treatment.It is now possible in the case of some inherited diseases to define exactly which DNA base pairs are anomalous and in which chromosome they appear.In a small number of animal models of such diseases,it has been possible to correct the abnormality by gene therapy,ie, insertion of an appropriate "healthy"gene into somatic cells.Human somatic cell gene therapy has been attempted,but the technical difficulties are great. Studies of a newly discovered receptor or endogenous ligand are often confounded by incomplete knowledge of the exact role of that receptor or ligand.One of the most powerful of the new genetic techniques is the ability to breed animals(usually mice)in which the gene for the receptor or its endogenous ligand has been"knocked out,"ie,mutated so that the gene product is absent or nonfunctional.Homozygous knockout mice usually have complete suppression of that function, whereas heterozygous animals usually have partial suppression.Observation of the behavior, biochemistry,and physiology of the knockout mice often defines the role of the missing gene product very clearly.When the products of a particular gene are so essential that even heterozygotes do not survive to birth,it is sometimes possible to breed "knockdown"versions with only limited suppression of function.Conversely,"knockin"mice have been bred,which overexpress certain proteins of interest. Some patients respond to certain drugs with greater than usual sensitivity to standard doses.It is now clear that such increased sensitivity is often due to a very small genetic modification that results in decreased activity of a particular enzyme responsible for eliminating that drug.(Such variations are discussed in Chapter 4.)Pharmacogenomics(or pharmacogenetics)is the study of the genetic variations that cause differences in drug response among individuals or populations. Future clinicians may screen every patient for a variety of such differences before prescribing a drug. PHARMACOLOGY THE PHARMACEUTICAL INDUSTRY Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to "big pharma,"the multibillion-dollar corporations that specialize in drug discovery and development.These entities deserve great credit for making possible many of the therapeutic advances that we enjoy today.As described in Chapter 5,these companies are uniquely skilled in exploiting discoveries from academic and governmental laboratories and translating these basic findings into commercially successful therapeutic breakthroughs. Such breakthroughs come at a price,however,and the escalating cost of drugs has become a significant contributor to the inflationary increase in the cost of health care.Development of new drugs is enormously expensive and to survive and prosper,big pharma must pay the costs of drug development and marketing and return a profit to its shareholders.At present,considerable controversy surrounds drug pricing.Critics claim that the costs of development and marketing aretreatment. It is now possible in the case of some inherited diseases to define exactly which DNA base pairs are anomalous and in which chromosome they appear. In a small number of animal models of such diseases, it has been possible to correct the abnormality by gene therapy, ie, insertion of an appropriate "healthy" gene into somatic cells. Human somatic cell gene therapy has been attempted, but the technical difficulties are great. Studies of a newly discovered receptor or endogenous ligand are often confounded by incomplete knowledge of the exact role of that receptor or ligand. One of the most powerful of the new genetic techniques is the ability to breed animals (usually mice) in which the gene for the receptor or its endogenous ligand has been "knocked out," ie, mutated so that the gene product is absent or nonfunctional. Homozygous knockout mice usually have complete suppression of that function, whereas heterozygous animals usually have partial suppression. Observation of the behavior, biochemistry, and physiology of the knockout mice often defines the role of the missing gene product very clearly. When the products of a particular gene are so essential that even heterozygotes do not survive to birth, it is sometimes possible to breed "knockdown" versions with only limited suppression of function. Conversely, "knockin" mice have been bred, which overexpress certain proteins of interest. Some patients respond to certain drugs with greater than usual sensitivity to standard doses. It is now clear that such increased sensitivity is often due to a very small genetic modification that results in decreased activity of a particular enzyme responsible for eliminating that drug. (Such variations are discussed in Chapter 4.) Pharmacogenomics (or pharmacogenetics) is the study of the genetic variations that cause differences in drug response among individuals or populations. Future clinicians may screen every patient for a variety of such differences before prescribing a drug. PHARMACOLOGY  THE PHARMACEUTICAL INDUSTRY Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to "big pharma," the multibillion-dollar corporations that specialize in drug discovery and development. These entities deserve great credit for making possible many of the therapeutic advances that we enjoy today. As described in Chapter 5, these companies are uniquely skilled in exploiting discoveries from academic and governmental laboratories and translating these basic findings into commercially successful therapeutic breakthroughs. Such breakthroughs come at a price, however, and the escalating cost of drugs has become a significant contributor to the inflationary increase in the cost of health care. Development of new drugs is enormously expensive and to survive and prosper, big pharma must pay the costs of drug development and marketing and return a profit to its shareholders. At present, considerable controversy surrounds drug pricing. Critics claim that the costs of development and marketing are