The fate of respiratory physiology.

Respiratory physiology is under threat. What was once regarded as the science underpinning respiratory medicine is now being eroded by a move towards cell and molecular biology that threatens its very existence. This trend is not confined to the respiratory field, but is also occurring in most other specialities. Some academic departments of respiratory physiology and research groups in physiology are already under threat of closure, or are being drastically reduced to make way for more molecular biologists (deoxyribonucleic acid (DNA) biochemists). As I write this editorial, one of the most prestigious and productive respiratory physiology departments in the world, the Department of Physiology in the University of Leiden, led by Professor Philip Quanjer, is about to be dismantled. The time has come to halt the erosion of physiology, before we lose a generation of trained individuals. As molecular biology advances, never has the need for integrative physiology been greater. Without innovative respiratory physiology, some of the most interesting questions posed by molecular and cell biology cannot be answered, and the enormous potential of the advances in cell and molecular biology cannot be fully realized. Molecular biology has grown enormously over the last 20 yrs and has provided techniques that can answer questions previously unimaginable. The attraction of molecular biology is that it will enable us to understand all human disease at a molecular level and, thus, lead to more specific treatments in the future. This is the rationale for the enormous expenditure on the Human Genome Project. The identification of particular genes has made it possible to study the genetic basis of disease, and to elucidate the detailed structures of important proteins, such as enzymes, receptors and signalling proteins. Many of the advances in molecular biology have relied upon cultured cell lines, which make it possible to study expression of genes and the factors that regulate their expression in great detail. However, there is increasing recognition that this approach may have limited application, because many cell lines do not function in the same way as cells in the living organism, and they are not subject to the same regulatory control mechanisms. This means that control mechanisms in the intact animal may be quite different to those identified in cell lines. Another problem that is becoming ever more apparent is that studying the regulation of gene expression by measuring the steady-state messenger ribonucleic acid (mRNA) content of a cell (by Northern blotting or solution hybridization), or by directly measuring the rate of gene transcription (by nuclear run-on assays), does not necessarily predict what will happen to the production of the protein product of the gene or its function, since several changes may occur in the mRNA level before the protein is translated, and changes may also occur after translation of the protein in the cytoplasm. This is now leading to the view that molecular biology in isolation is inadequate, and that to conduct molecular biology in isolation, without concomitant measurements of protein expression and function, may be misleading. Molecular and cell biology (the "new biology") are seductive because they offer so much. Unfortunately, this has persuaded national funding bodies to finance this research in favour of more traditional physiological and pharmacological approaches, from a diminishing pot of money. Physiology and pharmacology have become unfashionable. This short-sighted and unwise approach has led to the atrophy of physiology and pharmacology departments in universities. This attitude has also filtered down to students, who avidly study the new biology but are not taught the basic principles of physiology and pharmacology. This will lead to a generation uneducated in these important sciences, at a time when there will be the most need for these skills. Molecular biology does have enormous potential for increasing our understanding of all respiratory diseases (see [1]), but it will not be possible to take advantage of these approaches without integrating molecular biology into whole organ physiology, particularly in humans. There will be an increasing need to develop and apply physiology in order to exploit the fruits of molecular biology. Molecular techniques have commonly been applied to isolated or cultured cells because of the nature of the technology currently available. While this may give detailed information about a single cell (or transformed cell line), this approach misses the complexities of cell-to-cell interactions, which are the essence of complex organisms. The philosophy of integrative physiology is that the whole is more than the sum of its individual parts. This means that, in the future, the communication between cells and the control mechanisms regulating integrated responses must be taken into account, particularly when trying to elucidate dysfunction in disease. This is where physiology has much to teach molecular biology and in the future it will be necessary to apply molecular and cell biology techniques in the intact organism, where it will be important to make careful measurements of function. With understanding of the detailed function of individual parts we may still not understand how the intact human functions. What is needed for the future is the integration of molecular and cell biology with the approaches adopted in integrative physiology. Molecular biology will provide new tools that can be used to explore the pathophysiology of respiratory diseases. These will include complementary deoxyribonucleic acid (cDNA) probes to examine the expression of particular genes, but this information must be linked to functional information. At the end of the day, it is the functional information that must take precedence; an alteration in expression of a particular gene that is without functional consequence may not be clinically relevant (and vice versa). EDITORIAL