This article was originally published in OnSET.
(Note: for definitions of bolded terms, see glossary below)
Whether we are aware of them or not, natural products are ubiquitous in our lives. Many pharmaceuticals, pesticides and herbicides, food additives, and even some plastics are natural products, or derived from them. So what exactly are natural products?
Although in theory the term could be used to describe any substance derived from a microorganism, plant or animal, it is usually confined to describing secondary metabolites (Cannell, 1998). Natural products have recently become big business, but people have used them since ancient times.
Natural products in ancient times
Early cultures used specific products to cure specific diseases. Chances are that the ancient Egyptians had no idea that the Vitamin A in ox liver was what cured nyctalopia, but liver was used as a cure for this disease. In ancient Mesopotamia, Egypt and other countries, a wide variety of plants, animal products and even stones were used as treatments for various ailments. These cures were discovered by trial and error (Porter, 1997).
As early as 800 AD, the Benedictine monks were using many natural medicines, including the poppy (Papaver somniferum), which was used to alleviate pain as well as an anaesthetic. The active ingredient, morphine, was only extracted in 1806… almost 1000 years later. It was marketed by Merck in 1826. Many other natural products such as quinine, which was the only effective anti-malarial at the time, were also isolated in the nineteenth century (Grabley & Thiericke, 1999). However, these drugs were also characterised largely by random experimentation, and many other structures could not be isolated until much later.
Natural products in the twentieth century
The trial and error method of discovering new medicines continued into the twentieth century. Alexander Fleming, the British microbiologist who discovered the effects of some fungi on bacteria, essentially made his discovery by being careless and not practicing aseptic technique. He left a Petri dish of Staphylococcus aureus open when he went on a holiday. It was accidentally contaminated with Penicillium notatum¸ which inhibited the growth of the bacteria, apparently by excreting an antibacterial substance. Chemists Earnest Chain, his Australian co-worker, Howard Florey, and their team later purified penicillin and conducted animal and human trials with it, bringing it to the market in 1941 (The Nobel e-Museum, 2003).
Many secondary metabolites that were discovered after penicillin in the 1940s and 1950s were effective antibiotics but too toxic for human use. Some of these were usefully administered to animals. In the 1960s-70s, research turned to improving yields of existing biopharmaceuticals, as well as chemically altering them to reduce their side effects or improve their activity against micro-organisms (Grabley & Thiericke, 1999).
As a result, over 73 different variations of the beta-lactam antibiotics (including penicillin and cephalosporins) are available. Of these, 40 varieties are used to treat human disease in hospitals. The prevalence of beta-lactam antibiotics, coupled with the ease with which bacteria can mutate and share genetic information, has led to widespread resistance to beta-lactam antibiotics. A famous example of antibiotic resistance in bacteria is that of Staphylococcus aureus. Golden Staph, as it is commonly known, causes many problems in hospitals where bacterial infection spreads rapidly and patients may be more susceptible to disease than they are usually (Therrien & Levesque, 2000).
Natural products today
More recently, the competitive nature of the pharmaceutical industry in particular has brought natural product chemistry to a crossroads. Developing new drugs is profitable, and the pharmaceutical industry is constantly growing. New innovations such as High Throughput Screening (HTS), which involves automated, miniaturised assay techniques, have made it much easier to determine the potential uses of a new compound. State-of-the-art HTS machines can test up to 10,000 compounds in one week, a big improvement on the 10,000 per year that were tested in the mid-80s (Grabley & Thiericke, 1999).
These developments are fantastic both for the pharmaceutical industry and the consumer. However, the natural product industry is finding it difficult to keep up with the demand for new compounds to test. This is pushing the industry further, as marine biologists, microbiologists, ecologists, biotechnologists, biochemists and chemists team up to find new organisms with novel compounds, mainly from previously untested environments (Grabley & Thiericke, 1999). Advances in biotechnology mean that it is no longer necessary to collect large amounts of environmental samples in order to test for a new pharmaceutical. Rather, the sample is cultured in the laboratory where biotechnologists can create a clone library. The gene responsible for the production of the natural product of interest can then be isolated more easily, and the natural product itself can be produced in Escherichia coli (Lodish et al, 2000).
Ultimately though, natural product chemistry is still waiting for a breakthrough that will bring discovery of new compounds up to speed with the discovery of potential uses for these compounds.
Antibiotics: secondary metabolites that either kill microbes or hamper their growth.
Aseptic technique: maintaining sterility and avoiding contamination of laboratory instruments and microbial cultures.
Biopharmaceuticals: Medicines that are made from compounds produced by living organisms, such as penicillin.
Clone library: an organism’s DNA is fragmented and copied into a laboratory organism such as E. coli, allowing for easier analysis of the original organism’s genes and metabolism.
High Throughput Screening (HTS): robotic and computerised methods of testing samples and analysing data, which allow many samples to be tested in a short amount of time.
Nyctalopia: night blindness, the inability to see clearly in dim light.
Secondary metabolites: compounds produced by an organism that are not essential for its survival but may be useful to the organism.
- Cannell RJP (ed). (1998) Natural products isolation. Humana Press, Totowa, N.J.
- Grabley S, Thiericke R (eds.) (1999) Drug discovery from nature. Springer, Berlin.
- Lodish H, Berk A, Zipursky L, et al (2000) Molecular Cell Biology (4th Ed) WH Freeman and Company, New York.
- The Nobel e-Museum (2003). The Discovery of Penicillin. Available at: http://www.nobel.se/medicine/educational/penicillin/ (accessed Jul 05).
- Porter, R. (1997) The Greatest Benefit to Mankind: A Medical History of Humanity from Antiquity to the Present. Harper Collins Publishers, London.
- Therrien C, Levesque RC (2000) Molecular basis of antibiotic resistance and -lactamase inhibition by mechanism-based inactivators: perspectives and future directions. FEMS Microbiology Reviews 24: 251-262