Kendall Squared brings you dispatches from the world’s epicenter for biotechnology and drug discovery.
The sludge under the lab bench looks like leaf litter soup. Vials of brown, ochre, and reddish pollen extracts clutter the surface above. Beside them, a foil-covered beaker contains an herbal broth. It’s cloudy, like a bit of raw egg white left out overnight.
To biologist Jing-Ke Weng, that mess is a treasure — a rich source of potential medicines to treat cancer, perhaps, or insomnia, or blood disorders.
Many drug discovery experts would be skeptical. They’d point out that the biggest pharma companies in the world have spent decades, and millions, trying to make new drugs from plants. They’d tell him it’s just too hard.
Weng, though, isn’t worried. At 34, he’s already helped map the molecular factories that produce some of the most important plant chemicals around. And now that he’s working at the Whitehead Institute for Biomedical Research, he’s determined to harness peanut skins, and twisted roots, and an herb known as horny goat weed — and the strange blooms in a seventh-floor greenhouse — to treat human disease.
The idea is not new. Some of our best-selling commercial drugs come from plants: aspirin from willow bark, the tumor-slowing Taxol from the Pacific yew tree, the leukemia medication vincristine from a pinkish jungle flower called the rosy periwinkle. And last year, Chinese chemist Tu Youyou shared the Nobel Prize in Physiology or Medicine for her research on artemisinin, a malaria drug extracted from a delicate bush called sweet wormwood.
But this type of botanical sleuthing is an anomaly in the biotech hotbed of Kendall Square.
Most large pharmaceutical companies phased out their screening of natural products in the 1980s. It was expensive, and eureka moments often turned sour: The researchers kept rediscovering molecules that had already been identified.
Academic labs and small startups have taken over some of that research — but they’ve focused mostly on bacteria and fungi, because in those micro-organisms, the genes that code for medicinal compounds tend to stick together.
Not so with plants, said Gregory Verdine, a chemist at Harvard and founder of the natural products company Warp Drive Bio. “If you go into plants, you add another layer of complexity to what’s already incredibly complex,” he said.
Inspiration in ‘fishy-tasting grass’
Most scientists are loath to use the word “magical”— but that is Weng’s go-to adjective when describing his plants.
The conviction began when he was a kid in Hangzhou, China. If he got sick, his mother would walk out of their first-floor apartment to collect a potful of what he translates as “fishy-tasting grass.” In those days, it grew everywhere, like a weed.
His mother would bring it to a boil on the stove for 20 minutes, and then scoop out the soggy blades, serving him the blackish, smelly liquid that remained.
“It doesn’t look good and it doesn’t taste good, but I like it, because it really helps when you feel bad,” he said.
“We have the luxury of being opportunistic. There is potential absolutely everywhere.”
Michael Torrens-Spence, researcher in Weng's lab
Weng’s mother wasn’t a trained traditional Chinese herbalist, but she knew enough to treat the everyday colds, and scrapes, and stomachaches of childhood. His father was a geologist. He would take Weng out on field trips, pointing out different kinds of rocks, talking about continental drift.
But it was the plants and insects that Weng really wanted to play with.
He moved away from them as an undergraduate, doing neuroscience research. But he didn’t like having to kill mice for work. And so, for his PhD at Purdue, he began to work on the chemistry of wood.
Weng was investigating a compound called lignin. When it appeared millions of years ago, it hardened cell walls, making plants able to grow taller, prevent rot — and, eventually, allowing trees to produce enough oxygen for insects to evolve flight.
To make chemicals like lignin, the plant has to develop a kind of inner assembly line.
Imagine a series of autoworkers, each one responsible for tightening screws or punching holes over and over again. In the plant, enzymes play that role, taking the basic molecular chassis and adding an oxygen here, a carbon there, until the simple molecule has been turned into a sophisticated piece of machinery.
Weng was able not only to identify the steps in that molecular assembly line; he was also able to pinpoint the genes that had allowed them to evolve in that particular plant family to begin with.
“He was the most creative student I have ever had and probably will ever have,” said Clint Chapple, his PhD supervisor at Purdue. “Most PhD students graduate with one, two, three scientific papers that they’ve led. Jing-Ke published 13 papers out of his PhD. Normally, you get tenure for publishing that many papers.”
Looking to Amazon for guidance
Weng may have been a superstar of a PhD student, but the job offer from the Whitehead Institute surprised him.
The Whitehead is a center for biomedical research, full of cancer biologists. Weng had spent years unraveling the molecular pathways that allowed plants to stand up.
But he was unfazed. He knew how to break apart assembly lines of enzymes — and those tiny factories produced an almost infinite catalogue of strange chemicals, many of them medicinal.
He began to seek them out.
From a lecturer at a natural history museum, he heard that Melanesian tribes used the calming Kava Kava root for rituals. Soon after, he was unpacking live plants from a nursery in Hawaii. At a high school science fair, Weng’s father saw an experiment suggesting that peanut skins could help patients with low platelet counts. He mentioned it to his son, and Weng bought 11 pounds of peanut skins from China. They’re soaking in ethanol under a lab bench.
One of his postdocs — a surfer — pulled a wrack of red algae from a tide pool in California, having read that it harbored cancer-fighting compounds. Now they’re preparing to sequence it in Weng’s lab.
Sometimes Weng uses Amazon.com, where there is a lively trade in herbal supplements, to gauge the potency of a plant, by looking at the comments from people who have ordered extracts.
“People actually are [reporting] the type of response they’ve observed from their own body. It’s free information,” he explained. If enough people report a reaction, he figures the plant is worth investigating: “It’s reassuring that it’s not time wasted.”
In January, one of Weng’s postdocs ordered an extract of Kava Kava on Amazon and made a home brew. It tasted, he said, like spicy mud. At the suggested dose, the drink had no effect. But at a higher concentration? “Instant happiness.”
When he gets a plant, the first thing Weng does is to destroy it. He separates leaf from stem from root, even plucking off the minute hairs. Then each part is mashed up. The genetic material is extracted and sequenced, while in another machine, the plant’s molecules are bombarded with electrons so that the chemical compounds can be identified.
With those two sets of data, Weng tries to match the potent chemicals he’s interested in to specific genes. If he identifies the necessary genes, he can transplant them into E. coli or yeast, which will then serve as a living farm, churning out medicinal compounds.
A greenhouse full of potential miracles
A trip through Weng’s greenhouse shows why that microscopic mass production is so useful. Michael Torrens-Spence, a postdoc, stops beside a tiny reddish green plant called Tibetan golden root. It grows in rocky crags one mile above sea level, and it’s become so prized in traditional Chinese medicine that illegal harvesting has nearly wiped it out — making the compound “absurdly expensive,” Torrens-Spence says.
A single milligram of extract powder — a quarter the weight of a grain of sand — can cost $200.
To make things worse, if you grow the plant at lower altitudes, it stops producing the beneficial compound. Other specialized plant chemicals are similarly hard to get in quantities large enough even for basic research, not to mention a clinical trial.
Yet Weng and Torrens-Spence have succeeded at coaxing yeast into manufacturing the Tibetan golden root’s medicinal chemical in a beaker, providing a new, inexpensive way to collect it. Their paper should be coming out in the next few months — and they’re filing a patent to go with it.
It’s hard to say whether a Food and Drug Administration-approved drug will emerge from those beakers. Or from the flower across the greenhouse that looks like the frilly hem of a flamenco dress. Or from the surfing postdoc’s seaweed.
But walking among his beakers clouded with bacteria and his vials of pollen, Weng doesn’t look nervous. As Torrens-Spence puts it, “We have the luxury of being opportunistic. There is potential absolutely everywhere.”