Bioprospecting - an explanation of its failure to live up to expectations
Sir - The experts consulted by Colin Macilwain (see Nature 392, 535; 1998) provided useful evidence that bioprospecting for natural products is not the most productive way of finding biologically active compounds but they did not explain why this should be so. We would suggest that the high expectations for bioprospecting were partly based the erroneous belief that a very high proportion of natural products must have some biological activity. However the Screening Hypothesis, which we proposed to explain natural product chemical diversity, argues that specific, potent biological activity is a rare property for a chemical to possess, irrespective of whether a human, microbe or plant has done the synthesis. This is primarily because potent activity requires a very high degree of “fit” between the chemical and a target receptor. The hypothesis proposes that in organisms that make natural products, there will have been a selection of biochemical traits in natural product biosynthetic pathways which enhance the generation and retention of chemical diversity. Because potent, specific biological activity is an extremely rare property for any molecule to possess, much of this natural product diversity will possess no inherent biological activity. This model proposes that organisms making natural products have been conducting combinatorial biochemistry and have been screening for activity for hundreds of millions of years before humans adopted a similar strategy. However, most organisms will be screening for biological activity with no particular relevance to human physiology. Hence it is predictable that an efficient method of generating chemical diversity (combinatorial chemistry) coupled to high throughput screening based on a cell process of known importance to human physiology will be more efficient than bioprospecting when searching for drugs. Many compounds can be screened rapidly even though most will be inactive. The opportunities that do exist for bioprospecting possibly lie more with the discovery of genes coding for enzymes involved in natural product biosynthesis, many of which might be expected to have a broad substrate tolerance. The addition of such genes to organisms with an existing rich natural product diversity should generate even more chemical diversity, producing chemical structures that currently lie beyond the scope of combinatorial chemistry. This opportunity to build on the existing combinatorial biochemistry of organisms will only be realised if the genetic diversity underlying the synthesis of natural products is explored and understood. So the bioprospecting for chemicals might have been relatively unsuccessful but bioprospecting for genes to use in combinatorial biochemistry might be more successful.
Richard D. Firn
Clive G. Jones