Spotlight on

Dr. Gordon Cragg
Natural Products Branch

Spotlight Archive

Medicine Man Has Counterpart in Real Life

From Johnny Weismuller’s Tarzan’s Desert Mystery (1943) to Sean Connery’s Medicine Man (1992), movies have depicted the jungle as a mysterious place secreting cures that will save the world’s population from disease. NCI-Frederick’s own “medicine man,” Dr. Gordon Cragg, head of the Natural Products Branch of the NCI Developmental Therapeutics Program (DTP) is full of enthusiasm but also realistic about his chosen field. Doing research with state-of-the-art equipment in tree houses isn’t very realistic, he said in a recent interview, but the natural world provides a lot of answers to scientists’ search for treatments and cures for disease.

“I always feel like we are right at the front end of the whole discovery process: bringing the plants in from the rain forest or the marine organisms from the coral reefs and then coordinating the further processing. David Newman, of the Natural Products Branch, supervises the marine organism collections and also works with microorganisms, such as bacteria and fungi. I supervise the plant collections,” Dr. Cragg stated.

Collecting in Both Tropical and Temperate Regions

The NCI’s Drug Discovery Program began in 1955, collecting plants mostly in temperate regions of the United States, Mexico, Canada, and parts of Africa and Europe, and focused on both natural products and synthetic chemicals. Tropical region collections began in 1986.

“Since it’s difficult to predict ahead of time what part of a plant will be most useful, the collectors, avoiding endangered species, sample all parts of a plant—bark, leaves, roots, wood, blossoms, or fruit, if available,” Dr. Cragg said. Plants are dried in the field, not always an easy task in tropical regions, leading to inventive solutions such as the one in Madagascar, where local scientists have devised a solar-heated oven for drying specimens.

NPB contractors also collect marine organisms such as sponges, sea slugs, and cone snails. “They freeze the marine organisms within a couple of hours of bringing them to the surface because they decay very rapidly. We always collect invertebrates [without a skeleton], and they’re shipped and kept frozen to prevent chemical degradation until extracts are made,” Dr. Cragg said.

Working with local organizations, collectors prepare plant shipments in lots of about 200 samples at a time, each weighing 300 grams to a kilogram, to be airfreighted to NCI-Frederick. Marine organism shipments are sized similarly, but weigh more because the organisms are frozen with adhering seawater. When these materials arrive, they are sent directly to the Natural Products Repository (NPR). To avoid introducing foreign pests, the plant materials are immediately frozen at –20° C for 48 hours, as required by the U.S. Department of Agriculture.

The plant materials and marine organisms are mainly tested for products that will help treat diseases in the developed world. Extracts of each dried plant part are tested separately, and it may take years before a use is found for the plant. A good example of that is taxol, one of the best cancer drugs available now and marketed by Bristol-Myers Squibb.

Dr. Cragg explained, “Taxol came from the bark of the Pacific Yew tree. The USDA in a random collection in 1962 did the first collections in Washington State. After decades, this produced one of the best anticancer drugs available.”

Both taxol and another drug, camptothecin, were isolated by the same group at the Research Triangle Institute in North Carolina under the leadership of the late Dr. Monroe Wall. Discovered in the 1960s, the original, natural product, camptothecin, was too toxic. However, chemists have modified the molecular structure to develop a number of useful drugs.

The Natural Products Repository, managed by Dan Danner, stores the natural materials and extracts. Tom McCloud manages the extraction laboratory, and he “runs a wonderful extraction and chemistry set-up. The DTP routinely performs massive screenings to find potential drug products. The number of active leads found in these screenings is very small, but they’re very good ones,” Dr. Cragg stated. For example, very small quantities of dolastatins, compounds that are active in inhibiting cancer cell growth, have been isolated from sea slugs; some of these dolastatins are now in clinical trial. Cone snails may be a potential source of new, nonaddictive painkillers.

Recently, Dr. Cragg began a small-scale comparison between freshly frozen plant materials and dried specimens to determine whether significant activity is lost when plants are dried.

Researching Traditional Remedies

“Traditional” knowledge, obtained from native peoples or from researching folkloric medicine, can play an important role in developing drugs to treat common source country diseases. One folk remedy for treating malaria was a tea brewed from the bark of an Amazon tree. Spanish explorers in the 1600s made it a popular remedy in Europe. In the early 1800s, quinine was isolated from the bark and became the treatment of choice. More recently, chloroquine and mefloquine, synthetic chemicals with molecular structures resembling quinine, have become standard malarial treatments.

To Dr. Cragg, another fascinating aspect of his work is that many disease-causing organisms develop resistance to drugs, forcing a search for new drugs or alternative treatments, sometimes discovered through traditional knowledge. For example, researchers have found a traditional Chinese medicinal plant yields a compound, which has been developed into drugs effective against resistant strains of malaria.  

Vincas, small ornamental plants, “produce two of the most wonderful anticancer drugs,” Dr. Cragg said. “Originally, the plant was found in Madagascar, but the drugs were discovered from the same plants growing in Jamaica and the Philippines. To me, it’s incredible that such a beautiful little plant can actually produce two drugs, which really have turned the treatment of childhood leukemia into a disease that can be managed very well.”

Collaborations with “Source” Countries

Dr. Cragg and his colleague, Dr. Newman, travel frequently to developing countries, attending conferences to talk about the program and collaborations and meeting with government officials or representatives of the organizations that are collaborating with the NCI collection contractors, such as Missouri Botanical Gardens and the University of Illinois at Chicago.

With the help of the NCI Technology Transfer Branch, legal agreements have been signed between the NCI and local organizations covering collaboration and other considerations to fairly recompense the countries involved. “If something promising is discovered and licensed to a pharmaceutical company, we require that company to go back to the country and negotiate an agreement so that benefits, such as a small part of the royalties,will be returned to the country. That’s very important to keep the trust of the countries where we’re working. The NCI is very sensitive to the concerns of the countries where the materials are being collected. NCI covers costs of the collections as well as those of collaborating scientists from local organizations. Where source country organizations have the skills, expertise, and knowledge and some reasonable infrastructure in their labs, we support them by helping them further their own drug discovery research programs—that’s the ideal. And we invite them to work and train in NCI labs or at various universities in the United States. For instance, the DTP has provided a group at the Federal University of Ceara in Fortaleza, Brazil, with training and cancer cell lines to establish their own cancer drug discovery program,” Dr. Cragg explained. This group is now screening materials from research programs all over Brazil. Programs such as these could benefit cancer patients both in the United States and globally.

On the other hand, countries that don’t have resources, skills, or infrastructure are usually agreeable to sending their materials for evaluation and further study in NCI’s laboratories, or those of collaborating institutions. He further explained that the NCI has always been held up as an excellent example of how the U.S. government collaborates fairly with other countries. “I’ve been to meetings in Geneva, for instance, at the World Intellectual Property Organization, where some developing countries say they’ve lost so much of their natural resources and that the big pharmaceutical companies are making millions of dollars from these resources. Our government representatives from the Patent and Trademark Office, and from the Department of State always hold NCI up as an example of fair dealing. So, I've always felt a certain amount of pride that we’ve dealt very fairly with these countries and that NCI has got an excellent reputation.”

Dr. Cragg stressed that the NIH “does a fantastic job” in developing treatments for the diseases that affect many of the world’s population. “The National Institute for Allergy and Infectious Diseases has tremendous programs for malaria and the infectious diseases. And foundations, such as the Bill and Melinda Gates Foundation, provide hundreds of millions of dollars [to aid research in these countries], which I think is just tremendous. The U.S. Army are probably world leaders in malaria research, because, you know, the troops go to many exotic places where they could easily contract infections like malaria. The United States makes a substantial contribution toward treating and curing diseases worldwide.”

Dr. Cragg says the real strength in natural products lies in the fact that, once chemists have identified the core structure of a natural product, they can manipulate it to develop effective drugs that potentially will help humanity. 

Writing:

Maritta P. Grau,
Senior Technical Editor
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

Editing:

Nancy Parrish,
Senior Technical Editor
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

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Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

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