Multi-Center Consortiums Seek to Create Better Plant Medicines

Two multi-institutional consortiums funded by the US National Institutes of Health (NIH) have mapped the genes of dozens of medicinal plants in order to study how they create complex therapeutic compounds. Using this genetic data, the researchers plan to engineer plants to produce more of a specific naturally occurring medicinal chemical, or slight variations of these phytochemicals, hopefully resulting in new and better medicines.¹

The Medicinal Plant Consortium (MPC) and the Medicinal Plant/Human Health Consortium (MP/HHC)—2 separate but similar projects—are funded by grants totaling about $9 million, awarded by the National Institute of General Medical Sciences at NIH and made possible by the American Recovery and Reinvestment Act.^1,2 The MPC team is led by the University of Kentucky (UK) and also includes Iowa State University, Michigan State University, the University of Mississippi, Purdue University, Texas A&M University, and the John Innes Centre in Norwich, England. The MP/HHC is led by Washington State University (WSU), and has partnered with the Dorothy Bradley Atkins Medicinal Plants Garden of the University of Illinois at Chicago (UIC), Donald Danforth Plant Science Center in St. Louis, and National Center for Genome Resources in Santa Fe, New Mexico.²

MPC leader and UK plant science professor Joe Chappell, PhD, said the MPC’s work would not have been possible without the people at each of the participating institutions who had a particular interest in one or more of the target plants. “This is what made our efforts so rich. We had expertise for each of the identified plants, propagating the plant, and knowing a lot about where and how to look for interesting compounds in the plants” (e-mail, January 5-10, 2012).

Both consortiums started their work in 2009 and began by obtaining physical specimens. Norman G. Lewis, PhD, leader of the MP/HHC and Regents Professor and Director at WSU, emphasized that their team of experts in medicinal plant biochemical pathways carefully selected species with the most complex chemical structures, as well as those widely used in medicine today. “Many of the plants being studied are not only medicinally useful, but their molecules are structurally complex and it is therefore very expensive and difficult to synthesize them,” said Dr. Lewis (oral communication, January 17, 2012). Because many of the plants are over-harvested and even endangered in their native lands, the consortiums hope to engineer alternative plants and plants in cell culture in order to reduce the threat of species extinction.

Herbs analyzed by the consortiums include ginseng (Panax spp.), andrographis (Andrographis paniculata), marijuana (Cannabis sativa), hoodia (Hoodia gordonii), ginkgo (Ginkgo biloba), foxglove (Digitalis purpurea)—the source of the widely used heart drug digoxin—and periwinkle (Catharanthus roseus), which is used to make medicines that treat several cancers, childhood leukemia, and Hodgkin’s disease. Dr. Lewis pointed out that the medicinal plants chosen include those extensively used in pain management, such as morphine from the opium poppy (Papaver somniferum); cancer treatment, such as Taxus species harboring the anti-cancer compound paclitaxel (Taxol^®), podophyllotoxin from Himalayan mayapple (Podophyllum hexandrum), and camptothecin from Camptotheca acuminata; and others in consideration for disorders such as for Alzheimer’s disease and new cancer treatments.

Using almost any plant tissue, the consortium researchers were able to sequence the genes expressed throughout each plant, resulting in sets of data called transcriptomes. A transcriptome is not an entire genome, but a small subset of genome DNA comprised of “all the genes that are important for creating the individual plants,” said Dr. Chappell. Researchers can use the transcriptomes to look for the genes that are “switched on” and “sending messages” throughout the plant—which indicates that an important substance or process is being activated—and then reassemble these “candidate” genes using algorithms, said Dr. Lewis.

For example, scientists know that valerian (Valeriana officinalis) produces several different kinds of chemicals, but have not determined which is responsible for the plant’s sedative effects. According to Dr. Chappell, MPC’s work has generated information that will help them identify valerian plant lines or tissues where one or more of these compounds might accumulate. These genetic maps provide insight into how plants biosynthesize—or assemble—molecules to make complex and medicinal compounds. The researchers will also be able to produce the compounds and derivatives in alternative organisms.

“We should be able to create a yeast line that produces one of the active ingredients of the Valeriana plant,” said Dr. Chappell. “I know this sounds crazy, but it’s terribly exciting—if we can isolate one active ingredient, then we can probably make a few changes to the compound and possibly make it a more effective medicinal. We are trying to glean the secrets plants learned [throughout evolution] that has allowed them to make fantastic chemicals, chemicals that gave plants the adaptive advantages to live in all kinds of habitats on planet earth, and chemicals that man has learned to use for our own purposes (food, medicines, etc).”

Scientists could also potentially create better medicines by modifying the medicinal compounds. “Very often,” said Dr. Lewis, “plants make a chemical structure or scaffold that can be modified chemically upon and improved. Once you change or modify a compound with parts of other molecules it can affect the mode of action, and take it away from being, for example, very toxic or not very effective to being a blockbuster drug.”

The MPC made its transcriptomes available online in December of 2011, and MP/HHC has made most of the transcriptomes available, though it is waiting to obtain a couple of rare plants from places like Indonesia. Dr. Chappell said researchers and industry members around the globe are already taking advantage of the information. “You may know that the nutraceuticals industry wants to have higher standards for their products. So the manufacturers of supplements are using our information to develop better quality control standards for their products. One example of this technology is DNA barcodes, little technology tags that can be used by the manufactures to document what plant species are actually in their product and to inform the customer if any other plant materials (i.e., contaminants) might also be in the product.”

The consortiums’ members are now working on mapping the plants’ metabolomes and publishing them online. Metabolomes are “like a fingerprint of all the molecules that are in the plant,” said Dr. Lewis. Though previous work has been done in this area, Dr. Lewis noted that the progress has been limited due to the years of dedicated research it takes to identify each step in a biochemical pathway. According to UIC’s webpage for the MP/HHC, “The current understanding of the formation of plant-derived medicinal compounds at the enzyme, gene, and regulatory levels is very incomplete. Not a single complex plant medicinal pathway has yet to be completely elucidated at both the enzyme and the regulatory level.”³

“But with this consortium work,” said Dr. Lewis, “one has the expectation that one can identify the genes much faster. We’ve basically opened up a treasure trove of information.”

More information on MPC is available at http://medicinalplantgenomics.msu.edu and http://metnetdb.org/mpmr_public/. More information on MP/HHC is available at www.uic.edu/pharmacy/MedPlTranscriptome.


—Lindsay Stafford


References

1. New light on medicinal benefits of plants. Science Daily. December 15, 2011. Available at: www.sciencedaily.com/releases/2011/12/111215095243.htm. Accessed January 9, 2012.

2. Welcome to our website. Transcriptome Characterization, Sequencing, And Assembly Of Medicinal Plants Relevant To Human Health website. Available at: www.uic.edu/pharmacy/MedPlTranscriptome/#. Accessed January 9, 2012.

3. Soejarto S. Why the transcriptome project? Transcriptome Characterization, Sequencing, And Assembly Of Medicinal Plants Relevant To Human Health website. June 18, 2011. Available at: www.uic.edu/pharmacy/MedPlTranscriptome/about.html. Accessed January 9, 2012.