Endocrinology in the new millenium
JOHN R G CHALLIS | Features
The general public have never been more interested in healthcare and biomedical research than they are today. There is every reason to anticipate increased public awareness of issues surrounding the effectiveness, availability and costs of healthcare. Because health and healthcare occupy such a central position in the public policy agendas of European and North American countries, it is crucial that, as healthcare investigators and providers, and as an informed lay public, we contribute to the debate.
As biomedical researchers, we should help inform discussion concerning utilization of resources and determination of priorities, and assist in defining the moral and ethical limits of advances in healthcare. Ann Padilla and Ian Gibson (Nature, 27 January 2000) remind us that ‘scientific knowledge is playing an increasing part in political decision making. Scientists themselves will have to recognise that blind public acceptance of their work cannot be taken for granted. As a consequence, they and their representative bodies will have to examine their roles per se and in unfamiliar territory, both political and public’.
Healthcare policy in the new millennium will be dictated by an ability to prevent disease processes, insteading of simply treating them. New genetic techniques, arising in association with the completion of the Human Genome Project, will offer extraordinary new opportunities for partnerships between pharmaceutical companies and academia, in the pursuit of discovery-driven, rather than hypothesis-driven, science. Recognition of epigenetic effects and the role of lifestyle in health performance seem likely to emerge as trends that will influence the spectrum from basic science research to public health policy.
'Research will be driven in part by a requirement to appease shareholders instead of necessarily generating fundamental and new information.'
Healthcare and endocrinology in the new millennium will surely be influenced heavily by demographic shifts. The baby boomers will reach post-retirement age. Their children, the boom echo, having delayed marriage and beginning a family, will emerge with their parents as key public sector groups. Both groups have, in general, been relatively affluent. They will be demanding, vocal and politically active advocates.
It seems inevitable that science itself will undergo a major transition in the way that it is conducted. In Canada, the establishment of the Canadian Institutes of Health Research will see advances being made through a series of virtual institutes. Within these, biomedical and clinical investigators will learn to interact and collaborate with health service/health system investigators, as well as with those interested in population health, and the influences of society, culture and the environment. The use of rapid throughput technologies will see discovery-driven research as a major approach alongside hypothesis-driven activity. Those of us in academia will need to come down from our ivory towers to seek partnerships with colleagues in industry, the private sector and pharmaceutical companies. Although public funding for research in Europe, as in North America, appears ready to increase at a reasonable rate, the high costs of equipment and infrastructure seem likely to require private sector interaction. The lone investigator with the single PCR machine will be stretched to compete independently from genetics-based drug discovery strategies in an industrial setting, with a room full of PCRs running 24 hours a day, 7 days a week. There is no question that this relationship will threaten the integrity of the academic enterprise, and universities will need to rapidly develop policies to ensure that their foundational integrity is not compromised.
In this new paradigm, one might question whether endocrinology will retain a presence as a discrete entity. Already endocrinology itself is largely passé, having given way to paracrine, autocrine and intracrine approaches and explanations. Endocrinologists masquerade as developmental biologists, neuroscientists, cardiovascular physiologists, nutritionists and reproductive biologists. Their studies are crucial to an understanding of the ageing process. We have become the crosscutting glue that joins together other physiologic disciplines. The role of organizations such as the Society for Endocrinology in bringing together workers with a common interest in hormones is crucial to prevent total fragmentation of this discipline into the myriad branches of medicine.
In the new millennium, genes will emerge (if they have not already done so) as big business. The old concept of one gene/one protein is clearly wrong, and the importance of posttranslational modification of protein structure has given birth to the explosion in proteomics. Thus, while genomics leads to characterisation and sequence of the genome, and to an understanding of the relationship between gene activity and cell function (functional genomics), proteomics is the mass screen approach to molecular biology. Proteomic technologies aim to document the overall distribution of proteins in cells, characterise individual proteins and elucidate their relationships, interactions and functional roles. New technologies such as microchip arrays, laser capture microdissection, and the application of bioinformatics to two-dimensional gel electrophoresis and interrogation of protein databases will dramatically alter the approach that many of us adopt in conducting our science. Proteomic techniques should lead to new information concerning basic cell function and molecular organisation, studies of pathophysiology, genetic and pharmacologic perturbations, and the study of drug modes of action and mechanisms of toxicity. These techniques should lead to the discovery of molecular markers for diagnosis and monitoring of diseases, and the identification of novel biologically active molecules and drug targets.
'By 2020, one might anticipate that most medical matters will be handled by video or email.'
This research, however, will be driven in part by a requirement to appease shareholders instead of necessarily generating fundamental and new information. Already, pharmaceutical companies are reluctant to develop drugs for diseases that do not have a market, or where the potential of litigation seems likely to threaten or undermine their profit margin. Only the very brave amongst pharmaceutical companies – and clearly there are exceptions – venture freely into the area of drug development for pregnant women, even though premature birth occurs in 10% of pregnancies, accounts for 75% of early neonatal mortality and morbidity, and costs the American healthcare system upwards of $5bn annually. The memory of thalidomide is sadly just too recent when one can more safely seek drug targets in ageing, cancer, AIDS and obesity.
Genomic techniques have led to the rapid development of enormous databases. Fortunately, our national political leaders have recognized that patent approval for fundamental sequences of the human genome is an impediment to scientific advance, and unethical unless there is clear application and utility of that information. Nevertheless, it seems axiomatic that in the future ‘our children will grow up in a world where finding a new gene or protein will be as infrequent as finding, today, a new species of animal’ (David Landsman). In a post-genome world, we may envisage complete genotyping of all individuals, a genome-based pharmacology, animal models for every gene, near real-time measurements of gene transcription, and the microdissection of individual cellular processes.
By 2020, one might anticipate that most medical matters will be handled by video or email. Cancer will be treated by anti-angiogenic drugs. Cardiologists will conduct keyhole surgery using robotics over long distances, and will use genetically engineered muscle cells to repair damaged hearts. Hand-held biosensors will monitor blood glucose and pH, and drive artificial pumps in the pancreas to generate insulin, if diabetes itself has not already been eliminated. Each citizen will carry a ‘smart card’, the size of a credit card, with his or her full genetic code. It will be possible to test the effectiveness of thousands of drugs for that individual in an instant. However, the privacy of that information will require careful preservation. One can imagine prospective employers, potential spouses and exuberant insurance companies demanding a complete medical prediction for each individual entering a new job or relationship.
Jeremy Rifkin, Head of the Foundation for Economic Trends in Washington, DC, has argued that in the new millennium ‘animal and human cloning will likely be commonplace with replication increasingly replacing reproduction’. Development of stem cell technology with cloning techniques should allow the generation of specific tissues and/or organs for transplantation purposes. Isolation of genes within individual blastomeres has already allowed prediction of single gene disorders, with genetic diagnosis and gene therapy approaches to treatment or replacement of a defective gene, for example in cystic fibrosis. One predicts that mice will continue to be used in cloning strategies designed to understand basic biologic mechanisms; large animal species will be utilised for practical benefits, and generation of specific proteins. Human cloning will continue to generate moral and philosophical debate, and as scientists we must engage that debate and inform the public and political discussion.
Finally, one senses increasing recognition of the role of the environment as a determinant of health and modifier of gene expression. The studies of David Barker and his colleagues at the University of Southampton have shown clearly that the environment during pregnancy may permanently alter expression of genes in development in a way that determines adult-onset diseases including hypertension and type 2 diabetes. There is an urgent necessity to understand the underlying mechanisms behind this relationship, in order that appropriate scientific information can inform public health policy. In addition, the neutraceutical industry occupies a substantial market – in the USA perhaps $86–$250bn annually. The probiotic market seems likely to have major implications for endocrinology and requires thorough investigation. We need to understand why a population ingests oral extracts of Ginkgo biloba to improve alertness and concentration or uses mega-doses of antioxidants to fight disease and restore memory loss. We understand that physical and mental exercise promotes health through enhanced cardiovascular function, prevention of osteoporosis and promotion of neurogenesis, particularly in key hippocampal regions. Appropriate utilization of this information towards a healthy society would be a wonderful advance. In Canada, for example, it was estimated that in 1981 only 20% of the population could be regarded as physically active enough to be considered healthy; this mean number had increased to about 35% by 1995. But, clearly we have a long way to go. Fred Astaire said it best, ‘Old age is like everything else, to make a success of it you have to start young’. As we enter the new millennium we have a cacophony of technologies that should allow us to prevent disease and promote good health. We have a wonderful opportunity to ensure that at birth every individual has maximal potential for life-long health. The challenge will be to use that information wisely and in accord with moral and ethical principles that have been debated and deemed acceptable by society at large. Welcome to the new millennium!
JOHN R G CHALLIS
Chair, Department of Physiology University of Toronto, Canada (correct at the time of first publication)