Disease and genetics

in a recent issue of the journal Current Opinion in Genetics and Development (Vol 6, No 3), D J Weatherall and A O M Wilkie of the Institute of Molecular Medicine at Oxford, uk, provide a succinct introduction to the current state of understanding in the area of human genetics as applied to medicine.

They begin with the Human Genome Project, whose ultimate aim is to generate a complete sequence of the dna in a 'standard' human being. We are still some way from the end, nor is it certain what exactly is to be done once the sequence is at hand. In the meanwhile, so-called physical mapping has made remarkable progress. This has generated a series of ordered markers -- signposts, as it were, scattered all over the genome. Any day now we will have in hand some 30,000 markers separated, on the average, by approximately 100,000 bases of dna. In principle, we can now begin to understand the genetic basis of any inherited disease. One looks first for a marker that associates with the disease and then hopes to identify mutations in a prospective gene that might be a causal factor in the appearance of the disease. These steps are painstaking and fraught with uncertainty.

A second area of intense investigation involves looking for the genetics of an analogous disease but in an animal, most commonly the mouse. The logic behind this approach is that humans and mice, both being mammals, are built along similar lines and are expected to share genes that are involved in broadly similar pathways of embryonic development. There have been significant advances in the understanding of genetic diseases in four organs: skin, bone, genitalia and heart. Interestingly, a predisposition to cardiac arrhythmia appears to result from mutations in genes that encode proteins that specifically allow the movement across the cell membrane of sodium, potassium or other ions.

The genetics of sex determination has made remarkable progress, but as the number of genes implicated increases the concept of a single master gene that determines sexuality recedes.

Attempts to identify genes implicated in human cancers have long been at the forefront of genetic studies. The field experienced a breakthrough with the discovery, years ago, of oncogenes (cancer-causing genes), many of which function by suppressing the activity of other genes that, if unchecked, can cause tumours. Two genes that are involved in inherited breast cancer have been identified. This shows that what clinicians, not to speak of the lay public, think of as one disease may in fact have more than one possible genetic correlate. Mice that lack functional copies of one of the human breast cancer gene homologues (brca1) die as embryos and death is due to a large number of developmental malformations. This observation makes a second important point: a gene that we think is involved (when it is defective) in a specific cancer, can also have a hand in many seemingly unrelated aspects of development.

A large number of diseases, including inherited diseases for which a gene tic basis might be sought, are commonly correlates of growing old, an observation that has spurred research into the genetics of aging. Two factors have been implicated -- a general slowing down of metabolism with aging and a decreasing ability to resist the damaging effects of so-called free radicals -- derivatives of oxygen that can damage cells and tissues unless neutralised rapidly.

The onset of a 'genetic' disease is not dependent on certain genes alone but on the way those genes interact with other genes and with the environment. This makes it difficult to always tell parents with 100 per cent confidence that a certain child that they have conceived will come down with disease. If genetic counselling is not possible, or does not succeed, physicians can still make use of their knowledge of genetics to devise appropriate palliative measures based on drug therapy. A third approach to handle a genetically-based disease is known as gene therapy. This is easier said than done, because what it demands is a permanent, or at least long-term, change in the genetic composition of an individual. Its prospects have been inflated far beyond realisitic expectations for the forseeable future, even in the technologically-advanced West.

Despite a gradual breakdown of marriage barriers, India still constitutes a unique laboratory in that it offers a strong hope of finding a variety of inherited traits that tend to run in families. The opportunities of carrying out linkage mapping -- roughly, fixing the approximate geographic location of a trait-causing gene on the dna molecule -- are therefore rich; and linkage mapping is the first, essential, step in any programme of human genetics.

Therefore, we need to urgently press ahead with population studies on which basis scientists, physicians and anthropologists cooperate. The prospect is exciting, for it also opens up the possibility of meaningful approaches to genetic disease. Such a course of action would constitute the ideal combination of pure and applied sciences. On the other hand, gene therapy is an entirely different matter. A moment's reflection shows that our major public health problems are caused by a lack of access to adequate food and safe drinking water and an absence of hygiene. However exciting it may sound in a conceptual sense, gene therapy is a luxury that we can do without for the present.

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