Hard Times for Chemical Prospecting

Environment & Energy

THOMAS EISNER

Hard Times for Chemical Prospecting

Nature is a vast chemical treasury. Largely unexplored, it is the repository of countless substances of potential use. Nature is also vanishing, and this poses a problem in urgent need of solution. More than a dozen years ago, I proposed a scheme whereby the exploration and preservation of nature could be linked.

Specifically, the search for new natural products, so far carried out almost exclusively by developed nations, would be undertaken henceforth with the involvement of developing nations. I had earlier coined the term “chemical prospecting” to refer to such exploration, and pointed out that it would be to all-around advantage to have the initial phase of the prospecting effort–that is, the screening of biological samples for specific activities–carried out in partnership with developing nations. Because developing nations were the primary suppliers of the samples, it made sense that they should take part in the screening programs and be compensated for the involvement. The returns, in part, could be invested by the developing nations in conservation, thereby providing for the long-range preservation of their natural holdings. I predicted, rather optimistically, that, “in the long term one could imagine screening laboratories springing up worldwide. The opportunities inherent in chemical exploration are virtually boundless and cannot be allowed to pass.”

Opposition arises

Although I remain optimistic and firm in the belief that nature has a vast undiscovered chemical treasury in store, I no longer believe that chemical prospecting, in the immediate years ahead, will sustain the momentum that was part of its initial promise. Attitudes have changed with respect to chemical prospecting, and there is now a significant level of political opposition to the endeavor, as well as scientific indifference to it.

To relegate natural products chemistry to secondary status now is to be blind to the vastness of chemical information that remains to be uncovered in nature.

The political opposition was to be predicted. Prospecting partnerships between developing and developed countries have come to be viewed with apprehension by both the political right and left. The issues are, respectively, the loss of proprietary technological know-how by developed nations, and the unfair appropriation of the biological knowledge of developing nations. Increased concern over proprietary matters generally, including patent rights, had an overall effect in that it led to a toughening of the negotiating stances in contractual deliberations.

Prospecting agreements were nonetheless forged, of which one in particular, between the pharmaceutical giant Merck & Co. and the Instituto Nacional de Biodiversidad (INBio) of Costa Rica, received much publicity. The agreement was notable in one respect. Merck committed itself not only to payment of royalties from any products developed as a result of the exploration of Costa Rica’s tropical holdings, but also to a contribution of $1 million outright. Because royalties may take years to materialize, such upfront payment was of the essence to the Costa Rican partners. The INBio-Merck partnership, viewed favorably by many observers, persisted for several years.

Another major additional initiative is the International Cooperative Biodiversity Groups program (ICBG), established in 1993 and funded by the United States through the National Institutes of Health, the National Science Foundation, the Agency for International Development (from 1993 to 1995), and the Department of Agriculture (from 1997 to the present). The ICBG has brought as many as 12 countries into partnership with universities, botanical gardens, museums, conservation organizations, and pharmaceutical companies for the specific purpose of chemical prospecting.

Although political opposition can put a re-straint on the proliferation of prospecting agreements, it cannot block prospecting efforts altogether. Difficulties notwithstanding, the notion that chemical prospecting is rich with opportunities is likely to prevail.

Chemists dropping out

What may seriously prevent chemical prospecting from achieving its objectives, however, is a development from an unexpected quarter. Of fundamental importance to chemical prospecting is the participation of the chemist. Although the biological partner in the prospecting effort is usually the one to make the discoveries that provide leads to the existence of interesting chemicals, it is the chemist, and specifically the natural products chemist, who isolates and characterizes the molecule or molecules responsible for the activity noted. Natural products chemistry, a discipline flourishing for decades and absolutely essential to the understanding of the molecular processes that form the backdrop of life, has now been targeted for downsizing.

Natural products chemistry is no longer ranked as primary in significance within the domain of chemistry. Isolation of products from nature and their characterization is now viewed as routine effort, devoid of broader conceptual value and irrelevant to the postgenomic agenda. Totally disregarded in this appraisal is the explanatory potential of molecular identifications. Nature is, quite literally, a fabric of chemical entities, held together by communicative interactions that are themselves mediated by chemicals.

To relegate natural products chemistry to secondary status now is to be blind to the vastness of chemical information that remains to be uncovered in nature. Organisms by the millions have yet to be discovered, let alone the molecules on which they depend. Substances that organisms use in communicating with kin, pathogen, and foe–and which on further appraisal sometimes turn out to have reactive capacities suggestive of medicinal potential–are all part of the unknown awaiting to be accessed by the chemical prospector.

That natural products chemistry should be scheduled for curtailment at this particular time is ironic. Technical advances and improved instrumentation are making it possible to isolate unknown chemicals from complex mixtures with great efficiency, and to characterize compounds on the basis of infinitesimal amounts of material. Never before has the chemical prospector been better positioned to achieve success. Yet university chemistry departments, even at institutions where natural products chemistry once flourished, are cutting back on their commitment to the discipline or phasing it out altogether.

Perhaps natural products chemists should team up with molecular biologists and redefine the criteria that set priorities in their searches. Biorational criteria, based on molecular biological findings, could introduce logic and impart direction to the prospector’s efforts, which are now often in the nature of purely random searches.

Industry also is reducing its commitment to natural products chemistry. Once the principal employer of natural products chemists, industry is moving more and more in the direction of “rational” drug design. This approach–multipronged and bolstered by capacities such as the generation of combinatorial libraries of compounds for testing purposes–is being widely adopted. Although rational drug design is commendable and full of promise, it is to be regretted that its development is occurring at the expense of chemical prospecting.

Industry and academe may eventually realize that natural products chemistry should be reactivated. But chemical prospecting will doubtless suffer in the interim, as will conservation programs slated to be linked to the prospecting effort. One can only hope that logic will prevail and that natural products chemistry, modernized perhaps by closer affiliation with molecular biology, will eventually be readmitted to center stage.


Thomas Eisner () is J. G. Schurman Professor of Biology at Cornell University.