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Mary-Teresa Moran spoke on 29 November 1998 to members of the Gauchers Association about the research she is conducting at the Department of Medicine at the University of Cambridge into the role of gene expression (activity) in Gauchers disease and the exciting discoveries she has made in Prof Cox's laboratory which is based at Addenbrookeµs Hospital. Ms Moran will be writing up her results as a PhD thesis and will shortly be submitting her findings for publication in a Journal of Medical Research. The Gauchers Association has raised £15,000 for her laboratory expenses over the past three years.
We wanted to find out exactly what happens in the spleen, liver and bone marrow which are the sites most commonly affected by Gauchers disease,' explained Ms Moran.
The macrophage cells, which eat up old white and red blood cells and store up the fatty material, glucocere-broside, occur almost everywhere in the body but it is mainly in the spleen, liver and bone marrow that the accumulation of glucocerebroside occurs. It is here that the defective enzyme in Gauchers disease cannot break down the components into glucose and ceramide. As these macrophage cells become engorged with the fatty material, they become Gauchers cells.
We also wanted to look for reasons why some patients have inherited the same mutations for Gauchers disease and yet have a severity of their illness that differs, even between brothers and sisters and in one case, between identical twins. We felt it could not just be the deficiency of the enzyme glucocerebrosidase that accounts for this. There must be other reasons.
We wanted to discover which genes are turned on (active) in Gauchers cells as a result of their stored fatty material.
We took macrophages cells from five spleens which had previously been surgically removed for medical reasons: three spleens from Gauchers patients and two ''normal'' spleens from people with other conditions.
Using a very difficult and new tech-nique, we compared the population of active genes from Gauchers cells and the normal cells.
We extracted the genes which were in both populations and after subtract-ing one from the other, we obtained the difference in activity between the Gauchers tissue and the normal spleen. The first experiment took us six months of intensive work and cost more than £2,000 in laboratory expenses, alone.
'We next had to identify these genes precisely. We sequenced them and then compared them with existing information on a computer database of known genes. The sequences reveal the message which the gene carries in the body. I remember on 15 March at 8.30 in the morning, we were ready to analyse the genes we had discovered.
There were altogether five lysosomal genes, seven other genes and two hitherto unknown genes. This was an unbelievably exciting moment for me. Three of the lysosomal genes were for the enzymes, cathepsin B, K and S. Cathepsin is Greek for ?digest' and this well-known class of enzymes has been actively studied since their identification in 1929.
We know that the gene for cathepsin K is highly expressed (active) in osteoclasts, the macrophage-like cells which break down and eat up bone. We also know that cathepsins are lysosomal enzymes implicated in rheumatoid arthritis and a host of other disease processes including inflammation and hormone release.
Using different techniques, we discovered that all three cathepsins are more abundant at the RNA (gene activity) level in Gauchers cells compared with normal cells of the spleen. We also discovered that the same observation applies at the protein (enzyme) level both in the tissues and in the blood of patients with Gauchers disease. This was the final 'read-out' of the gene activation and confirms our findings in the whole patient.
The amount of all three cathepsins was increased many times in both treated and untreated patients compared with normal samples. There are 20 known cathepsins but so far only three have been found in Gauchers cells.
May Lead to Further Treatment
Inhibitors for a number of cathepsins are being developed for therapeutic use including osteoporosis (where the bones become thin and brittle). These inhibitors might lead the way to further treatment, for example, for bone disease in Gauchers patients.'
Prof Timothy Cox said at the end of the talk: 'This fundamental research is an important step in understanding Gauchers disease which is not a simple disorder. The deficiency of the enzyme glucocerebrosidase and the accumulation of glucocerebroside undoubtedly have complex effects on the tissue environment in which Gauchers cells occur. Gauchers disease cannot yet be fully explained: Mary-Teresa's and Dr Schofield's efforts have shown how this critical issue can be tackled.'
Ms Moran thanked Prof Cox, Dr Paul Schofield and all the colleagues in the lab for their support and encouragement and also warmly thanked members of the Gauchers Association for contributing funds to enable her work to be carried out.
Mary-Teresa Moran will be running in the London Marathon on Sunday 18 April 1999 in aid of the Association.
The Chairman writes
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Source: Gauchers News January 1999
© Copyright Gauchers Association 1999