The science of sick molecules

The notion that it might be possible to describe disease at the level of sick molecules is not new. In 1945 the distinguished protein chemist Linus Pauling struck up a conversation with the haematologist William Castle on an overnight train journey between Denver and Chicago. Castle, one of the unsung heroes of the discovery of vitamin V12 and the cure of pernicious anaemia, and many other seminal advances in modern haematology, told Pauling that he and his colleagues had noticed that the red blood cells of patients with sickle cell anaemia had an unusual appearance when examined under polarised light. Pauling was intrigued by Castle's observations, realising that the changes that he had described might be telling us that the defect lies within the haemoglobin molecule. On returning to his laboratory he suggested to his young colleagues that this might make an interesting research project - something of an understatement as it turned out. In 1949 Pauling's group announced that the haemoglobin of patients with sickle cell anaemia had a different rate of movement in an electric field to that of normal persons. This, they reasoned, must mean that the charges of the two molecules were different and hence that they must differ in their amino acid constitution. Pauling and his colleagues therefore coined the term "molecular disease" to describe sickle cell anaemia.

The change in emphasis in medical research from the study of illness in patients or their organs to their cells and molecules has led to some remarkable advances in our understanding of disease mechanisms, though it has yet to have a major effect on clinical practice. But this new field has immense possibilities for the future. In the case of the 5,000 or so monogenic diseases, it opens the way to precise diagnosis and counselling and, in the longer term, to a genuine possibility of correcting at least some of them. It is already yielding valuable information about the mechanisms of mental retardation and congenital malformation. By dissecting out the genetic component of the interactions between nature and nurture that underlie some of the common killers of western society, for example heart disease, stroke, major psychiatric disease and diabetes, it offers the possibility of understanding the basic pathological mechanisms and hence of providing new and more humane methods of treatment. It has already unravelled much of the cellular pathology of cancer, and again promises new approaches to management. And it has equally exciting applications to broader issues of human biology - evolution, development and ageing, for example.

Thus, although the term "molecular medicine" smacks more of optimism than achievement, this is unlikely to be the case for long. It is difficult to predict when the fruits of the Human Genome Project will make a major inroad into the provision of medical care. Undoubtedly it will take many years to find out how the whole thing works, and how our many genes are orchestrated in the complex circuitry that underlies the function of intact cells, organs and human beings. The transition from this extremely reductionist view of pathology to the holistic approach to disease that is required in clinical practice will undoubtedly be protracted, but however long it takes, there is little doubt that molecular medicine will play an increasingly important role in medical research and practice in the next millennium.

The speed of advance in the biological revolution of the post-DNA era has been quite extraordinary. One of the problems that has resulted from this information explosion is the widening communication gap between the basic biological sciences, clinicians and the public at large. The concepts and technology of molecular and cell biology are complex and rapidly changing; their implications for medical practice are not always obvious; and the doctors who might reap their benefits are caught up in the frenetic world of trying to cope with a rapidly increasing clinical load in the face of limited resources. Any efforts directed towards facilitating communication between the rapidly diverging worlds of basic science and clinical practice are therefore welcome.

The production of a six-volume encyclopaedia that aims to combine molecular biology and molecular medicine is one of the most ambitious efforts so far to solve this problem. The editor, Robert A. Myers, supported by a board that sports no fewer than seven Nobel prize winners and a vast international cast of authors, has set out to provide a multi-volume reference for what they describe as the "expanding number of scientists who will contribute to this field, many of whom, in the future, will enter molecular biology research from majors or careers in animal, plant, and cell biology and medicine, as well as physics, chemistry, mathematics and engineering". They believe that the encyclopaedia will also be a useful source of enlightenment for clinicians, both in practice and in industry, and for teachers who, they hope, will utilise the volumes for course preparation.

The work is comprised of nearly 300 main articles, each of which begins with a key word section, including definitions, designed to assist the reader who is unfamiliar with the field. It includes over 1,900 such words, some of which, because they have different meanings in different contexts, have more than one definition. Each volume, in addition, contains a glossary of basic terms. In this way it is hoped that most readers will be able to appreciate the articles without referring to a dictionary, textbook, or other reference work.

What is a reviewer to do when faced with such a massive work? Undoubtedly the first temptation is to turn immediately to those few subjects about which he or she has at least a smattering of knowledge. Alternatively, perhaps the only fair thing to do is to follow Alexander Pope's advice and "survey the WHOLE, nor seek slight faults to find". In desperation I tried both approaches. Because there have been several other dictionaries and similar works that cover molecular genetics and molecular biology it must have been easier to organise this aspect of the encyclopaedia than its medical coverage. Of necessity, because each of the topics is presented quite extensively in the form of a long and profusely illustrated article, the overall coverage of molecular and cell biology is less exhaustive than in some of the recently published dictionaries that cover these topics. But, overall, this field is dealt with very well and offers a particularly broad view of the biotechnological aspects of the molecular sciences.

The quality that makes this encyclopaedia different from recent competitors is that it attempts to wed molecular biology to molecular medicine. With the senior medical student or post-doctoral scientist in mind, and because some of the section headings have rather idiosyncratic titles, I scanned the index, all 125 pages of it, to try to gauge the coverage of the clinical applications of molecular and cell biology. Remarkably, most topics of importance seem to be listed. There are extensive sections on the aspects of human genetics that are essential for understanding the clinical applications of molecular biology, including reasonably up-to-date descriptions of the maps of all the human chromosomes, and good accounts of the technology that is required to study pathology at the DNA level.

Where the encyclopaedia is less successful in places is in the balance and organisation of the coverage of individual diseases. Cancer is a good example. After a two-page introduction to the biology of cancer, the next entry is entitled "Cancer chemotherapy, theoretical foundations of". This section, which occupies 16 pages, gives an extremely detailed account of this aspect of the cancer field. The introductory section, which is quite short, also refers to nine other sections which cover different aspects of cancer biology; three organs, the breast, colon and liver, have long sections to themselves. The final entry in this cross-referral list is "Antitumour", a section which does not exist at all. Thus although it would be possible for persistent students to gain a bird's-eye view of the remarkable advances in our understanding of the molecular and cellular basis of cancer, since the material is presented in this rather disjointed way, they would have something of a struggle.

There are other inconsistencies and problems of balance. For example, the monogenic disorders, Gaucher's disease and haemophilia have long and detailed sections to themselves. On the other hand, the thalassaemias and muscular dystrophies, though they have a few entries in the index, receive little attention. The coverage of haemoglobin and its disorders is particularly disappointing. While there is an extensive discussion of its structure and function, and a long section on artificial haemoglobins, the human variants, which tell us so much about structure-function relationships in disease, get scant coverage; sickle cell anaemia, which started the whole field off, is barely mentioned. The thalassaemias, the commonest monogenic diseases in man, about which more is known of the relationship between molecular pathology and clinical phenotype than for any other inherited disease, suffer the same fate; although the disease is billed in the index to appear in several sections, when it does, sometimes misspelt, it is never dealt with adequately.

There are a number of problems of this kind throughout the encyclopaedia. There is no section on gene therapy; I found the best short account under the heading "Tumour suppressor genes". Similarly, ethics, so important in this emotive subject, though it appears in the index only merits a few scattered remarks in different sections. And some of the authors have written very dense reviews without trying to analyse and highlight the really important features in a way that is needed for a student or non-specialist readership.

Overall, the short reading lists at the end of the major sections, though reasonably up-to-date, are disappointing in content.

Despite these criticisms, the fact that this encyclopaedia saw the light of day at all is remarkable. It must have been a tremendous undertaking, particularly since the six volumes were published in only two years. At a cost of nearly Pounds 1,000, I suspect that few individual students or graduates will be able to buy it. However, general reference works of this kind are becoming increasingly popular, largely, I suspect, because the field is so broad and is attracting students and graduates from many different backgrounds. If some of its idiosyncrasies can be ironed out in future editions, it should be able to hold its own with similar works of this genre, and become a valuable addition to the literature of the field, at least for those libraries that can afford it.

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