Model Organisms in Drug Discovery

Chapters Overview:

The chapters of this book are ordered along increases in evolutionary complexity towards humans, starting with yeast, nematodes and fruitflies and then proceeding into chapters centered around zebrafish and mice. One could also view this as a progression of technology development with an abundance of powerful genetic tools available in yeast, fruitflies and nematodes and the quest of zebrafish and mice researchers to develop similar technologies. The book will detail the incorporation of advances in the application of bioinformatics, proteomics, genomics, biochemical and automation technologies to simple organisms and how these advances constitute an integrated drug discovery platform. Detailed accounts of the application of model organism technology to specific therapeutic areas will be covered. The authors include leading experts in each field who will examine state-of-the-art applications of individual model systems, describe real-life applications of these systems and speculate on the impact of model organisms in the future. The first of these authors will delve into the relatively simple model organism, yeast.

Chapter 2 by Ross-Macdonald of Bristol-Myers Squibb describes the history of Saccharomyces cerevisae (yeast) research in drug discovery and how this simple eukaryote historically has been utilized mainly as a production vehicle due to its ability to produce compounds and proteins but also as a valuable tool in understanding biology. Yeast researchers have an unparalleled breadth of reagents to probe the genome, making it a natural choice for studying conserved targets and mechanisms of basic biological processes. With the sequencing of the yeast genome and the advent of such tools as transcriptional profiling, protein–protein interaction assays and genetic tools such as deficiency, overexpression and haploinsufficiency strain sets, yeast is now a workhorse in uncovering hidden links among genes and defining cell signaling circuits. Many of the genomics tools that are being applied to the other model systems were developed in yeast and the yeast model system continues to be an invaluable source of innovation and technology development. For this review, Ross-Macdonald has chosen to highlight the contributions of biotechnology and pharmaceutical researchers in order to focus this broad field.

Caenorhabditis elegans is a tiny worm composed of just around 900 cells and a life cycle of about three days, yet it contains many of the cell types and genes found in humans. It was the first multicellular organism to have its complete genome sequenced. It is in C. elegans where we begin to see the development of rudimentary tissues, organs and the beginnings of a more sophisticated nervous system. The level of complexity (complex but not so complex as to have little chance of ever understanding all of the various neuronal connections) is one of the attributes of C. elegans that first attracted Sydney Brenner to C. elegans as a model system. Research into C. elegans has played an essential role in our general understanding of more complex human diseases such as cancer (i.e. Ras oncogene), depression (i.e. neuronal signaling and drug mechanism of action), Alzheimer’s disease (i.e. presenilin genes) and cell death.

In Chapter 3, Kaletta, Butler and Bogaert from DevGen review the short but impactful career of C. elegans in drug discovery. They also take us through the detailed process of applying C. elegans technologies of ‘high-throughput’ target identification and compound screening. Clearly, there is a great future for C. elegans in drug discovery. Chapter 4, authored by Li and Garza from Novartis, describes the Drosophila technologies that have evolved over this long history, and in Chapter 5 Ernst Hafen and colleagues at the Genetics Company and the University of Zurich show howthese technologies have been implemented to decipher several important disease pathways. Any discussion of drug discovery would be incomplete without a clear discussion of compounds that lie at the very heart of and are the ultimate goal of the process. It is clear that one of the emerging areas of model systems will be ‘chemical genetics’.

Chemical genetics consists of combining the genetic tools of model organisms with novel compounds in order to get a better understanding of their mode of action. It also encompasses screening for compounds that interfere with biological processes and then using those compounds as tools, which, when combined with genetics, allow you to unravel pathways of gene interaction. Every chapter of the book touches upon this new emerging field and Chapter 6, authored by the editors and Rachel Kindt at Exelixis, is dedicated to this concept. Perhaps the most striking revelation contained in these pages is that compounds work on conserved targets across species and, although ultimately the compound affinities may differ, the mechanisms of action are similar. Chapter 6 highlights the utility and benefits of having multiple genetic systems to unravel a problem.

The emerging power of the zebrafish system is captured in Chapter 7 by Schulte-Merker at Exelixis and in Chapter 8 by Ho, Farber and Pack at Thomas Jefferson University and the University of Pennsylvania. Chapter 8 discusses a specific model where zebrafish are being utilized to study lipid metabolism with strong parallels to those found in humans.

Finally, Chapters 9 and 10 explore the advances in one of the workhorses of modern drug discovery, the mouse. These chapters are divided into forward genetic approaches contributed by Ingenium AG (Chapter 9) and the reverse genetics approaches based on work at Lexicon Genetics (Chapter 10). In forward genetics a phenotype is identified first and then the molecular basis of a given trait is identified. Historically, the process of phenotype to mutation has been laborious and time-consuming, but new genomics technology is rendering the process more robust. Chapter 9 reveals new approaches for novel, rapid, chemical genetic screens and mutation identification that allow for in vivo target discovery in unprecedented ways. Conversely, Lexicon Genetics (Chapter 10) describes its undertaking of systematic large-scale gene knock-outs of the ‘druggable genome’ in mice and the process in place to associate a gene’s functions with disease. Because most drugs act as antagonists, knock-out phenotypes should mimic drug action.