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.

Glossary

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.

References

• 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

This article was originally published in OnSET.

Sometimes, all I need is the air that I breathe’…to be a little bit cleaner. Asthma and allergies such as hay fever is on the rise in many countries. Many studies have shown that asthma and other lung diseases are aggravated by pollutants emitted from cars, industry, and cigarette smoke. So why aren’t we doing anything about it?

Asthma is a difficult disease to define. One common definition is that asthma is a lung disease characterised by a ‘reversible obstruction of airflow,’ characterised by wheezing and shortness of breath (Elias et al, 2003). This can occur when the airways are either more responsive than normal when dealing with foreign matter such as pollen that makes its way into the lungs.
It was previously thought that the lungs remained healthy in between asthmatic attacks, it has recently been shown that they can progressively deteriorate, leading to permanent airway blockage in the worst cases (Elias et al, 2003).

Although it is believed to be an inherited disease, at least in part, the genetics involved are not yet fully understood (Haagerup et al, 2001). Risk factors include family history, parents who smoke, major respiratory disease before the age of two, and exposure to allergy causing compounds (Asthma Australia). Other risk factors includes the nasty cocktail of carbon, nitrogen and sulphur compounds, as well as heavy metals and particulate matter that are derived from exhaust from cars, cigarette smoke, home heating and cooking, and industrial waste. The six main ‘criteria pollutants’ are particulate matter (PM), sulphur dioxide, oxides of nitrogen (NOX), photochemical oxidants such as ozone, carbon monoxide and lead (Hinwood et al, 2002).

PM consists of small pieces of matter. PM causes respiratory infections and irritations, as well as increasing the chance of death from cardiorespiratory disease. Children and elderly people with lung diseases such as asthma are particularly vulnerable. Sulphur dioxide can irritate the throat and exacerbate heart and lung disease, including asthma. These compounds are especially dangerous when combined with PM. NOX can irritate the eyes and increase respiratory disease, including asthma. Ozone (O3) is produced when light energy reacts with high-energy pollutants. Like NOX, it can irritate the eyes and throat. It also intensifies respiratory disease and reduces exercise capacity. Carbon monoxide (CO) is a potent toxin that can cause a variety of symptoms, ranging from headaches to coronary artery disease and death. Lead is produced was previously found in leaded petrol, now banned. It can cause developmental problems in children and hypertension in adults.

As most of these compounds have similar sources, it is often difficult to determine which is the most harmful. However, air pollutants have certainly been shown to decrease quality of life, as well as increasing hospital admissions and death. In Europe, it is believed that deaths due to vehicle emissions are twice as frequent as deaths due to car accidents (Kunzli et al, 2000). In New Zealand, 2% of deaths are caused by air pollution – more than double the figure of deaths caused by HIV/AIDS or malignant melanoma.

Although there is no evidence to suggest that air pollution causes asthma or hay fever, an Australian study has shown that air pollution can worsen these conditions. This is especially true for ozone; however it is difficult to separate these results from the effects of other allergens such as pollen (Rutherford et al, 2000). However, other studies have suggested that air pollutants may react with allergens such as pollen, thereby increasing their detrimental effects on the lungs (Glikson et al, 1995).

Another interesting factor that may cause or exacerbate asthma is the weather. Reports of an increase in asthma attacks during thunderstorms, in several parts of the world, has prompted studies on the effects of meteorological phenomena on the prevalence of asthma attacks. One study has shown that outflows of cold air during storms may increase the concentration of allergens in the air (Marksa et al, 2001).

Along with the United Kingdom, the Republic of Ireland, and New Zealand, Australia has one of the highest rates of asthma in the world. Asthma costs the Australian public over $700 million, including medical costs and loss of productivity. Several hundred people die each year from asthma complications in Australia. Although asthma is still on the rise in Australia, the death rate is now decreasing (Asthma Australia).

Given the complex nature of asthma, and the variety of factors that can cause or aggravate it, it may seem initially that little can be done for asthma sufferers. However, by dealing with each factor individually, at least initially, significant steps can be made to ease the burden of asthma. In Australia, many cases of asthma are inadequately treated. This can be caused by ignorance, where the patient does not recognise the symptoms of asthma and therefore does not seek treatment at all, or by laxness after treatment in taking sufficient medication (Woolcock et al, 2001). This problem can be remedied by increasing education about asthma, a task that is mainly being tackled by Asthma Australia, and its corresponding state organisations (Asthma Australia).

Something else that might help asthmatics is a decrease in pollution, although it is far from the only solution. As a society, we can consider changing our driving habits in order to improve our quality of life. In Australia and New Zealand, less than 5% of workers ride a bicycle to work, compared to 15-20% of European workers. We go shopping in cars; take our children to school in cars; drive to work in cars. Reducing the time spent in cars would reduce the amount of emissions produced. Industries such as mining, energy, and manufacturing also need to consider the health effects of pollution (Woodward et al, 2002). And perhaps then, asthmatics (or some of them, at least) will be able to take a deeper breath…without coughing.

References

• Asthma Australia website. Available at: http://www.asthmaaustralia.org.au/(accessed Feb 04).
• Elias JA, Lee CG, Zheng T, et al. (2003) New insights into the pathogenesis of asthma. Journal of Clinical Investigation 111, 291-297.
• Glikson M, Rutherford S, Simpson R. (1995) The microscopic and submicron components of atmospheric particulates occurring during high asthma periods in Brisbane, Queensland, Australia. Atmospheric Environment 29, 549-562.
• Haagerup A, Bjerke T, Schoitz PO, et al. (2001) Allergic rhinitis – a total genome-scan for susceptibility genes suggests a locus on chromosome 4q24-q27. European Journal of Human Genetics 9, 945-52.
• Hinwood AL, Di Marco PN. (2002) Evaluating hazardous air pollutants in Australia. Toxicology 181-182, 361-366.
• Kunzli N, Kaiser R, Medina S, et al. (2000) Public-health impact of outdoor and traffic-related air pollution: a European assessment. The Lancet 356, 795-801.
• Marksa GB, Colquhounb JR, Girgisa ST, et al. (2001) Thunderstorm outflows preceding epidemics of asthma during spring and summer. Thorax 56, 468-471.
• Rutherford S, Simpson R, Williams G, et al. (2000) Relationships between environmental factors and lung function of asthmatic subjects in south east Queensland, Australia. Journal of Occupational Environmental Medicine 42, 882-91.
• Woodward AJ, Hales S, Hill SE. (2002) The motor car and public health: are we exhausting the environment? Medical Journal of Australia 177, 592-3.
• Woolcock AJ, Bastiampillai SA, Marks GB, Keena VA. (2001) The burden of asthma in Australia. Medical Journal of Australia 175, 141-5.