Toxicogenomics, Drug Discovery, and the Pathologist

Abstract

The field of toxicogenomics, which currently focuses on the application of large-scale differential gene expression (DGE) data to toxicology, is starting to influence drug discovery and development in the pharmaceutical industry. Toxicological pathologists, who play key roles in the development of therapeutic agents, have much to contribute to DGE studies, especially in the experimental design and interpretation phases. The intelligent application of DGE to drug discovery can reveal the potential for both desired (therapeutic) and undesired (toxic) responses. The pathologist's understanding of anatomic, physiologic, biochemical, immune, and other underlying factors that drive mechanisms of tissue responses to noxious agents turns a bewildering array of gene expression data into focused research programs. The latter process is critical for the successful application of DGE to toxicology. Pattern recognition is a useful first step, but mechanistically based DGE interpretation is where the long-term future of these new technologies lies. Pathologists trained to carry out such interpretations will become important members of the research teams needed to successfully apply these technologies to drug discovery and safety assessment. As a pathologist using DGE, you will need to learn to read DGE data in the same way you learned to read glass slides, patiently and with a desire to learn and, later, to teach. In return, you will gain a greater depth of understanding of cell and tissue function, both in health and disease.

Toxicogenomics in Drug Development

“…The difficulties in assessing the relevance of this data must, therefore, not be underestimated. Consequently, expression data for a given toxic response needs to be put into perspective with other (biochemical, physiological, clinical, histopathology) data and integrated expert evaluation is essential (9). Adequate study designs together with good sample quality can significantly aid in the interpretation of differential gene expression results, such as in deciphering which genes are adaptive, beneficial or toxicologically relevant.…”

Report of the IFSTP Professional Standards Subcommittee (PSSC)

“…Another feature of the increasing workload of pathologists is the tendency in industry to commit pathologists to drug discovery teams, where the combination of both new technologies and the skills of pathologists prove to be effective and profitable in early detection of toxicity and efficacy 3,4 . For these reasons we encourage academic authorities to foster the future generation through recruitment and provision of educational opportunities.…”

Risk of human health by particulate matter as a source of air pollution -Comparison with tobacco smoking-

“…The qualitative and quantitative analyses of the rodent bioassay, especially with more meaningful data on low-dose effects (Haseman, 2003) will give a clue to their human carcinogenic potential. Non-genotoxic carcinogens will be evaluated by short to subchronic studies in combination with molecular pathology (Boorman et al, 2002;Preston, 2002). The wealth of the database generated from rodent bioassay in the past quarter of a century and the new genetically altered models for carcinogen screening will certainly contribute to more meaningful et al, 2003meaningful et al, , Ohnishi et al, 2007.…”