In the 1992 film Medicine Man, actor Sean Connery stars as a grizzled scientist who discovers a cure for cancer in the Amazon and then struggles to replicate his findings as bulldozers destroy the very forests that harbor it. "What don't you understand?" he wails. "I found the cure for the...plague of the 20th century, and now I've lost it!"

If Connery reprised that role today, his enemy might instead be Big Pharma, whose working methods have staunched the pipeline for medicines derived from nature. The advent of high-throughput screening technologies has allowed companies to test 100,000 compounds per day for specific biological functions, but that speed comes at a price: Drug approval rates are far lower for synthetic compounds than those derived from natural products, which, due to their complexity, are harder to screen.

 "I believe this is bad in the long term for both the pharmaceutical companies and the public," says John Vederas of the University of Alberta. "The current balance between high-throughput screening of synthetic libraries and pursuit of natural-product leads is skewed in an unfavorable way."

In this week's Science, Vederas and his student Jesse Li explain that this shift from natural products, along with tighter safety requirements and a focus on blockbuster drugs, is a key reason why the pharmaceutical pipeline is drying up. Today, just over 100 nature-derived drugs are currently in clinical trials, a 30 percent decline from just a few years ago.

The problem with current screening technologies is that compounds found in plants, animals and microbes have more complicated structures than those in synthetic chemical libraries, leading to challenges in their isolation, identification and manufacture. Moreover, natural compounds are often present at such low levels that they cannot be readily tested using current automated technologies. Finally, drugmakers exploring the natural world face the risk of isolating and identifying a known compound that cannot be patented.

Even so, there's a bright side to the story. Vederas believes that this trend could be turned around by automating the hunt for natural compounds. For instance, it may soon be possible to automatically separate all of the chemicals in an organism, identify them, and catalogue them in a library for future screening. He also advocates "smart screening" methods, such as using engineered E. coli in assays that help weed out common antibiotics produced by soil microbes to speed the search for new ones.

Whether or not all this novel technology means that Sean Connery, er, "Dr. Robert Campbell," will make a more credible scientist in the future, it's still worth taking a look at some of the greatest hits from nature's medicine cabinet.

[Slide show: Nature-Based Pharmaceuticals]