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“It is much more important to know what kind of patient has a disease than to know what kind of disease a patient has.” Caleb Parry, 18th century physician, Bath.

The structure of DNA established the basic framework that would develop into the field of molecular genetics. The information gleaned from this scientific endeavour continues to have a profound influence on our understanding of biological systems1. As most human diseases have a significant heritable component, it was soon recognized that the characterization of the genetic determinants of disease would provide remarkable opportunities for clinical medicine, potentially altering the way disease was understood, diagnosed and treated.

But despite the obvious potential applications to medicine, the development of significant genetic advances relevant to clinical practice could take generations. This is in marked contrast to many other medically related discoveries that occurred around the same time and which were translated rapidly into clinical practice. For instance, the development of penicillin by Ernst Chain and Howard Florey in 1941 was saving thousands of lives within months of their discovery of how to efficiently produce the antibiotic2. Discoveries relating to disease aetiology, such as the recognition in 1950 of a relationship between smoking and lung cancer, have had a profound effect on mortality3. This was despite the convictions of at least one distinguished statistical geneticist who argued against the causality of this observation, implying that a common genetic factor caused both lung cancer and a predilection to smoking cigarettes4!

Although other important discoveries have had demonstrably more impact on health care at the time of their fiftieth anniversaries than has the double helix, its slower transition from discovery to clinical implementation will be balanced by its potentially profound impact across all medical disciplines. Progress has been slow, but mounting evidence suggests that, while public health and antibiotics produced important healthcare outcomes in the past 50 years, the next 50 are likely to belong to genetics and molecular medicine.

The potential impact of genetics on clinical practice has been questioned by some observers5 who believe that the positive predictive value of genetic testing for most common disease genes will be insufficient to provide the beneficial effects seen with single-gene disorders, which affect only a tiny proportion of the population. Many advocates of genetics argue, on the other hand, that our understanding of disease is undergoing a major change. They contend that genetic research is playing a fundamental role in improving our understanding of the pathophysiology that underlies disease and that, inevitably, as this is applied, it will alter both the theory and practice of medicine in the future6.

A new taxonomy for human disease

Clinical practice has always been limited by its inability to differentiate clinical, biochemical and pathological abnormalities that accompany a disease from those events actually responsible for mediating a disease process. Clinicians may have moved on from calling 'fever' a disease7, but they still rely on phenotypic criteria to define most diseases, and yet these may obscure the underlying mechanisms and often mask significant heterogeneity. As Thomas Lewis pointed out in 1944, diagnosis of most human disease provides only “insecure and temporary conceptions”8. Of the main common diseases, only the infectious diseases have a truly mechanism-based nomenclature.

An understanding of the genetic basis of maladies is providing a new taxonomy of disease, free from the risk that the diagnostic criteria related to events are secondary to the disease process, rather than to its cause. Genetic information has allowed us to identify mechanistically distinct forms of diabetes, defining an autoimmune form of the disease associated with human leukocyte antigens (a highly diverse complex of immune-system genes), and recently has implicated dysfunction of factors that affect both expression and modification of gene products in mediating the adult form of the disorder9. Similarly, we are now aware of a range of molecules and pathways previously not recognized in the pathogenesis of asthma10,11,12.

A clearer understanding of the mechanisms and pathways that mediate disease will lead to the definition of distinct disease subtypes, and may resolve many questions relating to variable disease symptoms, progression and response to therapy seen within current diagnostic categories. Ultimately, this may provide the greatest contribution genetics will make to clinical practice: a new taxonomy for human disease.

A medical revolution

Knowing that a disease can arise from a distinct mechanism will alter a physician's approach to a patient with that disorder, allowing a more accurate prognosis and choice of the most appropriate therapy. The gene 'mutations' responsible for many single-gene disorders are now commonly used in diagnostic practice, whereas those associated with common complex diseases are just being characterized. Although their predictive value will be less than with single-gene disorders, their contribution as risk factors will be similar to other risk factors such as blood pressure, cholesterol levels and environmental exposures. Because much of clinical practice involves evaluating and acting on risk probabilities, the addition of genetic risk factors to this process will be an important extension of existing practice. The overall effect of genetic risk factors is likely to be significant. For example, recent estimates in breast cancer suggest that the attributable genetic risks are likely to exceed the predictive value of a range of existing non-genetic risk factors13.

Other potential applications of genetics in health care may be realized in a shorter timeframe. Individual variation in response to drugs and in drug toxicity is a significant problem, both in clinical practice and in the development of new therapeutic agents. Clear examples now exist of genetic variants that alter metabolism, drug response or risk of toxicity14,15. Such information provides an opportunity to direct therapy at individuals most likely to benefit from an intervention, thereby reducing cost and toxicity, and improving methods for drug development.

The discovery of the structure of DNA not only led to an ability to characterize genetic determinants in disease, but also provided the tools necessary for the revolution in molecular medicine that has occurred in the past 25 years. The description of the double helix was the first important step in the development of techniques to cut, ligate and amplify DNA. The application of these molecular biology and DNA-cloning techniques has already had a profound impact on our understanding of the basic cellular and molecular processes that underlie disease.

Molecular biology has improved our ability to study proteins and pathways involved in disease and has provided the technology necessary to generate new sets of targets for small-molecule drug design. It has also enabled the creation and production of a new range of biological therapeutics — recombinant proteins such as interferon, erythropoietin and insulin, as well as therapeutic antibodies, which are one of the fastest growing classes of new treatments. Further extensions of this methodology will see the inevitable introduction of DNA-based therapies that will produce proteins of interest in the appropriate cellular setting. DNA-based vaccines represent the first wave of such novel gene-therapy approaches to disease and many more are expected to follow.

We are undergoing a revolution in clinical practice that depends upon a better understanding of disease mechanisms and pathways at a molecular level. Much has already been achieved: an enhanced understanding of disease-related pathways, new therapies, novel approaches to diagnostics and new tools for identifying those at risk. But more remains to be done before the full impact of genetics on medicine is realized. Complex disease, with multiple susceptibility determinants (both environmental and genetic), will take time to dissect. This information must then be moved into the clinic and evaluated for its benefits.

As the practice of medicine moves to one more scientifically founded in disease mechanisms, many aspects of clinical practice will need to be transformed. Individual genetic variation is likely to explain a significant part of the heterogeneity seen clinically in the natural history of disease and in response to therapy. Tools to tailor medicine to an individual's needs rather than directing it at a population will inevitably become available. Similarly, as predictions of risk improve, early or preventative therapy of high-risk populations will become a reality, with screening programmes targeted to those at particularly high risk.

Transforming clinical practice

For fundamental changes to take place in clinical practice, sweeping transformation will be needed to healthcare provision, economic management and training. It is currently difficult to predict the cost–benefit ratio for such changes — certainly the present impact of molecular medicine has not made medicine less expensive. Few medical schools adequately train their students to think mechanistically about disease; indeed, the trend towards pattern-recognition medicine, away from basic science training, means that we are still far from educating the next generation of clinicians to apply the knowledge and tools bequeathed to us by the double helix. The evolution in health care that will incorporate these new principles of early diagnosis and individualized therapy will be a daunting challenge in an era of uncertainty for healthcare systems worldwide.

The influence of genetic and molecular medicine on the health of patients is already sufficiently ubiquitous that it will have an impact on most common diseases. Its influence will grow over the next few decades (Table 1). It will not, however, answer all of the questions about human health, nor will it provide all the answers for optimizing clinical practice. The reductionism that accompanies molecular genetics will identify the pieces in the jigsaw, but assembling these to understand how complex systems malfunction will require a substantially more integrated approach than is available at present.

Table 1 Molecular genetics in clinical practice
Full size table

The crucial role played by environmental determinants of disease will perhaps become more tractable when combined with an understanding of genetic susceptibility. Sceptics, rightly, will wish to see more data before they acknowledge that molecular medicine will be truly transformed over the next 50 years, despite the fact that its influence on diagnostics and new therapeutics is already clearly apparent. A transition is underway, the direction of travel is clear, but managing the change in clinical practice may prove at least as challenging as resolving the original structure of the helix.