Many commonly used medicines are still derived from plants. Scopolamine, used for motion sickness and to treat post-surgical nausea, is made from plants in the nightshade family. Digoxin, a heart medication, comes from the foxglove plant. Codeine and other opioid painkillers are derived from opium poppies.
But plants used to make medications are sometimes endangered or expensive. A poor growing season or geopolitical instability in the region where a plant is cultivated could cause a decline in medication supply.
Now, a Stanford scientist has figured out how to isolate the molecular “factory” within an endangered plant and assemble it within another, more widely available plant.
“This was a challenge, because plants are pretty complicated,” says Elizabeth Sattely, a professor of chemical engineering. “They’re pretty difficult to work with. Their genomes are very complicated.”
Sattely and her team worked with a Himalayan plant called the mayapple, which produces precursors to a commonly used chemotherapy drug called etoposide. Etoposide is used to treat a variety of cancers, including lymphoma, lung cancer, testicular cancer and some types of leukemia and brain cancer. It’s on the World Health Organization’s list of essential medicines—drugs considered crucial for medical system functioning. But mayapple is slow-growing, and supply has been in decline for years due to high demand.
Sattely realized that mayapple’s chemical assembly line starts up in response to its leaves being injured. Once this injury occurs, the plant starts producing a number of proteins. Some of these proteins eventually produce etoposide’s precursor. But the big question was which proteins? There were more than 30 present, but not all of them were involved in making the precursor.
“What was crucial here was really narrowing down our candidate list,” Sattely says.
She and her team tried out various combinations of proteins until they figured out which 10 constituted the assembly line. Then, they put the genes that made these 10 proteins into a different plant. The plant they chose was Nicotiana benthamiana, a wild relative of tobacco, chosen because it’s widely available and easy to grow in a lab. The Nicotiana plant began producing the etoposide precursor, just like mayapple. Sattely and her graduate student, Warren Lau, published their discovery in the journal Science.
“This is a very nice proof of concept,” says Sattely.
Sattely hopes to ultimately make microbes, such as yeast, produce the same molecules, skipping plants entirely. If she succeeds, she’ll be joining a number of scientists who have figured out how to turn microorganisms into drug-producing factories. Just this week, German scientists announced they’d made genetically modified yeast produce THC, the compound in marijuana that produces the “high” and can help treat side effects from chemotherapy and other illnesses. Last month, Stanford researchers published results showing how they had made yeast produce hydrocodone, an opioid painkiller similar to morphine. The breakthrough has potential to make such drugs cheaper and more accessible. In 2013, chemical engineers at Berkeley coaxed genetically modified yeast into producing anti-malaria drugs.
Making drugs with yeast is even simpler and less expensive than using common lab plants. The supplies are incredibly cheap and easy to produce, take little space or special care, and can be endlessly manipulated.
"The promise of the field of synthetic biology is that you can get cells to make or do anything you want," Sattely says.
But there’s still much to learn from plants and the chemicals they produce. As plants' molecular production pathways become better understood, scientists can learn to manipulate them, potentially producing better drugs with fewer side effects.
“Plants are some of the best molecular factories in nature,” Sattely says. “We have a lot to learn about these molecules that are so important for human health and also for plant health.”