Take one magic mushroom...

A chance finding by a young chemistry student has electrified both the scientific and medical worlds. Will highly toxic fungi prove to be a cure for cancer?
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The Independent Online

On the morning after the May Bank holiday in 1994, a young Romanian chemistry student called Ioana Popa returned to her laboratory bench at Bradford University. She had just spent the weekend in Germany and was quite unprepared for what she was to find. By chance, something had happened to her experimental materials which could prove to be a decisive factor in the war against cancer.

Dr Popa was working on a toxic chemical extracted from a wood-rotting fungus. For her research she needed to use the drug Tamoxifen, used to control breast cancer. Tamoxifen is made up of two forms, a Z form - the important one - and an E form, which is thought to cause endometrial cancer. Ioana Popa left a flask containing an oily mixture of Tamoxifen and her fungal chemical on her bench and expected to find everything as she had left it. But something happened in her absence.

"When I got back from Germany, I found beautiful white crystals at the bottom of the flask," she says. At first she was at a loss as to what to make of the crystals. An analysis demonstrated that the flask contained a pure form of Z-Tamoxifen, quite devoid of any E-Tamoxifen. It was an "accidental" breakthrough which looks as if it could lead to a new approach to treating cancer. The head of Clinical Oncology at the university, Professor John Double, goes as far as to suggest that the finding is a "penicillin-type discovery", a reference to the chance finding by Alexander Fleming of the penicillin fungus, which had made a home in a discarded petri dish.

Dr Popa's serendipitous production of the crystals is not the end of the story, nor is it anywhere near the beginning; rather it was the lynchpin in a change of events that involved forays for fly agaric toadstools and other fungi in woodlands from Britain to Malaysia.

The story began in 1953 when Ray Edwards, now a Bradford University scientist, was a young student of organic chemistry. At that time, the "natural" production of chemicals was in vogue. In the woods around Bradford, he gathered toadstools, such as the brilliant red and white spotted fly agaric, and examined the caps of these fungi for their chemical composition. Earlier, in the Thirties, an academic called Fritz Kögl had already described the chemical structure of the coloured pigments produced by the fly agaric, but Dr Edwards thought this assessment was wrong. He eventually proved that Dr Kögl was incorrect.

By then what had begun as an academic puzzle and a fashionable topic to gain a PhD had turned into a passion. He next looked at the Boletus species, a type of fungus whose flesh turns blue when bruised; it took him six years to crack the structure of their unique pigment. However, even in this rarefied field, Dr Edwards had a competitor, a German called Wolfgang Steglich. It became a race between them, but one that Dr Edwards could not hope to win.

The woods that surrounded Bradford were rapidly dwindling, and so were the toadstools. Dr Edwards ventured further afield, down to the south of England to places such as Windsor. But Dr Steglich had a major advantage: the Black Forest. This famous wood, which extends for over 90 miles along the Rhine valley, was right on his doorstep. Dr Steglich would always have easy access to far more fungi than Dr Edwards could ever hope to collect.

Dr Edwards faced a dilemma; he was losing the battle, but did not want to give up the fight. So he teamed up with Professor Tony Whalley, now at John Moores University in Liverpool. Professor Whalley was the perfect partner: not only did he collect and identift fungi from around the world, but he was prepared to give samples to Dr Edwards so that he could culture them in the lab. Moreover, Professor Whalley had the advantage of having researched one of the most widely distributed and common families of fungi, but one about which the least was known.

Professor Whalley's pet fungi was the Xylariaceae, a wood-rotting fungus that grows on trees, but can also flourish on other plants, in the soil and even in insects. It is found in places as far apart as the rainforests of Malaysia and the alder groves of middle England. Some grow in termite mounds and seem to enhance the growth of the termites, though how or why this relationship works is not yet understood.

In general, the Xylaria can be devastatingly toxic. Some contain toxins that can kill bacteria, fungi, fish and mice. Two per cent of America's aspens are killed by Xylaria; it causes root infections in cacao, coffee, rubber and tea; it infects macadamia trees, wipes out bamboo and can devastate an orchard within days. And yet it is from these fungi that a cure for cancer may be produced.

In 1985, Bradford gained a nuclear magnetic resonance spectrometer, a device which proved invaluable for probing the structure of unknown molecules. Dr Edwards began to collaborate with Dr Derek Maitland, and began the serious business of screening the Xylaria for chemicals that could be useful, particularly in the fight against cancer.

It may have seemed an unlikely place to search for a drug that could defeat the Western world's fastest-spreading disease, but as Professor Whalley says: "There are more than 1.5 million species of fungi worldwide, and they exhibit an impressive range of diversity of form, biochemical and physiological activities. They must rank as one of the world's most important living resources."

The problem lay in the toxicity of the fungi. In 1992 Ioana Popa came to Bradford as an exchange student from Romania. She was one of her country's brightest chemistry students and had gained a first-class degree. The university was naturally keen to keep her on, and funding was found with the help of Professor John Double from Clinical Oncology.

Dr Popa was given the task of analysing the biological activity of a group of chemicals extracted from a Xylaria species, Rosellinia necatrix, a fungus capable of wiping out entire orchards in Portugal and Spain. The chemicals that Dr Popa were looking at were called cytochalasins. As far back as 1965 there had been some interest in this group and it was thought that they would be important in the fight against cancer. However, the few cytochalasins known then were found to be so toxic that work was abandoned.

In the Eighties Dr Maitland and Dr Edwards isolated several new forms from the Xylarias. By culturing tumour cells in the laboratory, Dr Popa was able to identify which cytochalasins could be potential anti-cancer drugs. She then attempted to guide the killing action of the cytochalasins solely to the cancerous cells.

To do this, she used Tamoxifen as a Trojan horse. Tamoxifen binds to cells containing very high levels of oestrogen which is why it is used to control breast cancer. The idea was that Tamoxifen would guide the cytochalasin to the cancerous cells only.

It was during this period that Dr Popa took the eventful trip to Germany and returned to discover that her solution had turned into pure crystals of the non-cancerous Z-Tamoxifen. Her finding is important because of the potential side effects of endometrial cancer when taking Tamoxifen. It is thought that this may occur because commercial Tamoxifen contains a small percentage, as little as one per cent, of the E-Tamoxifen which sometimes causes this type of cancer.

Her accidental discovery is now being commercially replicated and could help to reduce the risk of secondary cancers arising during the treatment of breast cancer. "How far was I from finding the cure for cancer back in 1996?" asks Dr Popa. "Chemists are usually the people who start it all by synthesising or isolating the potential drugs. I always hoped (and still do) that one of my molecules would end up being 'the wonderdrug'."

Despite her discovery, Dr Popa was less successful at binding the cytochalasins to Tamoxifen. However, Dr Maitland is confident that by the end of the year Bradford will have solved the problem and will begin to evaluate a new anticancer drug created from a wood-rotting fungus. It all goes to show that no matter how hard scientists work, a little bit of luck, and a chance discovery, can make all the difference between success and failure.

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