Tales of cells and correction facilities

In the early 1980s editorials and reviews in scientific journals, entitled "Gene therapy just round the corner", or words to that effect, were commonplace. By then it was already possible to isolate human genes, and there was at least some inkling about how they might be regulated. Thus it appeared that it would be only a matter of time before it would be possible to transfer genes into human cells to try to correct genetic diseases or otherwise alter a cell's genetic machinery to a patient's benefit. Unfortunately these hopes were premature.

The lack of clinical success in the field of gene therapy has not been for the want of an enormous amount of research, directed at cultured cells, animals and humans. By the end of 1997, 175 clinical trials involving different gene-therapy protocols had been completed or were under way, and over 2,000 patients had been treated without any real evidence of success. The field had attracted two new journals and numerous books and, even more remarkably, at least two histories of the story had been written. This must be the only new form of medical treatment that has attracted a historical review before it has cured a patient.

Concerned about the costs of the increasing numbers of apparently unsuccessful clinical trials involving gene therapy, the National Institutes of Health recently set up a working party to assess progress. In essence, its conclusions were that the field had tried to run before it could walk, that fewer clinical studies should be funded and that priority should be given to studies that set out to tackle some of the basic biological problems that are inhibiting progress.

In retrospect it is easy to understand why this potentially productive endeavour has not moved as quickly as was hoped. The regulation of mammalian genes has turned out to be extremely complex. It has proved difficult to find the appropriate vehicles with which to transfer genes into cells and, in the case of many diseases, the target cells themselves have been equally elusive. But genuine progress has been made and there is no doubt that this approach has enormous promise. And it has a wide therapeutic scope for, as well as correcting disorders due to single defective genes, it has potential for the management of cancer, infectious disease, vascular disease and many of the major killers of western society. But it may still be a long haul before some of the daunting technical problems are overcome.

William Clarke sets out a well-balanced account of the complexities of this controversial field of medical research. He offers a clear description of how genes work and of the attempts that are being made to isolate and transfer them to new homes, highlights some of the early attempts at gene therapy, assesses its future potential, and ends with a short discussion of some of the ethical and pastoral issues that arise from human genetic manipulation. Many other books of this kind have appeared over recent years; this one holds its own against most of the competition and its discussion of the technical aspects of gene transfer is better than most.

Clarke's book is not quite so strong on some of the clinical aspects of his story. The subtitle on the cover is confusing, suggesting as it does that the book deals with molecular medicine in the 21st century; in fact it covers only one aspect of the quite remarkable potential of the applications of molecular and cell biology to the study and management of disease. And in parts it may puzzle non-medical readers and even a few clinicians. For example, in the prologue Clarke writes: "When all the diseases caused directly by microbial pathogens are accounted for, human beings still find themselves assaulted by a wide range of crippling, even lethal maladies. These are diseases that are idiopathic (the author's italics) arising within us because of some defect in the myriad molecules involved in the construction and operation of the enormously complex human body." In medical practice the word idiopathic is used to describe a disorder of unknown cause; the Concise Oxford Dictionary defines it as "any disease or condition of unknown cause or that arises spontaneously", reflecting its current and archaic usages, respectively. Although medical science may not have progressed very far, it is misleading to suggest that it has not managed to elucidate the causes of at least a few diseases that are not infective in origin. In the chapter on gene therapy for monogenic diseases the author includes rheumatoid arthritis and cardiovascular disease as two of his main examples; the appearance of these multigenic diseases with low heritability in this list will certainly confuse (and even alarm) many readers. And the account of what sounds like a reasonably successful attempt at gene therapy for monogenic hypercholesterolaemia, a relatively common cause of premature coronary artery disease, involves an experiment the results of which do not stand up to critical evaluation.

But those searching for a simplified explanation of the technology of human molecular genetics and the approaches being explored in the hope of developing gene therapy will find them in this book, which, unlike so many of the popular works of this kind, does not duck complexities or overstate progress. It is important that we try to appreciate what is going on in this field for, despite all the hype and disappointments, it is one that will undoubtedly have much to offer clinical practice in the long term.

Sir David Weatherall is regius professor of medicine, University of Oxford.