Challenges and Opportunities for the Future
The frontiers of medical genetics and molecular medicine are only limited by the lack of understanding of many fundamental disease processes and the ability to manipulate biological processes by recombinant DNA technologies. The benefits will be applicable directly to domestic animal diseases and the focused investigation of carefully chosen animal diseases will provide key information. The major directions for future research will be in the following areas:
Finding and Characterizing Disease Genes in Animals
The development of methods to map mammalian genomes has revolutionized the approach to identification, isolation and characterization of the mutations that underlie genetic diseases. Recent advances in genome sciences methods have made it more practical to use this approach in the dog and cat. The detection and study of a large variety of disorders with recessive and complex patterns of inheritance is greatly facilitated in the dog and cat because there is enough periodic inbreeding to reveal these defects, but the alleles that confer susceptibility still exist in sufficient frequencies in these populations to be available for study. Breeds of dogs and cats have the same advantages for such studies as human genetic isolates, but the number and diversity of the isolates (breeds) are many times greater than is found in the world’s human population. This is a resource in comparative medical genetics that is waiting to be mined for the purpose of better understanding of human disease, as well as for the improvement of animal health. This effort in the CCMG is focused on avenues of research where the animal models offer unique ways to investigate the genetics and biology. The diseases to be studied are selected for the medical characteristics, the underlying pathology, where the inheritance is sufficiently well documented that a focused investigation can be performed, and where scientific progress can be accelerated by studying the animal disease. Link to PGI (Genomics Institute)
Mechanisms of Disease-
Understanding the Cellular and Molecular Basis of Pathology
Although new disease-causing genes are being identified at a rapid rate, there are great gaps in knowledge of how the mutant genes cause the observed clinical and histopathological abnormalities. Animals with specific genetic diseases constitute a major resource for studying the natural history of rare disorders. Because cohorts of sufficient sizes can be studied, various stages of disease progression can be evaluated. Many studies on animal models have been instrumental in improving understanding of the human disease, where it is often impossible to obtain affected tissues during the course of the disease. In addition, a thorough understanding of the molecular and cellular abnormalities of each disease is critical for the rational design of new therapies.
Using Gene Based Approaches to Treatment
Advances in molecular biology are being developed into entirely new methods of treating disease. The concept of gene therapy for single gene inherited disorders is compellingly simple: treat a disease at the fundamental level of the DNA defect by inserting a normal copy of the gene into the affected cells of a patient to correct the biochemical deficiency responsible for the symptoms. However, after more than15 years of investigation by many laboratories, this goal remains elusive. It has been particularly difficult to scale up the methods from rodents to large mammals, including humans. The animal models being studied by CCMG investigators provide experimental platforms for understanding the problems of delivering genes successfully to a large mammal under actual disease conditions. In veterinary clinical medicine the best treatment for these very rare disorders will be to remove the mutant allele from the breeding stock. However, there are a number of diseases of veterinary importance where gene transfer methods may be applicable, e.g. cancers, degenerative joint disease in horses, neurologic abnormalities, and common metabolic diseases such as diabetes. Effective application in a clinical setting will depend on having a thorough understanding of the underlying biochemical, cellular, and pathologic mechanisms of each disease.
Direct viewing of Life Processes, Pathology and Treatment
Biological imaging using noninvasive methods is changing the landscape not only of clinical medicine but of research into biological processes in their natural settings. CCMG investigators use techniques such as NMR to study the progression of disease and responses to treatments and to gain new insight into pathologic mechanisms. Future research in this area will be done in close collaboration with the Metabolic Magnetic Resonance Research and Computing Center and the Department of Radiology in the School of Medicine to take advantage of the infrastructure, expertise, and instrumentation that is available to the biomedical community at Penn.