Lines of tobacco leaves hanging to dry
Stroll through ancient churchyards in England, and you’ll likely see yew trees with bright green leaves and stunning ruby red fruits guarding the graves. These coniferous trees are known in European folklore as a symbol of death and doom.
They’re anything but. The Pacific yew naturally synthesizes paclitaxel—commonly known as Taxol, a chemotherapy drug widely used to fight multiple types of aggressive cancer. In the late 1990s, it was FDA-approved for breast, ovarian, and lung cancer and, since then, has been used off-label for roughly a dozen other malignancies. It’s a modern success story showing how we can translate plant biology into therapeutic drugs.
But because Taxol is produced in the tree’s bark, harvesting the life-saving chemical kills its host. Yew trees are slow-growing with very long lives, making them an unsustainable resource. If scientists can unravel the genetic recipe for Taxol, they can recreate the steps in other plants—or even in yeast or bacteria—to synthesize the molecule at scale without harming the trees.
A new study in Nature takes us closer to that goal. Taxol is made from a precursor chemical, called baccatin III, which is just a few chemical steps removed from the final product and is produced in yew needles. After analyzing thousands of yew tree cells, the team mapped a 17-gene pathway leading to the production of baccatin III.
They added these genes to tobacco plants—which don’t naturally produce baccatin III—and found the plants readily pumped out the chemical at similar levels to yew tree needles.
The results are “a breakthrough in our understanding of the genes responsible for the biological production of this drug,” wrote Jakob Franke at Leibniz University Hannover, who was not involved in the study. “The findings are a major leap forward in efforts to secure a reliable supply of paclitaxel.”
A Garden of Medicine
Humans have long used plants as therapeutic drugs.
More than 3,500 years ago, Egyptians found that willow bark can lower fevers and reduce pain. We’ve since boosted its efficacy, but the main component is now sold in every drugstore—Aspirin. Germany has approved a molecule from lavender flowers for anxiety disorders, and some compounds from licorice root may help protect the liver, according to early clinical trials.
The yew tree first caught scientists’ attention in the late 1960s, when they were screening a host of plant extracts for potential anticancer drugs. Most were duds or too toxic. Taxol stood out for its unique effects against tumors. The molecule blocks cancers from building a “skeleton-like” structure in new cells and kneecaps their ability to grow.
Taxol was a blockbuster success but the medical community was concerned natural yew trees couldn’t meet clinical demand. Scientists soon began trying to artificially synthesize the drug. The discovery of baccatin III, which can be turned into Taxol after some chemical tinkering, was a game-changer in their quest. This Taxol precursor occurs in much larger quantities in the needles of various yew species that can be harvested without killing the trees. But the process requires multiple chemical steps and is highly costly.
Making either baccatin III or Taxol from scratch using synthetic biology—that is, transferring the necessary genes into other plants or microorganisms—would be a more efficient alternative and could boost production at an industrial scale. For the idea to work, however, scientists would need to trace the entire pathway of genes involved in the chemicals’ production.
Two teams recently sorted through yew trees’ nearly 50,000 genes and discovered a minimal set of genes needed to make baccatin III. While this was a “breakthrough” achievement, wrote Franke, adding the genes to nicotine plants yielded very low amounts of the chemical.
Unlike bacterial genomes, where genes that work together are often located near one another, related genes in plants are often sprinkled throughout the genome. This confetti-like organization makes it easy to miss critical genes involved in the production of chemicals.
A Holy Grail
The new study employed a simple but “highly innovative strategy,” Frank wrote.
Yew plants produce more baccatin III as a defense mechanism when under attack. By stressing yew needles out, the team reasoned, they could identify which genes activated at the same time. Scientists already know several genes involved in baccatin III production, so these ingredients could be used to fish out genes currently missing from the recipe.
The team dunked freshly clipped yew needles into plates lined with wells containing water and fertilizer—picture mini succulent trays. To these, they added stressors such as salts, hormones, and bacteria to spur baccatin III production. The setup simultaneously screened hundreds of combinations of stressors.
The team then sequenced mRNA—a proxy for gene expression—from more than 17,000 single cells to track which genes were activated together and under what conditions.
The team found eight new genes involved in Taxol synthesis. One, dubbed FoTO1, was especially critical for boosting the yield of multiple essential precursors, including baccatin III. The gene has “never before been implicated in such biochemical pathways, and which would have been almost impossible to find by conventional approaches,” wrote Franke.
They spliced 17 genes essential to baccatin III production into tobacco plants, a species commonly used to study plant genetics. The upgraded tobacco produced the molecule at similar—or sometimes even higher—levels compared to yew tree needles.
From Plant to Microbes
Although the work is an important step, relying on tobacco plants has its own problems. The added genes can’t be passed down to offspring, meaning every generation has to be engineered. This makes the technology hard to scale up. Alternatively, scientists might use microbes instead, which are easy to grow at scale and already used to make pharmaceuticals.
“Theoretically, with a little more tinkering, we could really make a lot of this and no longer need the yew at all to get baccatin,” said study author Conor McClune in a press release.
The end goal, however, is to produce Taxol from beginning to end. Although the team mapped the entire pathway for baccatin III synthesis—and discovered one gene that converts it to Taxol—the recipe is still missing two critical enzymes.
Surprisingly, a separate group at the University of Copenhagen nailed down genes encoding those enzymes this April. Piecing the two studies together makes it theoretically possible to synthesize Taxol from scratch, which McClune and colleagues are ready to try.
“Taxol has been the holy grail of biosynthesis in the plant natural products world,” said study author Elizabeth Sattely.
The team’s approach could also benefit other scientists eager to explore a universe of potential new medicines in plants. Chinese, Indian, and indigenous cultures in the Americas have long relied on plants as a source of healing. Modern technologies are now beginning to unravel why.
Shelly Fan
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