives of reshaping the NCCIH natural products portfolio are to concentrate the limited resources of the Center into areas that build on prior investments, align with overall priorities, and have the potential to yield impactful results that will move the field forward. Through NCCIH’s continued emphasis on product integrity, the results of NCCIH-funded research can be expected to reflect the high standards held by the Center and meet expectations regarding reproducibility of the scientific conclusions reached.

Craig Hopp, PhD, obtained his doctorate in pharmacognosy from Purdue University in 1997. He joined the National Center for Complementary and Integrative Health (NCCIH) in January 2009 as a program director. At NCCIH, one of his primary responsibilities is the administration of the product integrity policy, which involves evaluating proposed study materials to ensure they are safe and properly characterized. Additionally, he is the coordinator for the Botanical Research Centers Program and oversees other natural products projects supported by NCCIH. Dr. Hopp uses his expertise and experience in the field of natural products to help shape priorities at NCCIH.

*For simplicity, the Center is referred to as NCCIH throughout the remainder of this article, even though some of the events described took place before the name change.

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