• A brief history of Taxol
• How do scientests test plants for anti-cancer properties?
When threatened, plants stand and fight. They use chemical warfare.
“Plants are chemical factories,” explains Virginia Tech chemistry professor David G.I. Kingston. “They produce an array of complex compounds, both to grow and to avoid being eaten, as well as resist disease and fungi.”
His fascination with the complex molecules created by plants is what drew Kingston into chemistry research. He explains, "Exploring the chemical compounds plants create to survive gives me the feeling of ‘thinking God’s thoughts after Him,’ as astronomer Johann Kepler (1571-1630) so eloquently said.”
The potential uses of the natural compounds gave Kingston’s interest direction.
“The major motivation for what I do is to find a cure for cancer,” he says. “When I was about 8, my grandmother died of cancer. So I was aware of the problem, but I didn’t think I could do anything because I hate blood and killing animals.” Then, while he was a graduate student at Cambridge in the late ’50s, he attended a conference in London on cancer and chemistry. “I learned that chemists can make a contribution.”
For 30 years, Kingston has been working to adapt the natural products of plants to treat cancer. He is also looking for natural products that can be used to treat fungal infections, malaria, and mycobacterial diseases.
Fungal infections are a common complication for people with AIDS. Malaria and mycobacterial diseases, such as tuberculosis, are resisting traditional treatments. All three conditions are prevalent in the tropical countries where Kingston and other researchers search for natural products to fight disease. “We have an obligation to target these diseases,” Kingston says.
Natural product chemistry
Natural products already have a successful track record in disease treatment. One-fourth of prescription medicines are based on chemicals from plants, such as a treatment for leukemia from the Madagascar periwinkle. A compound from periwinkle was part of the chemotherapy that, in combination with surgery and radiation, helped Kingston’s graduate student, Joe LeFevre, recover from Hodgkins Disease. He is now on the chemistry faculty at SUNY-Oswego.
Plants produce complex structures that would take scientists years to develop in the lab. For instance, it would take 25 steps to duplicate the Madagascar periwinkle compound that reduces white blood cells. “Which is why we usually let the plant do the manufacturing for us,” except when the critical material is limited, says Kingston.
That was the case with Taxol, one of the most significant compounds in the fight against cancer. It has since been synthesized, although improved analogs of Taxol are still needed to overcome difficulties in administration of the drug and cancers ability to mutate and resist the drug. Kingston has devoted much of his career to understanding the chemical structure of Taxol to discover what part of the compound is the enemy of cancer and how it acts on the cancer cell. Supported by the National Cancer Institute and Bristol-Myers Squibb, he has created analogs with various enhancements, such as a Taxol that is soluble in water so that it is more easily administered.
Kingston is also leading efforts to find new compounds — by discovering new plants and by screening extracts with sensitive assays for sources of new pharmaceuticals. It is not only a race against increasing incidence of disease, but against third-world economics.
Suriname
As principal investigator and group leader, he is working with the Missouri Botanical Garden, Conservation International, Bristol-Myers Squibb Pharmaceutical Research Institute, and the Suriname drug company BGVS to develop a model program for drug discovery and biodiversity conservation in Suriname, South America. “Plants are collected and screened for bioactivity. Any royalties from the resulting drugs will be shared with Suriname as an economic incentive to maintain their tropical forests. If we find a Taxol, with $1 billion per year in sales, that would be a large percentage of the national budget of a small country like Suriname.”
Why Suriname? The former Dutch colony on the northeast coast of South America has a large area of undisturbed rainforest – 90 percent of the country five years ago. No other country has that high a percentage of rainforest.
It also has a diverse culture with two kinds of tribal healers. The 5 percent of the population who live in the forest are members of two different tribal cultures: Amerindian and the descendants of escaped slaves who set up an African culture.
The Rio Treaty on Biodiversity signed in 1992 provides the International Cooperative Biodiversity Group the legal authority to negotiate access to the rainforest with the national government of a host country. "“But it s more complicated than that,” says Kingston. “The tribal people are recognized as independent people. So approval and permission of the tribal leaders is also needed.”
Russell Mittermeier of Conservation International signed agreements with tribal leaders after more than a year of negotiation. The agreement provides access to the shamans knowledge, as well as to the forest. In exchange, a Forest People’s Fund, with up-front money from Bristol-Myers Squibb, has paid for an eco-tourism lodge, a transport project, an agricultural project, leadership and equipment-use training, the first meeting ever of all the tribal leaders, and the purchase of sports equipment.
The Suriname project also provided employment in the country, improvements to the National Herbarium of Suriname, and formal training in curation and botanical research. And the project has preserved the shamans’ knowledge, not only in modern databases, but through a shamans apprentice program. “Herbal remedies, a primary source of health care in many countries, are also threatened by biodiversity loss,” Kingston points out.
Meanwhile, Bristol-Myers Squibb has put more than 3,000 extracts through 32 screens each in six different therapeutic areas, with the result that one promising compound is continuing to be tested.
While looking for potential pharmaceutical products, project scientists conduct ethnobotanical and random botanical collections. Conservation International researchers work with the shamans over the course of many months to collect plants used to treat disease and injury. Meanwhile, researchers from the Missouri Botanical Garden collect plants of interest at random and collect more plants in less time.
Shamans vs. random collection
“We said to ourselves, ‘These plants have been picked out over centuries by the shamans, so one would expect them to be more active than plants collected at random.’ So we decided to compare the activity of extracts from plants collected by CI and the Missouri Botanical Garden,” Kingston says.
Using yeast-based assays, the Virginia Tech researchers found there was a slight benefit to the ethnobotanical approach: 3.8 percent of the shamans’ plants were bioactive while 2.8 percent of the plants collected at random were active in the yeast assay. “That’s all you can expect because the assays we are using aren’t specific to how the shamans use the plants.”
Current screens may be missing cures for gout or arthritis, Kingston admits. But the extracts will become a part of a collection that scientists can draw on later. Bristol-Myers Squibb is trying to identify assays that will correlate better with the diseases identified by the shamans. “Then we will retest,” says Kingston. Even at a later date, Suriname would benefit from any discoveries.
But if a promising compound is found in a natural product collection, will the originial plant still exist? The pace of discovery and development may be too slow compared to the certain, immediate payoffs from lumber sales. An Indonesian company wants to log about 30 percent of the Suriname forest. So far, the researchers have made the case that logging would not be the best use of the forest, and the Suriname government reduced the amount to be logged. But there need to be short-term incentives to reduce destruction of rainforests — to counter the poverty that contributes to the loss of biodiversity, the researchers pointed out in their progress report.
The Suriname project was supported by a grant from the National Institutes of Healths Fogarty Center and National Cancer Institute, and the National Science Foundation. In addition to Kingston and Mittermeier, team members are Jim Miller of the Missouri Botanical Garden; Jan Wisse of BGVS, which is carrying out plant extraction and data management; and Dinesh Vyas of Bristol-Myers Squibb Pharmaceutical Research Institute. As of September 1998, the project was extended an additional five years and expanded to include Madagascar. Dow Agrisciences and CNARP of Madagascar have joined as partners.