Genetics and genemoics: impact on drug discovery and development

complex diseases is limited by a still rudimentary understanding of the molecular basis of disease as well as of drug action. At the heart of this is our current inability to account for inter-individual differences in disease etiology and drug response. These inter-individual differences are determined, to a large extent, by inherited predispositions and susceptibilities. Knowledge of the genetic differences that explain these individual characteristics, and based upon it, the development of specific diagnostics and therapeutics, will therefore be critical for the successful transition to a future progress in health care.

The impact of genetics and genomics will leave its mark along all steps involved in the creation of a new medicine:

• in the discovery of new targets that carry-inherently, because genetic linkage implies causation-a greater likelihood of success;

• in the discovery phase of a new drug aimed at an existing target, where the knowledge of molecular variation of this target (SNPs) may provide clues to achieve higher selectivity; where genetic epidemiology studies will provide added value by validating the target; and where large scale gene expression profiling (gene chips) will help select compounds with a higher likelihood for ultimate success at an early stage;

• and in the development phase of an drug undergoing clinical evaluation, where pharmacogenetic studies, and genotype-specific patient selection may allow recognition and definition of drug-responders and non-responders, or help decrease the likelihood of adverse events.

Although the impact of genetic and genomic investigation will certainly accelerate progress in biomedical research, we believe it will do so in an evolutionary fashion, and as a logical extension of the history of medical progress towards a more detailed understanding of disease and the resultant more refined differential diagnosis as well as more accurate prospective risk assessment. If any, the fundamental change we are going to witness in the years to come is a (paradigmatic) shift from today's largely clinical disease definition and diagnosis to a molecular definition and diagnosis of disease. This shift is likely to greatly increase the importance of in-vitro diagnostics and will mandate, much more than is the case today, an integrated approach of diagnostics and therapeutics. Ultimately, we expert to derive the benefit of more successful, and more cost-effective medicines, and of possibly being able to prevent (or delay), rather than treat disease.

It is important to realize that genetic research and testing are areas of great public concern, and that a more comprehensive dialogue between scientists and the public is urgently needed to address the societal, ethical, legal issues that are being raised. Only then will we be able to truly take advantage of the significant advances in medical knowledge that genetic research will make possible, and fully realize the potential of these approaches towards the ultimate goal of all our striving, improving the human condition.

The utility of most drugs prescribed today for common, complex diseases is limited by a still rudimentary understanding of the molecular basis of disease as well as of drug action. At the heart of his is our current inability to account for inter-individual differences in disease etiology and drug response. These inter-individual differences are determined, to a large extent, by inherited predispositions and susceptibilities. Knowledge of the genetic differences that explain these individual characteristics, and based upon it, the development of specific diagnostics and therapeutics, will therefore be critical for the successful transition to a future progress in health care.

The impact of genetics and genomics will leave its mark along all steps involved in the creation of a new medicine:

• in the discovery of new targets that carry-inherently, because genetic linkage implies causation-a greater likelihood of success;

• in the discovery of a new drug aimed at an existing target, where the knowledge of molecular variation of this target (SNPs) may provide clues to achieve higher selectivity; where genetic apidemiology studies will provide added value by validating the target; and where large scale gene expression profiling (gene chips) will help select compounds with a higher likelihood for ultimate success at an early stage;

• and in the development phase of an drug undergoing clinical evaluation, where pharmacogenetic studies, and genotype-specific patient selection may allow recognition and definition of drug-responders and non-responders, or help decrease the likelihood of adverse events.

Although the impact of genetic and genomic investigation will certainly accelerate progress in biomedical research, we believe it will do so in an evolutionary fashion, and as a logical extension of the history of medical progress towards a more detailed understanding of disease and the resultant more refined differential diagnosis as well as more accurate prospective risk assessment. If any, the fundamental change we are going to witness in the years to come is a (paradigmatic) shift from today's largely clinical disease definition and diagnosis to a molecular definition and diagnosis of disease. This shift is likely to greatly increase the importance of in-vitro diagnostics and will mandate, much more than is the case today, an integrated approach of diagnostics and therapeutics. Ultimately, we expect to derive the benefit of more successful, and more cost-effective medicines, and of possibly being able to prevent (or delay), rather than treat disease.

It is important to realize that genetic research and testing are areas of great public concern, and that a more comprehensive dialogue between scientists and the public is urgently needed to address the societal, ethical, legal issues that are being raised. Only then will we be able to truly take advantage of the significant advances in medical knowledge that genetic research will make possible, and fully realize the potential of these approaches towards the ultimate goal of all our striving, improving the human condition.