Feature

Growing Drugs to Order

Scientists worldwide are scouring forests and oceans for organisms with an exciting chemistry, and promising species native to New Zealand have sparked a whole new prospecting industry.

Veronika Meduna

Hundreds of petri dishes full of agar with colourful globs of fungal growth stack up in a temperature-controlled room deep in the bowels of a University of Canterbury building.

Each dish contains a different marine fungus, growing on a congealed broth of nutrient, ready to be taken into large-scale culture and extraction. The extracts will be put through a sequence of purification procedures and, eventually, the extracted compounds will be let loose on malignant cancer cells.

This painstaking screening for biological activity in the simple organisms is bound to show up some "hot leads" -- species of marine fungi whose chemistry includes substances that either kill tumour cells or stop them from dividing. Any of these compounds could ultimately prove useful in the ongoing battle against cancer -- or at least yield a new tool for diagnostic medicine, agriculture, or industrial chemistry.

For chemists Dr John Blunt and Dr Murray Munro, and mycologist Tony Cole, this collection of marine fungi is only the latest offshoot from their work, which pioneered the screening of marine sources for new drugs in New Zealand.

Scientists have always looked towards the natural world for chemical clues. The discovery of penicillin more than half a century ago is a classic example, but even in modern times of biotechnology and molecular genetics, researchers are prospecting rain forests and oceans in the hope of discovering new molecules. They are driven by the pharmaceutical industry's ongoing need to develop new drugs to combat the problem of treatment-resistance of some tumour cells and microbial pathogens.

Among the latest substances approved for commercial use in the United States is a painkiller extracted from a sea-going snail, an osteoporosis treatment based on a hormone produced by salmon, and a bone-filling substance taken from corals.

In New Zealand, antioxidants extracted from pine bark, anti-inflammatory compounds distilled from manuka oil, and anti-tumour agents found in liverworts are all at various stages of investigation or commercial use.

In collaboration with universities and the drug industry, two of New Zealand's crown research institutes -- the National Institute of Water and Atmospheric Research and Crop and Food Research -- have programmes screening our flora and fauna for useful substances.

Spongy Star

One of the most promising anti-cancer agents so far comes from the chemistry laboratory in Christchurch. During an underwater excursion more than 10 years ago, Blunt and Munro brought up a specimen of Lissodendoryx, a bright yellow marine sponge also known as Yellow Slimy.

Munro says the sponge produces two chemically closely related and complex molecules (halichondrin B and isohomohalichondrin B) which effectively stop the division of certain tumours such as melanoma, ovarian, and breast cancer. The compounds are both very potent and very rare.

"From one tonne of sponge you will get very much less than a gram of material," says Munro.

The sponge extract is currently being tested by the American National Cancer Institute and is only one step away from clinical trials. Any further development could spell million-dollar benefits in royalties and production efforts for New Zealand, he says, and this discovery of the rare sponge's properties has already sparked interest from a range of companies that put the country in a good position to become a leader in this area of research.

Blunt says Lissodendoryx grows only in New Zealand waters and was originally found in a small area off the Kaikoura coastline. The total resource is estimated by NIWA at a maximum of 300 tonnes.

While the extracted compounds showed early promise, the scarcity of the organism made it impossible to provide further material through harvest. The solution is aquaculture, says Blunt, and the techniques to take Yellow Slimy and other sponges into culture have been established successfully by a team led by Dr Chris Battershill at NIWA in Wellington.

In co-operation with the Canterbury chemists and the company New Zealand Pharmaceuticals Ltd, NIWA has developed a two-pronged collection programme. Marine organisms are screened for new drug leads and any promising candidates are taken into culture to avoid depletion of the natural resource. Simultaneously, the organism's chemistry and genetics are investigated with view towards finding the best genetic stock and possibly synthesising the target compounds.

"For those compounds that can't be synthesised we are looking at a production industry based around aquaculture or some form of fermentation technology," says Battershill.

He says many of the currently available drugs are either produced by micro-organisms or extracted from terrestrial plants. The sea harbours a vast diversity of species and habitats, but its potential to yield new drugs is still largely underexplored.

"New Zealand has the fourth-largest exclusive economic zone globally and a vast diversity of marine environments ranging from subtropical to subantarctic and antarctic. From the first moment that people began looking to the sea for new drug leads they found that marine organisms produce some very unusual large compounds with very exciting activities."

For Munro, it all comes back to biodiversity.

"By sampling marine organisms, particularly invertebrates, you're actually taking a slice through the greatest collection of phyla available on earth. Also, there is some evidence to suggest that the primitive invertebrates, of which things like sponges, tunicates, and bryozoa are examples, have a chemical-based immune system, a precursor of what later developed in reptiles and subsequently in mammals, to fight off invasion by pathogens."

Blunt says that particularly immobile species are likely to have an efficient chemical defence system.

"Many of these organisms are very attractive and they don't rely on camouflage for their defence. They presumably rely on something about their chemical makeup which makes them very unattractive to either eat or to settle on. Since most of the compounds that could be used for this purpose appear to be growth-inhibitory substances, the argument is that it might be useful to exploit these properties and develop them as anti-cancer agents where we require a growth inhibition on cells."

Battershill says while the screening programme has sparked a new drug industry in New Zealand, it goes hand in hand with marine conservation and biodiversity protection.

"We're finding that by exploring the nooks and crannies in shallow coastal areas with divers, we are constantly finding new species. All our results are additionally transferred into the NIWA biodiversity programmes and to the Department of Conservation and the Ministry for the Environment, because nowadays there is an urgent need to know what we've got on our coast line in order to manage the resources properly and to protect the habitat of species at risk."

While these modern explorers focus on the marine environment, a team of botanists and chemists from Crop and Food are scouring our native forests with a similar aim in mind. Dr Nigel Perry says native forests here don't have the range of species of a tropical rain forest, but the majority of all plants found in New Zealand are endemic. Sometimes the entire plant family will grow in abundance here but nowhere else. "We certainly have some unusual plants with their own peculiar chemistry."

The Crop and Food screening programme covers everything from lichens and mosses to trees and shrubs and the results support the idea that primitive organisms are likely to have a complex chemical defence system. "We take advantage of that in terms of the plants' toxicity to some of the classic pathogens like bacteria that we find dangerous."

Liverworts, small plants similar to mosses and "about the simplest plants that grow on land", stand out as a promising source for anti-tumour agents and a number of species are under close scrutiny at the American National Cancer Institute.

Another promising candidate is miro, a native tree long known for its medicinal properties, which produces an anti-fungal agent. However, Perry says while the compound has not been reported anywhere else in the world, it did not show sufficient activity to justify commercial production.

"That's the way it goes," says Perry, "the odds of finding something are relatively low, but on the other hand, if we can find something with health or crop protection properties, it can be very rewarding."

Even if only a small number of organisms end up providing new leads for the pharmaceutical industry, there are many spin-offs from this work. Any compound which proves unsuitable for medical use may still become useful as a natural biocide in agriculture or industrial chemistry or as a new fragrance for the cosmetics industry.

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