Making green drugs: Tapping into nature without tapping it out

Making green drugs: tapping into nature without tapping it out
Yew aril. Credit: stanze, CC BY-SA 2.0

Roland Kersten made his way down the aisle of the local supermarket, selecting different varieties of potato. This was one of the easier collection trips that a researcher in Whitehead Institute Member Jing-Ke Weng's lab has made to gather different plant species for investigation. Kersten, then a postdoc in Weng's lab, has also collected specimens on the coasts of California and Panama. Lab members regularly track down different species growing throughout Harvard University's sprawling Arnold Arboretum. They visit botanical gardens and plant repositories throughout the region, or if they cannot find what they need there, farther abroad; recently, several lab members traveled to a nursery in the Yukon. Weng has had his parents send him pollen from China.

What are the researchers hoping to discover? Plants are full of an astonishing variety of chemistry, much of it unique to specific species. The Weng lab wants to understand that chemistry and how it can be put to use. Plants are stationary, so unlike animals they cannot run away from predators or move from a worsening location to a better one. Instead, they have developed a vast and varied chemical arsenal to do things like attract pollinators, deter or defend against pests, and otherwise interact with the world. Some of the chemicals they make have proven useful for people, in particular as medicines. Traditional forms of medicine have made use of plant chemistry for thousands of years, such as, in ancient China, prescriptions of ginger to treat upset stomachs and willow bark (a precursor to aspirin) to relieve pain and inflammation.

Drug discovery from nature continues to the modern day. Successful drugs derived from plants in addition to aspirin include the antimalarial artemisinin, extracted from sweet wormwood (Artemisia annua), and the cancer paclitaxel (taxol), extracted from yew. But with hundreds of thousands of plant species in existence, many specific to small regions, much of plants' medicinal potential remains untapped. Weng hopes to discover in unexplored or underutilized plants, starting with the plants used in traditional medicine to help direct his search. Additionally, because the demands of the pharmaceutical industry now often exceed what nature can sustainably provide, Weng has developed a system for recreating plant chemistry in more scalable systems. By learning from nature without overtaxing it, Weng aims to help develop potent new drugs for a plethora of medical problems while addressing some of the environmental concerns of typical drug development.

The cost of drug discovery

Most modern pharmaceutical drugs are not discovered in nature but rather designed in the lab. Chemists manipulate molecules in the laboratory, step by step, in long series of reactions to create medicines. This process has led to effective drugs, but it has its limitations: researchers most commonly create two-dimensional or flat chemical structures, like strings or sheets of molecules, for the ease of their synthesis. Plants can innovate in three dimensions, creating all kinds of shapes, like origami folded out of the basic strings and sheets, whose configurations enable more specific interactions inside of cells. Researchers are also much less efficient than plants at creating complex molecules: what a plant can achieve with a few enzymes may require many more chemical transformations to accomplish in the lab—with varying efficiencies at each step—and the elaborate processes required often have high energy demands and create a lot of environmentally hazardous waste.

As researchers' awareness of and concern about the negative environmental impacts of synthetic drug development and production has grown, many are turning to "green chemistry" approaches in order to reduce the environmental footprint of their work. One way to be greener is to expand the search for drugs that already exist in nature. Harvesting drugs directly from plants eliminates much—though not all—of the energy consumption and pollution linked to producing artificial chemicals in the lab.

Making green drugs: tapping into nature without tapping it out
Postdoc Roland Kersten studied how plants including goji berries and potatoes produce lyciumins, molecules that may be able to treat high blood pressure. Credit: Left: Goji berries,r CC BY 1.0. Right:red potatoes . Credit: Mike Mozart, CC BY 2.0

However, harvesting from nature has its own environmental drawbacks. As the demand for a plant-based drug rises, that plant can become at risk of overharvesting. This is already a concern for some plants used in popular health supplements, such as American ginseng (Panax quinquefolius), guggul (Commiphora wightii), and goldenseal (Hydrastis canadensis). Some plants, such as the yew tree, the source of taxol, take a very long time to mature and become ready for harvesting, which reduces supply of the drug and puts pressure on the existing population. Several species of yew are considered at-risk and others are endangered. Other medicinal plants are rare or grow only in particular environments—which may themselves be vulnerable. For these reasons, suppliers may struggle to procure enough of a plant-based drug for a clinical trial, let alone for . In an effort to meet demand, they risk harvesting an unsustainable quantity of the plant and endangering the species.

Golden root (Rhodiola rosea), which the Weng lab studies because it produces salidroside, a chemical that may help treat a number of brain and mental health issues such as depression and fatigue, and kava (Piper methysticum), which they study for its potential pain relief and anti-anxiety properties, have both suffered from overharvesting in recent years due to growing commercial interest in them as herbal medicine, leading to concern about overharvesting in the wild.

Gaining from nature without draining it

To address the risk of overharvesting, Weng has developed a pipeline for drug development that allows plant-derived medicines to be mass produced without harvesting much of a plant at all. Weng and his researchers begin by searching out valuable chemistry in plants. Then they identify the complete assembly line of enzymes that a plant uses to create the molecule they are interested in. They use this information to recreate the biological pathways that the plants use to produce their molecules in new hosts that are better suited to large-scale harvesting, such as yeast, bacteria and tobacco, by copying the genes for all of the necessary enzymes and inserting them into the chosen host. If they have mapped the pathway correctly, the new host will start producing the desired chemical. The hosts that the lab uses are all relatively easy to grow, quick to produce the molecules, and could be farmed at scale in order to increase production. The researchers have done this successfully for a number of molecules, including salidroside from golden root; kavalactones from kava; lyciumins, which may be able to treat high blood pressure; salicylic acid, commonly used to treat skin conditions such as acne and warts; and more.

The Weng lab's process for reproducing plant chemistry also allows them to tailor the molecules they are interested in by altering the assembly lines of enzymes when they recreate them, letting them create new-to-nature variations on the pre-existing molecules. These variations may be more effective or safer medications than the original molecules, further expanding the potential library of drugs that could be derived from .

The goal in creating this pipeline for scalable production has been to show that it is possible to make sustainable, green pharmaceuticals. Mass producing plant-derived medicines this way would make drug production easier and cheaper and protect the species and their natural habitats from the damages of overharvesting. Protecting the environment is also important to the medical field, because hidden somewhere in the hundreds of thousands of out there is the next artemisinin or paclitaxel, waiting for a researcher like Weng to uncover it. Protecting the uncharted biodiversity around us gives researchers a chance to find that drug, whereas overtaxing our environment—through both overharvesting and contributing to climate change-driven loss of plant diversity—may mean that the next big medicinal plant disappears unnoticed, taking its chemical secrets with it into extinction.

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