1. Introduction: The New Meaning of Functional Genomics
Gene functional analysis is at a critical phase now, as companies turn to this discipline for the proof that genomics can deliver better drug targets, faster and more efficiently than traditional means. Pharmaceutical companies using genomics technologies for drug discovery hope that this approach will replenish dwindling drug pipelines (and, especially, provide commercially successful, breakthrough drugs), but whether genomics can provide new targets quickly and cost-effectively enough remains a major question. Key to this endeavor will be the development of high-throughput and system-wide functional genomics approaches to match the extraordinary power of today’s genomics technologies to provide sequence information for all the genes of humans and model organisms. As the map of the human genome approaches completion, drug companies face increasing pressure to stake their claims on those genes whose products will be the most valuable drug targets. Deft use of functional genomics will provide a key advantage in this race.
1.1 Functional Genomics: A Rapidly Evolving Field
1.2 What Is Functional Genomics?
2. Scientific Background: Reverse Genetics Allows High Throughput System-wide Analysis
The traditional approach to genetics—termed forward genetics—does not allow for the type of high-volume and high-speed screening required for today’s drug discovery and development programs. As a result, researchers have turned to a new strategy, called reverse genetics, that allows for greater speed and efficiency. This shift is allowing exponential increases in the numbers of genes that can be studied simultaneously and in multiple samples. In short, functional genomics is entering the age of high throughput.
2.1 Going Forward to Reverse Genetics
The Traditional Approach: Forward Genetics
Key Tools: Focus On Positional Cloning
The New Approach: Reverse Genetics
2.2 Achieving Genome-wide Scale
3. Current and Emerging Technologies: The Push for High Throughput
Leading new technologies for functional genomics include bioinformatics, model-organism databases, systematic gene-disruption methods, gene expression monitoring, gene expression libraries, phage display libraries, and systems to study protein-protein interactions. The first two of these technologies—bioinformatics and model organisms—provide the underpinning for all other methods of functional genomics research. The newest technologies can be implemented in a high-throughput fashion and will allow system-wide studies. Each technology, however, has its limitations, and researchers are growing more aware of the need to develop platforms that use multiple technologies in a synergistic way. In addition, researchers recognize the importance of bringing target validation into the process as early as possible.
3.1 Bioinformatics and Data Mining
3.2 Key High-Throughput and Systematic Approaches
The Yeast Two-Hybrid Assay and Variations
Advanced Knock-out and Knock-in Approaches
Analyzing Human Orphan G-Protein-Coupled Receptors
Whole-Genome Expression Monitoring with Arrays
4. Business and Strategic Considerations: The Race to Realize True High-Throughput Capacity
Several companies have already gained an important lead in functional genomics by building advanced integrated platforms, some of which include substantial databases. Among these leaders are Amgen, Aurora Biosciences, CuraGen, GPC, Human Genome Sciences, Incyte Genomics, Millennium Pharmaceuticals, Novartis, Merck & Co., Rigel, and ZymoGenetics Companies such as Arcaris, Cadus Pharmaceutical, Exelixis Pharmaceuticals, Genetica, and Lexicon Genetics have developed critical tools that have attracted significant interest. Given the very different levels of in-house expertise found at various pharmaceutical companies, the roles of both tool providers and service providers/collaborators represent significant opportunities in this field. We anticipate that major new technologies will be developed over the next few years. These developments will constitute just the first phase of evolution in this field, however—the discovery phase. Those companies that most quickly use functional studies to establish possession of critical genomics-related targets and therapeutics will have an important advantage in the next phase—the development phase.
4.1 Industry Leaders
4.2 Industry Dynamics
Tool Providers Pairing with End-Users
Tool Providers Pairing with Software Providers
5. Outlook: Marrying Advanced Functional Genomics Technologies to Hypothesis-Driven Research
5.1 Technological Issues
5.2 What the Future Holds
5.3 Expert Commentaries
Appendix A: Company/Technology Profiles