Djaja D. Soejarto has been trekking through the rain forests of Laos and Vietnam for over two decades in search of cytotoxic molecules—the anticancer drugs of the future.
It's a quest—a biological prospecting—that depends on carefully-crafted partnerships with national governments, village communities, and local healers.
"The community has to know what we intend to do. They have to permit us to go in there," Soejarto told The Daily Beast. "When you want to sit down with the [traditional] healer, before you ask any questions, you have to ask permission to the healer whether he or she wishes to be interviewed."
An emeritus professor of the College of Pharmacy at the University of Illinois at Chicago, Soejarto recently contributed to a paper with first author Joshua Henkin. It describes two expeditions in Laos during a recent “dry winter season” in Xiengkhouang along with Bolikhamxay, a lowland rain forest recovering from the devastation of past fires and logging. Soejarto's team collected over 200 samples from nearly 100 species in total.
The report found that, based on intel from traditional healers in Laos, six unique plant extracts from six different species “exhibited notable cytotoxicity” against colon cancer.
Five of these plant extracts killed more than half of HT-29 colon cancer cells—a notoriously hard-to-treat cell line (adenocarcinoma).
"It's not that you necessarily can translate these results directly to [...] a tumor, but at least it gives you some idea that it's killing these cells to a significant degree," Henkin told The Daily Beast. "There aren't more of them. And there are, in fact, [colon cancer cells] that died as a result of this."
This success rate—a high 'hit rate' against colon cancer cells—is exceedingly rare, ethnobotanist and anthropologist Glenn Shepard told The Daily Beast. "They found that plant species derived from traditional medicine had a 6.25 percent success rate in bioassays for some kind of anti-cancer activity, a much higher hit rate than the 1 percent success rate of randomly screened plant extracts for anti-cancer activity documented in a decade-long random screening project by the National Cancer Institute," he said.
But how can we be sure that what's in the lab can actually help cure what's in the body?
"There's no guarantee that the cell lines you have in the lab really have exactly the same characteristics as the tumor cell line, but there are ways of investigating that further," Henkin said.
One way to solve this is to ask potentially bioactive agents to pass a migration assay, which tests a molecule's strength against a cancer cell by tracking its moxie and persistence. Can these agents follow the cancer as it moves across the plate?
"The ones that will actually move across the gel all the way to the other side," Henkin explained, are the agents that might show the most promise. A tumor, after all, is always on-the-move: It's a thing that invades, then metastasizes.
That said, Henkin added, it's worth noting that the colon cancer cells that were used in paper were originally derived from an epithelial colon cancer that was removed from an actual human being.
"And to that extent, it isn't different from a normal human," he said.
Plant-derived drugs and treatments are becoming more prevalent in allopathic medicine (so-called 'Western' or 'mainstream' medicine): a 2012 paper estimated over 60 percent of anticancer drugs originate from natural sources. "Nature is the best source of anti-cancer drugs," a 2017 index of scientific literature on the topic proclaimed.
Soejarto and Henkin's paper outlines how the old-school bioprospecting method—collecting a diverse range of wild plants at random testing them in the lab—was actually less successful than a strategy called "ethnobotany,” a culturally- and community-oriented approach that takes folk medicine seriously.
"What I think is really interesting about the plants that we found with active plant parts against the HT-29 cells is that three of the plant parts were in fact used locally for various purposes of medicine," Henkin said. (None of the plants featured in the paper are used locally in Laos for cancer, though some healers do use plants to treat cancer.)
Shepard’s research explores how sensory experiences impact emotions, which can affect both prognosis and treatment.
“All illnesses have a psychological component and a cultural component,” he said.
The process from plant to treatment is long, expensive, and arduous. The most recent FDA-approved single molecule was derived from Cephalotaxus harringtonia, a conifer in Japan. It perfectly illustrates this difficult journey from plant to drug.
For one thing, there’s the time element. It took 40 years from isolation to drug approval: the plant's initial isolation work started in the 1960s, and the anticancer drug omacetaxine mepesuccinate was approved by the FDA in 2012."
Vincristine and vinblastine, two chemotherapy drugs, were first approved by the FDA to treat cancer in the 1960s. The two alkaloids are now commonly used as chemotherapy agents against several types of cancer. Their history began in the West Indies, when researchers isolated extracts from the plant Madagascar periwinkle (Catharanthus roseus), a small decorative plant with delicate white or pink flowers.
"Beautiful plant," Soejarto said. "It spread out to other parts of the world as ornamental." In the West Indies, the plant was used by local healers (ethno-botanically) to treat diabetes. Researchers from the University of Western Ontario planned to test its extracts for that potential.
"But then, they found that it was killing all of the rodents," Henkin said.
The researchers found something surprising: Though it had no effect on the mice's blood sugar levels, it did lower their white blood cell counts—dramatically. That's when they realized that it had the potential to fight leukemia.
"It was just a tremendous success story," Henkin said. The researchers weren't looking for an anticancer drug—but they found it.
Paclitaxel, an anticancer drug from the Pacific Yew tree (Taxus brevifolia), has also undergone a development process that also spans a few decades. Researchers first began collecting the plant in the 1960s; it was approved by the FDA for cancer treatment in 1993.
At first, the only source of the cytotoxic extract was the bark of the tree, which is found across the Pacific Northwest in the U.S. The drug's popularity began to concern environmentalists.
"You girdle the tree, and you can destroy it," Henkin explained. "There was a concern that they would make the species extinct, because it was that popular as an anti-cancer drug."
So researchers searched for an alternative. Eventually, they figured out that clippings of the leaf material from a closely-related hybrid produced the same result. They isolated a precursor compound that became Paclitaxel.
In doing so, Henkin explained, the researchers were able to preserve Pacific Yew as a species—so it wasn't made extinct for its anti-cancer usage.
"Ethnopharmacology"—using traditional medicinal practice to begin the earliest stages of drug discovery—should be a back-and-forth dynamic, Soejarto said. He added that local healers own a right to the drug via "indigenous intellectual property."
From 2000 to 2010, Soejarto said, his team discovered several promising molecules in Vietnam. "There were at least two really very potent," he said. "It allowed us to file protection and intellectual property."
One promising molecule in development was honed to become a stronger compound, Soejarto explained, moving forward to animal testing after nearly half a decade of work.
The steps beyond that, however, can seem daunting.
"Well, who knows how long it will take!" Soejarto said with a laugh. He estimated three or four years for Phase 1, and the same for Phase 2. Then Phase 3, finally, which is the longest stage. The entire process could take between 15 and 20 years—"if the molecule will make it," he said.
Shepard's work documenting indigenous medicinal practice might eventually lead to big breakthroughs that could treat and heal, beyond the Matsigenka. However, his approach differs from Soejarto's work, which is funded by the National Cancer Institute.
"I became worried that my research might ultimately benefit companies without bringing any benefit or recognition to the indigenous people who have been stewards of this knowledge," Shepard said.
"The incentives for pharmaceutical companies is ultimately to develop drugs for the rich, and not to treat the illnesses of rural populations," he added.
Over time, Shepard became selective about the plant information he shares in publication. He developed a policy: He only refers to medicinal plants by family or genus names alone. "[I am] reserving the specific species identifications for some future date when I would hope for a more fair agreement to be made with the indigenous cultures who were so generous to me," he said.
"With royalties, that is where it gets quite complicated to negotiate. You can negotiate," Soejarto said, adding that in his 12 years on the ground, he has successfully negotiated with partners and community members in Vietnam and Laos. "So it can be worked out."
