Professor Trevor Jones (director-general of the Association of the British Pharmaceutical Industry) delivered the annual Chiltern Region lecture to members of the Royal Pharmaceutical Society on November 25. His title was "The gene revolution". The event was held at the Stockley Park premises of Glaxo Wellcome UK
Professor Jones said that genomics was the fourth major revolution in drug discovery, following chemotherapeutics, pharmacology and molecular biology. The genomic track had begun in 1871 with the isolation of DNA, but it had been almost 80 years before Watson and Crick proposed its double helix structure in 1953. The first recombinant molecule had followed in 1972. The present decade had brought, in 1993, a physical map of the human gene and a protocol for gene therapy - and three years later the arrival of Dolly the cloned sheep. Mapping had led to the description of over 55,000 distinct human genes. The task of sequencing the full human genome would be complete in the next few years.
|
Professor Jones (left) with Mrs Pat Hoare (chairman, Chiltern region, and a member of the Society's Council), Dr Gavin Brooks (who gave the 1998 Chiltern lecture) and Professor Bill Dawson (a member of the Society's Council and chairman of its Science Committee) |
Improved knowledge of genetics and genomics was leading to a clearer understanding of the basis of living processes and what could go wrong, and of the impact of inherited and environmental factors on health and illness. It would also provide: targets for intervention; new screens for diagnosis and prognosis; new therapies; and better assessment of trends in population health.
Professor Jones showed how the traditional concept of the drug discovery process was being superseded, contrasting the 400 targets upon which the entire collection of today's therapies acted with the tens of thousands of potential new targets revealed by the human genome project and by pathogenomics (the genome of pathogenic micro-organisms).
High throughput screening and combinatorial chemistry would soon be able to handle 200,000 samples a day - an essential development for identifying potential targets. From that followed the task of preparing quantities of the desired target for the purpose of drug design. Ten pharmaceutical companies, together with the Wellcome Trust and a number of academic centres, were collaborating under the umbrella name of "The SNP Consortium" to identify a minimum of 300,000 single nucleotide polymorphs, and map half of these, in two years. The aim was to complete the sequencing of the human genome by the end of 2001.
In drug development, genomics offered fast screening for drug metabolism and genotoxicity. In clinical trials, it enabled a selection of genotypic subjects to be made from the patient population. But when would gene therapy be a reality? The first trial had been conducted in 1993. By 1998, 150 protocols had been approved, mainly in the United States. Seventy per cent were in oncology.
Recent attention had focused on the role pathogenomics might have in ameliorating antibacterial resistance. No antibacterial agent acting on a new molecular target had been introduced in the past 20 years. However, the complete molecular structure of 14 micro-organisms had now been made public and the sequencing of 40 others was in progress. Professor Jones went on to describe the process of signature-tagged mutagenesis for identifying the composition of mutant bacterial genes. Genomic-driven antibacterial discovery, if accorded a success rate of, say, 5 per cent, should yield at least 10 entirely new classes, he estimated.
Applying the principles of pathogenomics, new antiviral drugs should also be possible, and new vaccines for prophylaxis. The mechanism had been devised for an oral typhoid vaccine. The genome project had determined many new protease targets, although well over 2,000 human proteases still remained to be identified. Twelve antiretroviral agents were now on the UK market - eight reverse transcriptase inhibitors and four protease inhibitors. Two- or three-way combinations could significantly enhance changes in HIV RNA levels, and accelerate treatment times.
The impact of antiretroviral therapy on patient care had been well illustrated in a 1997 report from the City hospital, Edinburgh, where admissions were down 45 per cent, the death rate was down 40 per cent and bed days attributable to AIDS patients were down 45 per cent. In the same year, the British Medical Journal had published a 10-year study involving 5,000 HIV subjects. Triple combination therapy administered in the latter period of the study had helped to reduce deaths by 62 per cent and the risk of progression to AIDS by 73 per cent. HIV drug-resistance could now be monitored very rapidly and the future would hold new ways of prolonging virus suppression.
Turning to population genomics and its prospects for better disease management, Professor Jones said that gene data banks linked into health information systems could provide a disease alert service for at-risk groups and assist in the selection of appropriate therapy. Such banks would also help to enable disease risk profiling and genetic counselling. As an example, variation in cytochrome or N-acetyltransferase polymorphism could impair drug metabolism, placing patients at increased risk from certain therapies. In other cases, the most appropriate and effective therapy might be chosen depending upon a particular genotype or depend entirely on the presence of a gene defect.
Though the future was exciting, it would also throw up dilemmas, new challenges and responsibilities. Cataloguing a person's genetic predisposition had complex clinical, moral, ethical and social implications. "We all have defective genes - so when do we become patients? When the gene is identified, or when we believe the prognosis, or when we experience symptoms or when we are treated?" Patient access to more information was leading to more understanding and more benefit, but also to more confusion and more conflicting information: "The genie is out of the bottle." This, said Professor Jones, presented an opportunity to the pharmacist and the industry to cultivate relationships with patient types. He concluded thus: "The future does not exist - it is for us to invent!"
During discussion, Professor Jones gave an assurance that pharmacology would need to remain a central discipline. Clinical trials could become problematic: just how many variants were feasible for subpopulations? Regulatory agencies had to rise to the challenge of getting up to speed. Preservation of intellectual property rights was critical, in the face of huge pressure from "biophobics". — Contributed.