FROM GOUT TO AIDS

Prof. David Blake, Royal National Hospital for Rheumatic Diseases, on 26 July 2002

Professor Blake gave a wide-ranging talk demonstrating how molecular chemistry can link apparently unrelated diseases and conditions, and how serendipity can lead to important developments in the treatment of AIDS in Africa. He started by showing a picture of an Indian woman who had identical twins; one of these had been breast fed and was healthy and survived, but the other had been given one of the regular formula feeds, looked distinctly weaker, and died shortly after the photograph had been taken. The question was why.

The RNHRD has a long history and was the first hospital to treat a given condition on a national scale. Amongst its first patients were aristocrats suffering from gout, which has remained a common object of study. The first ideas of gout being caused by `rheum' settling in joints has of course now been replaced by an assemblage of peptides, proteins and genes. There are about 100 genes and their interactions are so complex and non-linear, that assessing the effects of any one of them is a daunting task and in many cases impossible with current techniques. Some are known; for example, it has been discovered that people with ankylose spondulitis not only have stiff and deformed spinal columns, they are also immune from the current strains of the AIDS virus.

One disease that has been cracked, however, is gout. Prof. Blake and his colleagues discovered that it is caused by deposits of crystals of uric acid in the joints and limbs, giving rise to the painful condition. The body creates uric acid by oxidising purine, a common constituent of food, using the enzyme xanthine oxidase. On further analysis, the gene that codes for the enzyme seemed not to be activated by any conditions that would be associated by lots of purine, but rather with the sex of the organism and excess oxygen in the tissues. The structure of the enzyme is approximately a triangle with a molybdenum (Mo) ion at one corner, a flavine group (FAD) at another and ferrous sulphide (FeS) at the third. To oxidise purine, only the Mo part was used; there was too much in the molecule for this to be the only function it had.

By a curious accident, Prof. Blake discovered that there was a molecule in plants that was essential for reducing nitrates to nitrites, and this had the same structure as the Mo-FAD side of xanthine oxidase. This led ultimately to the understanding of its relation to nitric oxide and that the enzyme can act as a proxy nitrate. And this explains in turn its powerful bactericidal effects and why it is found in large quantities at the main entrances to the body. It is also present in large amounts in milk fat globules. Further analysis of this showed that the form in which it is found favoured the environment in the child's stomach, not that of the mother's breast.

At this point, one of the team at the RNHRD asked whether the enzyme was present in formula feeds. On checking the labels of the common feeds, they appeared to do so, but yet they did not work. The manufacturing process had de-activated it. After some considerable effort, Prof. Blake has now patented a method of processing xanthine oxidase so that it remains active in the feed, and started to look for a place to test it out.

Figures for the prevalence of AIDS in Africa are unreliable. For example, it is estimated that one third of teachers in Botswana are affected, but the numbers that are dying annually, points more towards two-third being a more accurate figure. Children seem to be protected from acquiring AIDS from their mothers (for example through a cracked nipple) in the first three months, but thereafter they are prone to it. So if a better formula feed could be used, the number of children growing up with the virus would be dramatically reduced, but their parents would die. With the idea of trying this feed, a factory will be set up in Botswana to make it and distribute it.

If this is successful, then we will see a large increase in the number of orphans, which will test the political and financial capabilities of the country, but it seems one of the most interesting developments. We wish Prof. Blake success in his venture in trying to control this scourge of Africa.

Andrew Pepperdine