Associate editor: P.K. Chiang
Model systems in drug discovery: chemical genetics meets genomics

https://doi.org/10.1016/S0163-7258(03)00059-7Get rights and content

Abstract

Animal model systems are an intricate part of the discovery and development of new medicines. The sequencing of not only the human genome but also those of the various pathogenic bacteria, the nematode Caenorhabditis elegans, the fruitfly Drosophila, and the mouse has enabled the discovery of new drug targets to push forward at an unprecedented pace. The knowledge and tools in these “model” systems are allowing researchers to carry out experiments more efficiently and are uncovering previously hidden biological connections. While the history of bacteria, yeast, and mice in drug discovery are long, their roles are ever evolving. In contrast, the history of Drosophila and C. elegans at pharmaceutical companies is short. We will briefly review the historic role of each model organism in drug discovery and then update the readers as to the abilities and liabilities of each model within the context of drug development.

Introduction

Drug discovery has evolved over the years mostly due to the development of new technologies combined with a less simplistic view and better understanding of biology. Drugs were once developed through a trial-and-error process where combinations of plant or animal extracts were experimented with in vivo on human subjects. While such trials may have shown some therapeutic benefit, they most often resulted in no effect or adverse effects. Through these types of experiments, rudimentary medicinal knowledge was obtained. As technology advanced, complex mixtures of chemicals from extracts were separated and the individual components were tested for therapeutic value. In addition, animal models, such as rats, pigs, dogs, and mice, were harnessed to test the effects of isolated compounds before they were tried in humans. Bacteria and yeast were utilized in the drug discovery process, mainly as a method of producing complex organic molecules in large quantities for testing. Drug discovery took yet another turn with the advent of molecular biology and combinatorial chemistry. The combination of these technologies allowed for the development of specific compounds that bound to and affected the activity of individual proteins. The challenge in drug discovery was to choose the correct protein to target with compounds. The advancement of genetics in yeast, Caenorhabditis elegans, and Drosophila and the recognition that many biological mechanisms and protein functions have been highly conserved has led to their more recent integration into the drug discovery process. Bacteria, yeast, C. elegans, Drosophila, and mouse models all have a unique utility and history in drug discovery, and the combination of these systems is helping to drive the selection and validation of tomorrow's small molecule medicines.

Section snippets

Brief history

Bacteria have long been the subject of scientific study due to their ability to cause disease in humans (Lederberg, 2000). One of the major advances in the health and well-being of human civilizations was the development of the antibiotic. While the introduction of antibiotics had an enormous impact on the ability to treat bacterial infections, they continue to be the leading cause of death worldwide (Binder et al., 1999). Moreover, the effectiveness of antibiotics has been eroded by the

Yeast as a research organism

Saccharomyces cerevisiae, commonly known as baker's, brewer's, or budding yeast, has been the subject of study for over 100 years. The species has many features that endear it to scientists. Unlike a mouse, it produces a pleasing odor and can be left in a refrigerator or freezer for many months without complaint. It is nonpathogenic and divides every 2 hours, growing as dispersed cells in liquid or as colonies on solid media, and its nutrient requirements are very economical to satisfy. It can

Brief history

From the humble beginnings of a single landmark paper published by Brenner (1974) has grown an entire field of research into the small roundworm C. elegans. Having been born so recently as a research tool, C. elegans have much less of a history and tradition in drug discovery as have the model systems of yeast, bacteria, Drosophila, or even mice. Yet, this unique organism is poised to make an enormous impact in the future of drug discovery. C. elegans was the first multicellular organism to

Mouse models

Historically, drug discovery has consisted of a linear process whereby a large number of compounds are tested in relevant models. It is estimated that currently only 483 targets account for all drugs now on the market Drews, 2000, Reiss, 2001. The publication of human sequences has resulted in the availability of large amounts of data that are potentially directly relevant to the discovery of novel and useful drug targets, which will necessitate a change in this linear process. Of the ∼30,000

Conclusions and perspectives

The use of animal models in drug discovery is an essential component of the entire drug discovery process. Genetic models allow investigators to probe complex biological questions that would take many years to answer and in some cases would require experiments that are considered unethical in humans. Moving from the unicellular systems such as yeast to the relatively more cumbersome rodent models, one exchanges speed for relevance to human disease. Experiments done in yeast are often lightning

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    1

    Authors contributed equally.

    2

    Current address: Abbott Laboratories, Chicago, IL, USA.

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