UC Santa Cruz- led research center focuses on botanical natural products

Although millions of people take plant-based dietary supplements or herbal medicines, understanding the effects of these natural products on human health has proven to be extremely challenging. Clinical trials like those used to evaluate drugs have largely failed to show efficacy for botanical natural products.

A new research center led by UC Santa Cruz and funded by the National Institutes of Health (NIH) will focus on understanding how botanicals work on the molecular and cellular levels to provide a better foundation for clinical trials of these complex natural products.

We're trying to put a scientific foundation behind the use of botanical natural products, so that people can make informed decisions about what botanicals might be helpful to an individual."

John MacMillan, principal investigator, professor of chemistry and biochemistry at UC Santa Cruz

In addition to MacMillan's lab at UCSC, the center includes research groups led by principal investigator Roger Linington at Simon Fraser University in British Columbia, and Nadja Cech at the University of North Carolina, Greensboro. With a grant of $5 million over five years, it is one of five research centers to receive joint funding from the NIH Office of Dietary Supplements, National Center for Complementary and Integrative Health (NCCIH), and National Institute on Aging (NIA) to support clinical trials of complex natural products.

"These research centers demonstrate NIH's firm commitment to rigorous investigation of natural products as they pertain to complementary and integrative health approaches," said Helene Langevin, M.D., director of NCCIH. "Exploring basic biological mechanisms of natural products is a strategic priority for us."

The UCSC-led center will address two major challenges in studying botanicals. One is the variability of botanical materials and the difficulty of determining what their active components are. The other issue relates to how clinical trials are designed.

"In drug trials, we usually have a clear end point--we want to know if it reduces a particular lipid level or shrinks a tumor. But many people take botanicals for overall health benefits or to enhance their immune system, so how do you measure that? If we have a mechanistic understanding of how they work, then maybe we can design a clinical trial with a more definitive and measurable end point," MacMillan said.

The center will use two innovative screening platforms the researchers have developed to measure the effects on cells of complex botanical natural products--FUSION, developed by MacMillan's lab, and Cytological Profiling, developed by Scott Lokey, professor of chemistry and biochemistry at UCSC. These high-throughput, information-rich screening platforms, combined with a bioinformatic pipeline for data analysis, will yield insights into the basic mechanisms underlying the activity of the botanical products.

"Both approaches take advantage of fairly simple cell systems to provide a lot of detailed information," MacMillan said. "We can look at hundreds of features within the cells, from the dynamics of specific proteins to the expression of specific genes, to see what these botanicals might be doing."

The center's approach will also enable the researchers to address the question of whether multiple compounds in complex botanical products interact synergistically to have an effect. "With our tools, we think we can start to understand synergy in complex mixtures," MacMillan said.

The team has selected a list of priority botanicals for deep analysis, focusing on several well-known natural products that have been used for anti-inflammatory effects or for enhancing the immune system. The list includes sweet Annie (Artemisia annua, also called sweet wormwood), goldenseal (Hydrastis canadensis), feverfew (Tanacetum parthenium), and ashwagandha (Withania somnifera).

"Whether these natural products have the benefits for which people take them is still an open question," MacMillan said. "We want to know what molecules are present in these botanicals, is there a robust biological effect on immune cells, and if so, what chemicals are responsible for driving that response?"

The results of the center's analyses will be made broadly available to the natural products research community through open-access algorithms and web-based search tools.