SCIENCE: MYSTERY OF A MIRROR IMAGE

With Dr Steve Davies's breakthrough in molecular study, the tragedy of thalidomide need never have happened. Lionel Milgrom explains

IF YOU want to tell your left hand from your right, it is easy. All you have to do is look: your hands are mirror images of one another. Molecules, too, can be left-handed or right-handed, their atoms arranged in one of two different ways. Every cell in our bodies can distinguish between these two forms (known as "chiral" forms), but on a conscious level we humans have much more difficulty spotting the difference.

In the laboratory, such a failure can have dramatic consequences. Many synthetic drugs have molecules that come in left- and right-handed forms; sometimes one is beneficial while its mirror image is harmful. Thalidomide, prescribed to treat nausea in pregnant women in the 1960s, is the most notorious example. One form of the molecule is a sedative, the other a teratogenic that causes gross limb deformities in babies. The drug used 30 years ago was a mixture of both.

Nature produces molecules exclusively in one chiral form or another; all enzymes, for example, are "left-handed". By comparison, most chemical reactions in the laboratory have produced equal amounts of the left- and right-handed forms - until now, that is. Dr Steve Davies of Oxford University has learned to mimic nature, using tiny pieces of molecular scaffolding called "chiral auxilliaries" to effectively mould molecules in the correct form. So far-reaching are the commercial possibilities of Dr Davies's research that many of the world's top drug companies are now beating a path to his door.

"Each one of the body's chemical reactions is controlled by an enzyme," Dr Davies explains. "When you become ill, one or more of those reactions goes wrong and you have to put something into your body to put them right." That something is a drug.

The enzymes in the body are made up of simple amino acid molecules. Nature uses only left-handed amino acids when building enzymes, so enzymes too are "left-handed". For a patient to derive maximum benefit from any drug, it is important that the molecules of the drug are compatible with the enzymes, ie, that they too are left-handed.

Clearly, we need drugs whose molecules are all of one "handness" - and that is what Dr Davies's discovery has made possible. As an organic chemist, he is chiefly interested in the vast number of molecules containing the element carbon. In many of these, each carbon atom is chemically bonded to four other groups of atoms in the structure. It is the geometric arrangement of these groups around the central carbon atom that determines a molecule's handedness.

The problem with identifying the handedness of molecules is that they have identical chemical properties, and so react in the same way. If they are solids, they will melt at the same temperature; if they are liquids, they will share the same boiling point. In fact, they only differ from one another in one tiny but important respect. As befits compounds made of mirror-image molecules, they interact with light in totally opposite ways. Left-handed molecules twist plane-polarised light in one direction, while right-handed molecules twist it by the same amount, but in the opposite direction.

If identifying the handedness of chiral molecules is difficult, making them is even tougher. "It's as if you're trying to make a hand from a box of thumbs and fingers," says Dr Davies. "You start from the left, putting the little finger on first and finishing with the thumb. An 'up' palm gives you a right hand while a 'down' palm produces a left hand. The trouble is, you don't know whether the palm is up or down. So you end up with a mixture of right and left hands."

To manufacture consistently one type of molecule or the other, an extra piece of information is needed - whether the palm is facing upwards or downwards. Nature gets over this problem by using enzymes as molecular moulds. Molecules of the required "handedness" are made inside the mould, a principle which Dr Davies's work also utilises. "We use a much smaller piece of molecular scaffolding," he says, "which is called a chiral auxilliary. This has the left or right-handedness already built in, and as we construct our molecule on the chiral auxilliary's surface, that information gets passed on."

To drive home the difference between natural enzymes and his own chiral auxilliaries, Davies throws out another analogy: "If nature tried to construct a garden shed, she would use a piece of scaffolding the size of the Forth Bridge. We use something the size of a wheelbarrow." The company Dr Davies has founded, Oxford Asymmetry, will help a pharmaceuticals firm scale up these chiral building blocks to help in the synthetic production of new drugs.

Chiral auxilliaries have other applications, too. New work at Oxford Asym-metry involves more environmentally friendly ways of dealing with insect pests. Earlier this year, a joint team from Davies's company and the zoology department at Oxford University managed to synthesise large quantities of a pheromone used by female woodworms to attract males.

Spraying an infested area with the substance, which is just as effective as the natural pheromone, confuses the male woodworms and could interrupt the breeding cycles. Also, infestation can be assessed by using the synthetic pheromone inside traps to capture, and so monitor, the insects. Ultimately, this treatment could reduce the amount and cost of insecticides used.

When Dr Davies launched his company in 1988, commercial rewards were far from his mind. It was love of his subject that inspired him to do so, as it would free him to do more research in his specialist field. He saw it as a more time-effective way of financing his 30-strong team of researchers than conventional academic fund-raising.

"In academia," he says, "the more successful you are at attracting research funding, the more time you have to spend writing grant proposals to keep it all going, and the less time you have to do research. Chemistry is what motivates me, not form-filling."

With money from BP Chemicals and BP Ventures, Davies and four research- ers started Oxford Chirality from rented space in the university. The recession, and BP's contraction back to its core businesses, meant that in 1991 they pulled the plug just as Oxford Chirality was beginning to take off. Undeterred, Davies took a gamble, personally guaranteeing the salaries and costs of Oxford Chirality, while he went looking for backers - a brave move for a man with a wife, mortgage and young child.

He found his backers in the shape of a group of Oxford-educated business angels called Wardsend Associates, who were prepared to commit themselves in the long term and allow Davies to build a sustainable company. With £100,000 and one of his former students, Davies relaunched his company as Oxford Asymmetry in 1991 (Oxford University took an equity stake in it). The company now has a catalogue of around 150 compounds and custom- made chemical products, selling to the top 50 per cent pharmaceutical companies. Earlier this year, after major new investment by the 3i group, Oxford Asymmetry was valued at £14 million.

Dr Davies's only previous business experience was of selling vegetables in the market during his school holidays, something for which he found he had a talent. "If you can sell vegetables, you can sell chemistry," he concludes. "Most academics still think it's wrong to make money out of fundamental research, but if setting up a company is the only way to do it, then fine." Even so, he hasn't taken a penny out of the company and still needs to write major proposals to fund new research.

Despite his mounting success, in the world of science he is better known as the husband of Professor Kay Davies - the human geneticist and vice- president of the human genome project. She resigned from her post at the Hammersmith Hospital, London, earlier this year and now occupies the chair of genetics at Oxford University. Their seven-year-old son gives them a reason to keep their feet on the ground, and the couple always make sure at least one of them is in the country at any one time. "We only ever seem to meet up at airports these days," says Davies. !

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