Foreword

Abstract

Spectacular technical and conceptual advances in modern biology will, within a short and predictable time, bring us the complete sequence of the human genome. This expectation has created a fair portion of overstatement and, inevitably, a backlash of scepticism. Headlines have thus far exceeded tangible benefits. However, away from this public debate, the science moves steadily on, making some gains and running into some blind alleys, but inexorably widening the range of available information. Virtually all genes associated with common monogenic disorders have been identified and their mutations catalogued. Theoretically, although not yet entirely in practice, precise diagnostic tests have been developed. These diseases have not been rendered readily treatable, but genetic counselling has brought substantial benefits to some families. Research into monogenic disorders remains active, but has moved from genetics into biochemistry and functional biology. For some of these diseases cloning the genes involved has allowed, for the first time, glimpses of the underlying biological problems. The moving front of genetic research has now gone from these genetically fairly straightforward disorders, to the more complex, multifactorial disease in which multiple genes and environmental factors interact to produce the phenotype. The process of gene mapping leading to “positional cloning”, is now evolving to investigate these more common phenotypes. This work will be facilitated by the availability of large banks of genetic markers, single-nucleotide polymorphisms, and the genomic sequence. The potential medical benefits of understanding the genetic contribution to complex diseases include population screening for disease predisposition, new targets for drug development, prediction of individual responses to specific drugs, and knowledge of gene-environment interactions. Finding these genes is much harder than was mapping the common monogenic disorders, but steady progress is evident. As this work progresses, the biochemistry of “common diseases” will steadily unravel, and it seems probable that different aetiological variants of each main phenotype will be revealed. It remains to be seen whether there really are any “common” diseases, or whether those that appear to be common are merely aggregates of less common disorders, whose phenotypes are indistinguishable in our current state of ignorance. This collection of articles is intended to illustrate the enormously wide range of topics, the many corners of medicine into which gene-based advances are now creeping. Reviewers have been encouraged to express unbridled optimism only where it is justified by current progress. The stage is set by a background description of the human genome project, and of the techniques for genetic testing which this has spawned. Difficulties in identifying genes that contribute to multifactorial diseases are discussed, with some specific examples. The particular and unusual problems of mitochondrial inheritance, and the fascinating complex interactions of priori genes with environmental factors, provide insights into how genetic approaches help unravel biological problems far removed from mendelian genetics. Genetic diagnostics extends well beyond simple inheritance testing, and is now moving into all areas of pathology. Gene therapy, although in a phase of sober consolidation after an exuberant youth, nevertheless holds very real promise. Understanding the molecular basis of tissue differentiation, perhaps with the use of nuclear-replacement techniques, may allow the creation of histocompatible, specialised tissues for transplant purposes—”tissue engineering”. This success of this technique presumes that medical scientists can convince a bewildered public and government that each individual is in himself a “clone”, and that creation of new tissue in cell culture is fundamentally different from “making a twin in order to deliberately destroy it”. All genetic medicine must operate in a social and ethical context—an issue particularly accentuated in the early days of medical genetics by the availability of prenatal tests for untreatable disorders. One way of looking at these dilemmas is to consider what sorts of genetic tests are now available, and to ask which of them a sensitive and knowledgeable individual would wish to have for himself. Judgments people make for their own use are sometimes more humane, and less strident, than when prescribing the behaviour of others. The prominence of this class of ethical controversy in genetic practice will very likely diminish with time, as the products of molecular medicine range further away from pure diagnostics and into treatment. But lessons of the social dimension, and of the crucial importance of patients' information and consent, so much discussed and carefully worked out for monogenic disorders, will stand all of medicine in good stead in developing its future relationship with society. The dimensions of the revolution in medical genetic research no longer allow for a systematic assessment. By concentrating on a few conventional, and a few less conventional, topics under this rubric, we hope that a flavour will come through of the range of interesting advances that may emerge and affect medical practice over the coming years in diagnostics, therapeutics, and most of all, in increasing our understanding of human biology in health and disease.