Medicine. As we approach the next millennium, it is good to review the challenges it will bring for research, even though all good scientists know perfectly well that no discontinuities are to be precipitated by such an artefact of the calendar! We are at the end of a century of unparalleled change, in the sciences as much as in technology, the economy, politics, culture, religion and a great deal else.
In medical and biological sciences, we have seen the great illuminations from theoretical physics open up our understanding of chemical structure and reactivity, thence creating a tidal wave of knowledge and techniques converging with the thrust of classical genetics to construct an entirely new picture of the living world. This has been applied to complex physiological systems and processes, including the nervous system and embryonic development to reveal inner mechanisms in unprecedented detail. Not least have been the consequences for medical services and health care, such that it would seem to a visitor from earlier times that - in comparison with his own times - suffering from illness and disease has been largely eliminated, at least in the developed world. New industries have been created from health research to generate wealth and employment, some, such as in agriculture and biotechnology, in areas beyond as well as within health.
Great challenges nevertheless remain and must be met for purely practical as well as other reasons. The public is all too aware that the rise of science and technology has created problems as well as solving them. Environmental hazards; population growth; miseries, for both sufferers and carers, of physical or mental deterioration; new infectious diseases devastating a more mobile population on a more crowded planet - these are just a few examples. We need to approach these problems in a spirit of enlightened utilitarianism, but without weakening the driving force of intellectual adventure and achievement. The parallel pursuits of utility and insight must join forces rather than compete, not least to encourage public belief in and commitment to the scientific enterprise as the only feasible way ahead. It is a challenge to young scientists to achieve a better and healthier synthesis of curiosity and application, at least in the United Kingdom, than we earlier generations have managed to establish.
The biomedical research community is busy with a great deal of unfinished and important business, and young scientists who begin research careers soon will join one or other of the crusades already begun. But what of the prospects beyond? Let us assume that, early into the millennium, the human genome will have been sequenced, along with the genomes of many other organisms. The ways in which genes are expressed will be known in increasing detail. We will have solved the protein folding problem. We will have established the three-dimensional structures of all the major proteins, and know how they do their work in the body. We will understand the structure of receptors and regulatory proteins, and be able to predict from structure how they bind with small molecules and interact with a range of larger molecules from proteins to nucleic acids.
So we will know and understand the molecular rules that govern biochemical interactions in life processes and hence in human sickness and health. Does that mean, then, that the end of the scientific task is in sight? Far from it. What we will shortly see is the drawing to a close of a long and fruitful stage of reductionist science. We will know what are the component pieces of the mechanisms of life, and what they do. A new emphasis will beckon, which will in my opinion call for even more creativity and imagination, to advance the mission to synthesise. The cogs and the sprockets, pistons and camshafts, levers and flywheels, will all be classified and characterised. We will be privileged to embark on the enthralling task of reconstructing the fantastic machine. I would like to illustrate with four examples.
A general theory of the cell
We know a great deal about the structure and organisation of cells, including the functions of and processes within the many different organelles. What we still lack is an understanding of how the whole thing adds up - as it surely must - to more than the sum of its parts. The cell marks the boundary between life and non-life. It grows, it divides, it receives and sends signals, it moves. What is more, it does these all at the same time, mediated through multiple series of molecular events. Each event has its own sub-steps, each sub-step its own kinetic and thermodynamic parameters. We lack a theoretical framework for understanding the cell as an autonomous and integrated system. It is, after all, the smallest unit of that very special thing that we call life. It functions as a whole yet we do not understand it as a whole. To do so must surely be within the realms of scientific possibility, but will require great feats of imagination.
A second key area for future research must be to take our powers of prediction of susceptibility to disease from the level of population statistics to each human individual. The new genetics and immunology will need to integrate with knowledge of the influence of variables in the social and biological environment to construct a basis for risk assessment for individuals.
You can see the problem all around. Take any class of children in which one child has, say, mumps. Not all the children will develop the disease, and not all who do develop it will do so to the same degree. During this century we have developed increasingly sophisticated ways of calculating average risks of contracting a range of illnesses and conditions.
These calculations are the basis of a great deal of public health and environmental legislation, and there is no doubt that they have played a part in protecting everyone. Yet what individuals really want to know is what their own, individual risk is. Never mind the overall risk - given my environment and my genetics, for example, what is my individual chance of contracting cancer from a fortnight's holiday in Cornwall? Given my lifestyle and my individual biochemistry, will I develop diabetes or not?
Global health and population
The 20th-century expansion of global population might in one sense be said to represent a triumphant success for the human species. A world that could not feed all its citizens 40 years ago is now feeding more than twice as many as the entire population in 1955. It is only too clear that continued growth cannot continue if each child is to have an adequate nutrition, let alone the other opportunities that we associate with civilised societies. Among the many advances needed from medical science are simple, cheap forms of birth control to provide the possibility of choice and control on the part of women over the planning of their families and so that each new child has a better chance of being born into an environment in which she or he can be nurtured and provided for. There are leads to follow but their pursuit is less than wholly vigorous, partly for political and religious reasons, and partly because of a lack of commercial attractiveness. Compounds are known which "antagonise", or cancel out, the effects of progesterone, a hormone essential for the establishment and maintenance of pregnancy - the so-called antigestagens used in "abortion pills" which might also form the basis of a "once a month" pill. Nature's way of extending the age gap between offspring is the natural and reversible infertility which breast feeding imparts. An understanding of the neuroendocrinological mechanisms through which suckling inhibits menstruation could give rise to novel methods of contraception. Sperm production is stimulated by gonadotrophic hormones, whose production in turn is inhibited by testosterone. This self-regulating system could be a target for contraception by administering an antagonist to suppress the secretion of gonadotrophins. Recent developments in molecular biology and immunology along with the characterisation of specific binding sites both on the surface of the egg and on the sperm offer the potential for developing specific antibodies targeted against these sites which would prevent fertilisation, hence providing a contraceptive vaccine.
Just how and to what extent new technologies are employed is for national societies to determine, no doubt influenced by the ethical and religious convictions which prevail. For science, the goal is twofold. First, it is to increase our understanding of reproductive biology, at molecular, cellular and physiological levels, so that we can deliver increasingly safe, effective and beneficial influence over conception, foetal development and birth. Second, recognising that the paramount objective is to enable human dignity and fulfilment rather than merely to provide new interventions in personal biology, the medical and social sciences must join forces with each other and the humanities to support and facilitate personal and social aspirations rather than merely to provide tools for social engineering.
Repairing the irreparable
Brain damage can occur unpredictably, at any stage of life, and for many reasons. The effects are frequently devastating for the individual and place heavy demands on families and health care services. For most of this century scientists have looked on the brain and the central nervous system as having a limited capacity for recovery. Now we are starting to consider them as adaptable structures, and increasingly to understand the factors which cause and determine the consequences of damage. The challenge here will be to find ways of repairing the brain and the central nervous system.
The first step could well be developing strategies for damage limitation, on the basis of a detailed understanding of information processing mechanisms in the central nervous system. The next - possibly concurrent - aim is to understand the existing processes of regeneration and plasticity in the central nervous system as a basis for promoting regrowth and the barriers to them. Where damage could not be limited or overcome through natural (or encouraged) regrowth, techniques of cellular implantation could repair the brain and the central nervous system. This opens up an exciting vista of research scarcely even imagined until recently. And there is no reason why repair should be restricted to damage incurred through accidents or stroke. As people in the developed world live longer, diseases such as Alzheimer's are requiring increasingly urgent attention.
Mind and body
Another area of high future priority must be the linkage between psychological and physical well-being. For example, it is a cliche to say that stress can be bad for health - but how, why and when does it make you ill? Clues are emerging from the Medical Research Council-funded work of Michael Marmot which have shown a startling health gradient in the general UK population. In civil servants, for example, none of whom live in absolute poverty nor (I hasten to say) fabulous riches, life expectancy increases for each increase in grade. The lower the grade, the higher the risk of diabetes and heart disease, for instance. The difference in life expectancy between the lowest and highest grades is about five years. All the evidence points to an explanation in the job itself, rather than in any other influence from diet, lifestyle or environment. If it is the stress of the job, those with lowly rather than top jobs are at most risk. It turns out that statistical correlations in human populations, backed up by the study of animal communities in the wild as well as stress hormone levels in the laboratory, show clearly that health differences arise because subservience depresses and stresses, whereas autonomy releases and rewards, despite job pressure.
How can such psychological and social factors influence health? Our moods, feelings, perceptions, and even reasoning must translate into the body's biochemistry in fundamental ways - just as the body's biochemistry through food, drink, sleep and exercise can influence moods and feelings in reverse. This poses the challenge of unifying psychology and physiology, not merely to learn how to live healthy lives but to better understand human beings and human nature. What is it in our genes and biochemistry and their interactions with environment, which sets human beings apart from the rest of creation, that represents - whatever the fairy tales might say - the fundamental differences between the Prince and the frog? Embedded here are the secret origins of childhood fantasy, teenage delinquency, artistic creativity, human love and man's inhumanity to man, all of which will in due course be revealed.
Sir Dai Rees is chief executive of the Medical Research Council.