Lined up in a glass cabinet in one of the National Cancer Institute (NCI) drug discovery labs is what looks like a miniature tea brewing factory. Pieces of roughly ground plants in deep yellows, greens, and reddish browns soak in glass containers about the size of two-liter bottles. Like many teas, these plants hail from exotic locales–Madagascar, South East Asia, South America. But some soak in organic solvents about as drinkable as gasoline.
Scientists at the NCI’s Developmental Therapeutics Program (DTP) are after something bigger than the next chamomile or echinacea. They are searching for natural compounds that have anti-cancer activity.
There are good precedents for looking to nature for drug discovery. According to the World Health Organization, 25 percent of modern medicines are made from plants that were previously used in traditional medicine. Many drugs–aspirin, morphine, quinine (an anti-malarial drug), multiple antibiotics and cholesterol-lowering drugs–were originally derived from plants, bacteria, fungi, and marine invertebrates. Many drugs used in chemotherapy were derived from bacteria and fungi. The drug Taxol, which is used to treat cancers such as breast and ovarian cancer, comes from the bark of a tree that grows in the Pacific Northwest, the Pacific yew.
It is no coincidence that these organisms contain useful chemicals. “Nature produces these molecules for a reason,” says Gordon Cragg, head of the DTP’s Natural Products Branch (NPB). Often these compounds are part of how organisms ensure their survival. Bacteria, for example, have become a good source of antibiotics–drugs we take to kill bacteria–because they are in constant competition with one another to live and grow. Bacteria survive better when they secrete compounds that kill off surrounding bacteria that are not part of their colony. Sluggish bottom-dwelling sea creatures such as sea cucumbers would be defenseless if their skin did not contain toxins. “These little marine organisms are brightly colored and nothing’s touching them,” Cragg says.
Since its inception in 1955, the NCI’s drug discovery program has collected tens of thousands of specimens from around the world. Contractors in partner countries collect and immediately freeze marine invertebrates and plants (which they dry in the field), label them, and ship them to the NPB along with detailed records. Although plant are not currently being collected, there are many in storage waiting to be tested.
Once they arrive in the United States, specimens are stored at the Natural Products Repository in Frederick, Md. At the repository, freezers are lined with bags of frozen sea cucumbers, starfish, and nautilus; cabinet shelves carry muslin bags of dried bark, leaves, and fruit. The specimens are meticulously labeled and tracked: a barcode tag on each links the specimen to a computer database containing detailed information about each specimen. In the database, NPB scientists can find information such as who collected the specimen and at what longitude and latitude, the specimen’s taxonomy, and how it is used by locals, if at all.
When its turn comes, each specimen is ground up and extracted in water and solvents. Ground plant specimens are soaked in an organic solvent, strained, and washed, then soaked in water, strained, and washed again. Scientists break up frozen marine organisms with a hammer and mix them with dry ice. They grind the specimens in a meat grinder, remove the dry ice, and then mix them with water. The water-soluble compounds in the sample will go into solution in the water, just as sugar would. This “aqueous extract” is separated from what remains of the sample, which is freeze-dried and mixed with an organic solvent. The solvent dissolves compounds that are not soluble in water, such as oils. The aqueous and organic solutions contain not cells but molecules from within cells. What remains of the sample–crushed up tissue–is incinerated.
The two extracts from each specimen are tested for anti-cancer activity against multiple kinds of cancer cells including leukemias, melanomas, lung, kidney, colon, central nervous system, ovarian, breast, and prostate cancers. If an extract shows anticancer activity, DTP scientists use chromatography, a kind of molecular filtration, to separate the compounds into what are called “fractions”. At each step of the separation process, fractions are tested for anti-cancer activity in order to isolate the active compound or compounds.
When NPB scientists find active compounds, they are tested in lab animals for activity and toxicity; if they are active but non-toxic, they move on to pre-clinical and then clinical trials, which are conducted by the NCI or drug companies.
Cragg and others at the NPB try to be as sensitive as possible to the rights of countries where successful samples were collected. The drug companies who want to develop and market drugs derived from these samples must negotiate agreements for compensation with the source countries.
In return for their country’s cooperation, the NCI brings scientists from these countries to the United States for scientific training. The aim is to give the scientists the tools to do drug testing on their own so that they can go home and work on discovering treatments for cancer and for diseases that are prevalent in their country but not in the United States. For the most part, cancer is not a prevalent disease in the countries where the NPB collects samples–infectious diseases such as malaria and AIDS have a much greater impact.
Cragg acknowledges that from collection to the end of testing, developing drugs from natural products is often a slow process. “It’s not a high-yield project, but that’s the nature of drug discovery and development.” He points out that other efforts at drug discovery and development, such as synthetic chemistry done by drug companies, have similar success rates. But “no matter how good our synthetic chemists are, they’re not going to think of compounds with the molecular architecture we find in nature,” he says. “Nature produces beautiful molecules that are totally unique.”Print This Post