Most people have probably heard of Alexander Fleming’s chance encounter with a penicillin-producing fungus. What is not quite well-known is that penicillin is hardly a quirk of nature, an isolated incident. Fungi, bacteria, and other microorganisms are prodigious producers of compounds that turn out to be beneficial to humans — powerful, top-of-the-line agents that you may pick up at the pharmacy. These include:
- Cyclosporine, a “popular” immunosuppressive natural product, from a fungus
- Lovastatin, the first FDA-approved statin, also originating from a fungus
- Doxorubicin, an oft-prescribed anti-cancer agent, coming from a bacterium
In fact, the proportion of compounds in the early drug discovery stage that are at least based on a natural product is just shy of half.
Recent research has revealed, however, that these little critters had another surprise in store for us. Much effort in the last fifteen years or so has gone into sequencing the genomes of bacteria and fungi. The result is that we have DNA read-outs from an ever-increasing number of species, and our knowledge is such that we can go through the sequences and predict where genes are present, and we often have at least a vague idea about what they do. Some genes are responsible for the biosynthesis of natural products.
It turns out that, for quite a lot of these organisms, there are many more natural product genes than the number actually isolated. For example, researchers may have extracted five natural products from a particular fungus in all of history, but its genome suggests that it has the potential to make thirty-five more!
Considering that many natural products are medicinally useful, this finding certainly excited natural product scientists. It is not clear-cut why these microorganisms don’t live up to their genetic potential, yet it is likely significant that, in a laboratory, a studied microorganism is living an artificial life with an abundance of nutrients to enjoy and no competitors or predators to worry about.
Researchers have come with up with ways to nudge a microorganism to produce compounds it normally keeps under wraps. The following strategies have been used with success:
- Change the way you are growing up the microorganism. Feeding it glucose? Try sucrose. Is it hanging around in room temperature? Raise the heat. Subtle differences can lead to dramatic results.
- Bring the natural competition to lab. Fungi grown alongside bacteria may suddenly feel inspired to generate a natural product.
- Tinker with the genetics. Scientists are learning more about the regulation of natural products. A gene that is amped up – or removed altogether – may influence an organism’s natural product output.
Often, the above strategies are useful in uncovering another natural product or two, but the bulk of hidden genes remain just that. While efforts continue, genome sequencing is only accelerating. We are faced with an expanding sea of data, a multitude of genes silently tantalizing us. The possible source of the drug of the century, these genes wait for the talented, lucky researcher to give them a voice.
 Newman, D.J. et al. 2003. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod. 66: 1022-1037.