A POISON from mistletoe, a plant long used as a herbal remedy, may be about to enter the armoury of mainstream medicine now that crystallographers have worked out its structure.
An international team of scientists has begun tinkering with the toxin to work out how it functions. They hope to turn it into a potent 鈥渨arhead鈥� for destroying cancers and cells that cause rejection of transplanted organs (see 鈥淜issing times are here again鈥�, 24/31 December 1994).
The compound, mistletoe lectin 1 (ML1), is similar to ricin, the poison used on the tip of an umbrella in 1978 to kill Georgi Markov, a Bulgarian dissident. ML1 is milder than ricin, and the newly established structure should help to explain why.
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Rex Palmer and Edel Sweeney of the department of crystallography at Birkbeck College, London, found that 鈥� uniquely among these toxic lectins 鈥� ML1 exists as a pair of identical molecules, called a dimer. 鈥淚t鈥檚 very unusual,鈥� says Sweeney. 鈥淣ow we know it鈥檚 a dimer, it tells us why ML1 has different properties to ricin.鈥�
The ricin molecule contains two chunks of protein, the A and B chains. As in all toxic lectins, the B chain binds the toxin to cells and helps it to infiltrate through the cell wall. Once ricin is inside a cell, its A chain breaks loose and wreaks havoc 鈥� killing cells by destroying their ribosomes, the cell鈥檚 protein factories.
Sweeney says that the crystallographic images show that ML1 looks like two ricin molecules bound together, with two A chains and two B chains. Once inside the cell, the four units break apart, with the A chains killing the cells just as they do in ricin. The reduced toxicity of ML1 seems to lie in its slower rate of transfer across the cell wall. This may be due to its greater bulk and the wider molecular 鈥渏aws鈥� with which it grips the cell wall.
Alexander Tonevitsky of the Institute of Genetics of Microorganisms in Moscow plans to tether parts of the ML1 toxin to agents such as antibodies so that together they can seek out and destroy target cells. Paired molecules of this type 鈥� called immunotoxins 鈥� have already been tried as drugs, the most usual combination being ricin with an antibody.
Sweeney says trials with immunotoxins in cancer patients have been disappointing because of a phenomenon called 鈥渧ascular leakage syndrome鈥�. The ricin A chains leak away from the tumour in fine blood vessels and are destroyed by the body鈥檚 immune system.
鈥淚f we knew the mechanism for this, and could find a better A chain that stays in place, we could use much lower, much more effective doses of immunotoxins,鈥� says Sweeney.
Tonevitsky, who visited Birkbeck last week, hopes to experiment in animals with different mixtures of A chains and B chains from toxic lectins. Now that he knows the structure of ML1, he hopes that he will be able to genetically engineer variants that might be more potent.
His first goal, working with John Fabre at Great Ormond Street Hospital in London, is to make immunotoxins that will destroy white blood cells on donated organs prior to surgery. Other immunotoxins will be aimed at bone marrow as part of leukaemia therapy.