Every biomedical scientist who writes grant proposals knows the value of mentioning the relevance of his or her research to cancer, Alzheimer's disease, or another high-profile condition. But in practice the connections may be tenuous. One way to ensure that laboratory studies remain focused on clinical goals is to place a research institute right inside a hospital. That is what Britain's Medical Research Council did five years ago when it set up the Clinical Sciences Centre at Hammersmith Hospital in London. "The idea is to promote interactions between clinicians and scientists," says Christopher Higgins, who was appointed director of the CSC in September 1997. "What we're doing here is not just excellent basic science, but basic science with clinical relevance."

The CSC is the flagship of a Clinical Research Initiative launched in 1990 by the MRC, which distributes almost £300 million ($480 million) per year in government funding for biomedical research at many insitutions. MRC planners realized that basic and clinical researchers in Britain were not collaborating as effectively as they could be - particularly when compared to their colleagues in the United States. In response, the planners refocused spending and established a number of small centers in medical schools around the country, each specializing in particular clinical problems.

Then in 1993 the MRC set up the CSC by bringing together nearly 15 research groups at Hammersmith Hospital, a leading postgraduate teaching institution that already had a strong reputation for research. Now incorporated into the newly-established Imperial College School of Medicine, which includes Hammersmith and three other major London teaching hospitals, the CSC is housed in new, custom-built laboratories. Its mission is to undertake basic research using modern biological approaches such as molecular genetics and non-invasive imaging to understand the basis of human disease and to apply its findings to novel methods of diagnosis and treatment.

Higgins has come to his new post from Oxford University, where he was a professor of clinical biochemistry. His research group at the CSC is pioneering the development of new methods of treating disease by gene therapy: delivering healthy genes to tissues that lack their own. "We are working with cystic fibrosis as a model disease," says Higgins, "but the technologies we have developed could have much wider applications." He and his team deliver genes packaged in tiny fat droplets called liposomes, which can introduce genes across cell membranes, rather than use viruses as vectors. Already the team has completed two clinical trials of the method, in which cystic fibrosis sufferers were treated with the gene that they lack, delivered via a nasal spray. These preliminary studies show that the genes do enter cells and produce the membrane protein needed by patients to prevent their lungs from clogging up with mucus. "We're optimistic that an effective therapy will eventually be developed," says Higgins.

Terry Partridge, who heads the Muscle Cell Biology Group at the CSC, is also getting promising results in gene-therapy experiments, but his patients are laboratory mice. These rodents have a form of muscular dystrophy. This disease, carried on the X chromosome, leads to disability and early death in boys who have the faulty gene, as their muscle fibers degenerate and regenerate before finally becoming choked with fibrous scar tissue. Partridge and his colleagues have found that certain types of cells taken from the muscles of normal adult mice and grown in culture, if injected into the muscles of dystrophic mice, will repair the degenerating muscles. Despite such successes, Partridge warns that this technique is a long way from successful application in human patients. "I am unconvinced that anything we have in the armory at present is going to be the final answer," he says. "Before we can go further, we feel it is important to devote some effort to discovering the cellular mechanisms behind the maintenance of skeletal muscle during normal life and in disease."

Other researchers at the CSC are looking at another major group of diseases that could be candidates for gene therapy: blood clotting disorders. Edward Tuddenham heads the Haemostasis Research Group investigating the complex interplay of factors that control the clotting of blood; their work on the cloning and expression of factor VIII in the early 1980s led to the commercial availability of recombinant factor VIII for the treatment of hemophiliacs. All of the genes making these clotting factors have been cloned for more than 10 years. But recently Tuddenham and his colleagues located a further gene that regulates production of both factor V and factor VIII on chromosome 18. The gene, which also has been identified by David Ginsburg's team at the University of Michigan, could provide a basis for new anticoagulants to replace warfarin and heparin for the treatment of thrombosis. "There's a link between factor VIII levels and thrombosis," says Tuddenham. "So there's a lot of interest in a gene that controls how much factor VIII is produced."

Fundamental to any attempt at gene therapy is an understanding of how genes are turned on or off in the cell. While each cell in the human body contains the same set of genes, only a subset of genes is active in any one cell. During development, cells take on specific identities - as skin, muscle, or blood cells, for example - and keep these identities through later stages of cell division. CSC researchers Amanda Fisher and Matthias Merkenschlager are trying to understand how patterns of gene expression are maintained in lymphocytes, the white blood cells that are an important component of the immune system. The two scientists have already identified a candidate protein in mice that seems to localize with silent areas of the chromosomes within the cell nucleus, suggesting that it might be responsible for "switching off" genes that are not needed in lymphocytes.

Any attempt to treat disease by grafting foreign cells, or even previously unfamiliar genes, runs up against the problem of rejection. This issue is examined by the CSC's transplantation biology group, a team that was originally set up by Nobel prizewinner Sir Peter Medawar. The group is now headed by Elizabeth Simpson, who has focused on the action of minor transplantation antigens in genetically different individuals. Such antigens are responsible for the slower rejection of transplants even when there is a match between a donor's and recipient's major transplantation antigens. She and her colleagues have identified a group of peptides encoded by genes on the Y chromosome, which, she says, "could be powerful tools for manipulating the immune response in tissue transplants."

Complementing the expertise in molecular and cell biology at the CSC are two units that provide state-of-the-art imaging facilities. The first, the magnetic resonance imaging and spectroscopy unit (headed by Graeme Bydder), applies its sensitive techniques to a variety of clinical and experimental problems. For example last year, working with pediatrician David Edwards and manufacturer Oxford Magnet Technology, the team installed a unique magnetic resonance imaging system in the neonatal intensive care unit at Hammersmith. The magnet is disk-shaped, rather than cylindrical, allowing pediatricians maximum access to the very tiny and sick babies undergoing examination. Edwards now routinely scans the brains of all pre-term babies cared for in the unit, some born after only 24 weeks of gestation. "It's taken us a year to do the basic groundwork," says Edwards. "Now we're getting started on hypothesis-based studies." He is using the scanner to look for areas of brain damage that might be linked to infection in the mother or the baby, or that might be connected with periods of oxygen deprivation before or during birth. Already the scanner is providing good prognostic information on babies thought to have suffered from oxygen deprivation.

The other half of the CSC's imaging team, the MRC's pioneering cyclotron unit, provides the national center for positron emission tomography (PET) scanning. While magnetic resonance imaging provides detailed anatomical information, PET is unique in its capacity to detect low concentrations of radioactively labeled tracers as they participate in molecular interactions in the body. As well as working with clinicians in neurology, psychiatry, cardiology, and oncology at Hammersmith and elsewhere, Terry Jones and his colleagues in the cyclotron unit find themselves in demand from private companies wanting quantitative data on the binding of new compounds or on the timing of their passage through the body. "Molecular imaging can bridge the gap between biological studies in the laboratory and work on diseased human tissue," says Jones.

With so much going on, Higgins has a right to be excited with the possibilities offered by his new post. "There are not many places that have world-class cell and molecular biology, and excellent imaging facilities, all at a clinical site," he says. "Gene therapy and other new approaches based on our understanding of cell and molecular biology were only started a few years back - and it's going to be a few years yet before they will help us treat or cure people. But it will happen, of that I've no doubt."

The Clinical Sciences Center - contains an introduction, descriptive brochure, and contact information.

The Medical Research Council - the major source of government funds for biomedical research in Britain. Details of policy, projects, and research institutes.

Introduction to Gene Therapy Home Page - starts with the basics of gene therapy (including some background information on molecular biology), then clearly discusses the techniques and applications in great detail. It also provides an extensive list of gene therapy links. Maintained by the Vanderbilt Clinical Research Center.

HAMSTeRS - the Haemophilia A Mutation, Structure, Test and Resource Site is maintained by the Haemostasis Research Group at the MRC Clinical Sciences Centre. This site also provides access to a factor VIII mutation database. A separate Factor VII site is under construction.

Cystic Fibrosis and Muscular Dystrophy - these OMIM entries provide an in-depth history of the research carried out on these diseases, including a list of the allelic variants of their respective associated genes.

MedWeb: Transplantation - a service of Emory University Health Sciences Center Library, this well-organized site provides links to online documents and resources related to transplantation.