Concept: Consortium Advancing Research on Botanicals and Other Natural Products (CARBON)

Project Concept Review

Council Date: September 8, 2023

Program Directors: Barbara C. Sorkin, Ph.D., Office of Dietary Supplements (ODS), National Institutes of Health (NIH) and
D. Craig Hopp, Ph.D., National Center for Complementary and Integrative Health (NCCIH), NIH

Background

Plants, plant-derived products, and other dietary supplement–relevant natural products are widely consumed for basic nutrition, to promote health and well-being, and for medicinal purposes, worldwide and in the United States. Despite this prevalent use, many of these products have not been rigorously evaluated; the challenges of doing research on these complex materials continue to slow progress toward understanding their contributions to public health. The National Institutes of Health (NIH) Office of Dietary Supplements (ODS) is Congressionally mandated to support research initiatives to address this gap. Since 1999, ODS has fulfilled this mandate by partnering with the National Center for Complementary and Integrative Health (NCCIH) and other NIH components to support the Botanical Research Centers Program, now a part of the Consortium Advancing Research on Botanicals and Other Natural Products (CARBON). The Centers and pilot projects of the current CARBON have addressed, for products with highly promising supporting data, gaps in knowledge of the products and their causal, molecular mechanisms of action to support the conduct and design of future highly informative clinical trials. The current CARBON has also developed a methodological pipeline using untargeted methods to generate testable hypotheses on the molecular mechanisms underlying biological effects of chemically complex natural products. The program has generated methods and resources to support utilization of and sustainable access to relevant structural and biological activity data from natural products.

An Expert Panel convened by ODS and NCCIH in 2022 noted that the CARBON program is one of the few in the United States to support the development of innovative methods for the elucidation of the mechanisms of action underlying the effects of chemically complex botanical products on resilience to environmental and behavioral challenges including social stressors, aging, unhealthy eating patterns, and insufficient sleep.

Purpose of Proposed Program

To continue the successful components of the CARBON program as well as to address the challenges raised by the Expert Panel, the proposed renewal of the CARBON program will support innovative mechanistic research to investigate how chemically complex botanicals and other natural products (including natural product foods) influence whole person health and resilience. As discussed by the 2022 Expert Panel, the botanical research component of the program will place a greater emphasis on translational and clinical research, on the inclusion of doses relevant to traditional practice or dietary exposure, and on modulation of effects by individual factors, including diet and other health-related behaviors such as physical activity and sleep. Translational research and mechanistic clinical trials to understand the effects of ingested natural products on human health, realized through the work of highly integrated, multidisciplinary research teams, will be a high priority. The technology and methodology component of the program will place a greater emphasis on computational approaches to analyze and synthesize large data sets to generate testable hypotheses. Also consistent with the Expert Panel discussions, the program will continue to support innovative approaches to expand the range of natural products entering the translational research pipeline, as well as data repository resource development and maintenance.

Objectives

To achieve the purpose of the renewed CARBON program, we propose support of the following objectives and associated activities:

Promote innovative mechanistic and translational research on the effects of well-characterized natural products, such as botanicals and dietary supplements, on human resilience in both model systems and human subjects
Develop cutting-edge computational methods and technologies to enable the generation or testing of novel hypotheses on health effects of natural products, potentially expanding the sources of products studied in the future
Support the development and transition to sustainability of a data repository relevant to the CARBON program

Consistent with recommendations from the Expert Panel, plans for fostering diverse research teams and natural products research pipeline diversification and for capitalizing on innovative ideas generated by the diverse points of view will also be required as an integral element of each component of the program.

Examples of proposed CARBON activities could include, but are not restricted to:

Translational Botanical Research

Application, for highly promising botanical products, of innovative approaches to elucidate molecular, cellular, tissue, and organ level mechanisms of action in preclinical models coupled with mechanistic clinical trials assessing optimal dosing, safety/toxicity, and translational relevance.
Investigation of intercomponent interactions between bioactive compounds within a product, and between a product and other environmental exposures including diet and molecular and cellular mechanism(s) required to generate clinically relevant biological effects.
Application of state-of-the-art approaches, as well as the development of new methods or adaptation of cutting-edge methodologies from other areas of biomedical research, to better understand resilience and health-relevant modulation of natural product health effects by individual differences including genetics and epigenetics (including microbiota), and/or by historical and environmental contexts, including timing of exposures and health-relevant behaviors such as sleep and physical activity.
Development and validation of methods to elucidate dynamic, reciprocal interactions between the gut microbiota and metabolism of chemically complex ingested plant products and their implications for modulating or mediating health effects of the products.

Technology and Methodology Development

Development of innovative computational methods to discover, across multiple levels of human health and/or resilience, mechanisms or multisystem effects that are modulated by chemically complex materials such as foods, herbs/botanicals, and/or other natural products.
Development of methods integrating informatics, machine learning, artificial intelligence, and/or high content screening data to understand multisystem effects.
Development of computational methods to generate strong hypotheses regarding previously undescribed resilience-relevant biological activities of nonnutritive constituents of dietary plants and other botanicals, which may include traditionally used botanicals.
Development of computational methods to accelerate identification of active constituents in mixtures and development of hypotheses about potential associations between natural products and whole person health- and resilience-relevant outcomes.

Resource Development

Further development of open access databases and resources to accelerate natural product research more broadly by facilitating the elucidation of structures.