MM 2001: Death sentence for disease?

December 21, 2000

Cures for Alzheimer's, Aids and cancer are all potential prizes for geneticists. Geoff Watts spoke to some of those working at the cutting edge of research

Health care has always been shaped by technology and by socio-political change. The community is best served when these two work together - as they did in the late 19th century. Without the public health movement, the political project that brought clean drinking water and a sewage system to urban populations, Louis Pasteur's germ theory of disease would have been a hollow achievement.

The dominating technology now is genetics. The announcement of the first draft of the human genome will shape the medical research agenda for decades. Its full effects will be felt as scientists work out the function of each gene, discover the corresponding protein molecules by which they exercise control, and then devise ways of intervening. Stimulating inactive genes, suppressing overactive ones, inhibiting or mimicking their protein products - these are some of the tricks scientists are already practising.

The socio-political themes likely to form the backdrop to these developments are less predictable. But the chances are that questions of equity - within countries and between them - will figure prominently. Globalisation will point up the gulf between haves and have-nots. The study of variations in health will move centre stage as governments absorb some of its telling - and counter-intuitive - research findings.

These two themes, genetics and equity, find reflections in virtually every branch of medical research. One type of illness and one class of remedy - neurodegenerative disorders, and the search for new vaccines - will serve as illustration.

One of the few blessings of dying young is avoiding neurodegenerative diseases such as Alzheimer's, most of which are age-related. But as mortality rates in the developing world fall, even countries such as India are beginning to feel the burden such illnesses impose. Alzheimer's runs in families - which is what prompted researchers to begin looking for genes predisposing people to it. The initial success was in finding genes that trigger the Alzheimer's that afflicts younger people. But Alzheimer's mostly affects those over 65; here the search is much harder, the precise role of the genes less clear.

Among those looking is psychiatrist Mike Owen, professor at the University of Wales College of Medicine. He studies families with two or more affected siblings. "We think there are probably three or four genes that act as the main players. We look for bits of the genome that are shared between siblings. We've looked at more than 400 families and have recently found evidence of another gene on chromosome 10. But there could be many more having minor effects on susceptibility. Most Alzheimer's is caused by the effect of a number of different genes added together."

And the clinical pay-off? "Knowing the genes involved should offer us clues to the cause of the disorder. And that should lead to better treatments. So genetics can play two roles: giving doctors a better handle on the disease, and helping identify the individuals with most to gain from any preventive treatments that become available."

Research groups around the world are grappling with the biology of Alzheimer's. Slowly, very slowly, it is beginning to look preventable. One day, there might even be a vaccine. For the moment, though, other diseases are preoccupying the vaccine researchers: in particular malaria, HIV and cancer.

Malaria has been frustrating researchers for decades. The malaria parasite has a multi-stage life cycle and powerful defences against attack. One assault is being mounted by Adrian Hill, a Wellcome Trust principal research fellow at Oxford University. He has what is called a "DNA vaccine". That is, one that relies not on the normal vaccination trick of injecting bits of the microbe into people so that they can build immunity to the disease, but on injecting instead the genetic material that codes for those bits.

His vaccine targets one stage of the infection. "It is designed to attack the parasite when it is growing inside the liver cellsI before you develop any symptoms." The vaccine has passed its first phase of assessment in Britain. Vasee Moorthy, who is supervising the trial, is in Gambia overseeing another preliminary study of 35 subjects. "In 2001, we aim to do a larger study involving about 300 people," he says.

Another Oxford researcher, Andrew McMichael, of the Medical Research Council's Human Immunology Unit, has also developed a DNA vaccine. His target is the HIV virus, and preliminary trials have begun. Traditionally, vaccination has been a way of preventing disease. But a vaccine such as McMichael's is intended to treat an existing illness. The same is true of several anti-cancer vaccines on initial trials. One has been developed by the Imperial Cancer Research Fund. Joyce Taylor-Papadimitriou found some years ago that one chemical group located on cells in the breast was often altered in cancer patients. The gene responsible is now the basis of a vaccine being tested by her colleague, David Miles, at Guy's Hospital, London.

In the long run, gene research may give us health care that is more effective and cheaper, too - so helping us cope with problems of equity. Or it may not. If the new medical care fulfils its promise, but only at a steep price, it may yet again prove the inverse care law: that health care is available in inverse proportion to the need for it.

One of the first systematic attempts to exploit our new knowledge of the human genome is under way at the Sanger Centre in Cambridge. The Cancer Genome Project has been set up to identify each of the genes involved in causing cancer. That the illness is the result of defects in certain genes has been known for years, though estimates differ even on the precise number already identified. "The figure I use is more than 100," says project director Mike Stratton. "We think that about 400 genes in total may be playing a part. Others say 1,000. But it is speculation."

The genes most directly involved fall into two broad groups: oncogenes and tumour suppressor genes. "Oncogenes can be considered the accelerators within a cell," explains senior team leader Richard Wooster. "They encourage the cell to divide and replicate." By contrast, tumour-suppressor genes are like brakes. "They slow cell division. They are guardians that make sure defective cells do not go on reproducing." Mutations in either type of gene can lead to uncontrolled division - to cancer.

The search for cancer-inducing genes will rely on two approaches. One will use 800 cancer cell lines derived from a range of tumours that now grow in the lab. The idea is to compare cancerous cells with normal ones. "That's where the human genome sequence comes in," Wooster says. "It is our baseline for the comparison. We will be able to say that in a normal DNA sequence this gene is present, but in a particular cancer cell line it is missing. Then we will check the gene in another, larger set of 2,000 tumours of that type. This should tell us how often the gene is altered, and if it really is significant." If there are 40,000 genes in the human genome, this phase of the project will take about two years.

Then there is the second approach, whose aim is to look for smaller changes. This will involve DNA from a set of 50 tumours. Besides comparisons with the published normal sequence, this genetic material will be checked against the DNA of healthy tissue from the same person. "For each tumour we'll need to do one and a half million assays. With the normal tissue as well, that comes to 150 million assays altogether. We think it'll take seven years," Wooster says.

Whether this approach will be applicable to other types of disease is hard to say. Stratton hopes it will, but he admits that the enterprise will prove even more laborious than the one for cancer.

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