Gene expression analysis: solid tools, real results

From Cambridge Healthtech Institute (CHI)

The tools for generating and analyzing gene expression data have matured to the point where they are producing breakthrough results with real clinical implications. This article reviews the tools and companies that are leading in efforts to turn the data into drug targets.

Gene-expression-analysis technologies—especially DNA arrays—are already producing real, valuable results in groundbreaking research studies, particularly in cancer. This progress comes at a time when a key enabling field—bioinformatics—is also maturing, helping researchers get from gene expression data to insights about possible therapeutic targets.

For groups seeking to identify and validate drug targets based on gene expression data, it is essential to develop interpretive (i.e., bioinformatic) tools in tandem with data collection. This article—based on Genomic-Scale Gene Expression Analysis: Advancing from DNA to Disease, an upcoming report from Cambridge Healthtech Institute (CHI)—identifies key tools and the companies offering them while reviewing important insights being uncovered with DNA arrays. It also discusses the high level of competition and dealmaking surrounding gene expression analysis—indicators of the strong interest in the field.

Although a variety of technologies are available for gene expression analysis, we focus on DNA arrays because they offer the high-throughput capacity and cost-effectiveness crucial for large-scale analysis of genomic data. With this technology, DNA probes from hundreds to thousands of genes are placed on a substrate. Hybridization reactions between the array and a cell or tissue sample indicate that certain genes represented on the array are active in the sample. Arrays help elucidate patterns of gene expression that may be associated with states of health and disease.

Microarrays provide important new insights into cancer
Several recent and ongoing cancer studies using microarrays (an array type that is being widely used in research) could help researchers identify and validate targets for cancer drugs and identify which available therapies would be the most effective for certain cancers.

Leukemias and lymphomas. In a pioneering study published last year, researchers led by Eric Lander and Todd Golub of the Whitehead Institute and MIT used microarray technology from Affymetrix to generate gene expression profiles that allowed them to distinguish between acute myeloid leukemia and acute lymphoblastic leukemia; these two types of leukemia are difficult to distinguish by conventional pathological examination.

And in a study published in February 2000, Louis Staudt of the National Cancer Institute, working with Patrick Brown and David Botstein of Stanford, used array-based gene expression monitoring to classify leukemias and lymphomas; notably, they uncovered new subtypes of lymphoma.

Melanomas and breast cancers. Similarly, Paul Meltzer's group at the National Human Genome Research Institute has found, based on microarray experiments, that a group of melanoma patients could be classified into two subgroups according to gene expression profiles. These subgroups were not distinguishable pathologically.

And researchers led by Patrick Brown and David Botstein at Stanford University have also used gene-expression-monitoring technology to identify two classes of breast tumors—one in which the gene for the estrogen receptor was expressed and one in which it was not. These two types of breast cancers were already known; however, the researchers found that these two tumor groups may have further subgroups.

Key business trends, companies, and tools
Gene expression analysis is a hot business area in which at least 80 companies are competing, according to CHI. These businesses range from microarray and database providers to suppliers of imaging instruments and reagents.

Furthermore, gene expression monitoring has been the focus of a high level of dealmaking, indicating strong interest in this field. According to CHI's Drug Discovery and Development Deals Database, gene expression monitoring represented one of the two most active categories of deals (based on CHI's technology codes) in 1999, accounting for 19% of all deals last year. (The other most active class was bioinformatics, also accounting for 19% of deals.) In the third quarter of 2000—the most recent quarter for which complete statistics are available—this technology was the focus of 43 deals, compared with 19 such deals in the same quarter of 1999. Since the inception of CHI's database in January 1999, 185 gene-expression-monitoring deals have been logged.

In the following sections, we review the activity of a few leading companies (the top dealmakers in gene expression monitoring, as shown by the table below) and also point out some emerging players in the field.

Affymetrix. Affymetrix offers high-density oligonucleotide arrays (GeneChips), which are currently the market leaders for gene expression analysis and genotyping. These chips are being used by major pharmaceutical companies, biotech companies, and academic institutions. The company's arrays have been employed in some of the groundbreaking cancer research discussed previously. By cultivating academic research groups and biotech companies as customers and collaborators, Affymetrix is establishing its technology platform as the tool of choice for the cutting-edge applications of gene expression monitoring being developed by these nonprofits and smaller companies.

As already noted, array experiments help elucidate patterns of gene expression that may be associated with states of health and disease. But proving these linkages would be impossible without enabling tools and technologies—especially bioinformatics—that help interpret the data. Fortunately, bioinformatics has been maturing at the same time as gene-expression-analysis technologies. Affymetrix and other companies offering arrays are also providing bioinformatic tools for analyzing the array data.

In particular, Affymetrix provides the GeneChip Analysis Suite for conducting bioinformatic analyses of experiments with GeneChips. This suite has image-analysis, data-management, and relational-database capabilities. Affymetrix also supplies Stingray software for gene expression analysis. It purchased ownership of the rights to this software from Molecular Applications Group.

Since 1997, Affymetrix has signed a large number of "EasyAccess" deals with major pharmaceutical companies, giving these companies broad access to standard and custom GeneChip arrays, instrumentation, and software to monitor gene expression for research and development activities. More recently, Affymetrix has developed new Academic Access and Biotech Access programs (volume incentive arrangements designed to meet the needs of these types of institutions that want broad and preferential access to Affymetrix' GeneChip technology). The company has signed deals with several academic institutions and biotech companies in 1999 and 2000, both under these programs and under other types of agreements.

Incyte Genomics. Databases of genomic information are at the core of this company's business. Incyte databases include LifeSeq Gold (its flagship database of more than 120,000 gene transcripts), ZooSeq (containing gene sequences for animals commonly used in preclinical studies), and PathoSeq (a database of microbial gene sequences). In addition to using Incyte databases to characterize genes' functions, researchers can purchase full-length clones from the LifeSeq database and use them to create custom arrays.

GEM microarrays constitute Incyte's primary gene-expression-analysis product line. Individual arrays contain up to 10,000 genes, but when several nonredundant microarrays are used, up to 50,000 different genes can be assayed. In addition, Incyte has developed GEMTools software to analyze results of experiments with GEM arrays. This software can compare gene expression in, for instance, normal and diseased cells and identify which genes are over- or underexpressed in the diseased cells.

Incyte, the second most active dealmaker in gene expression monitoring, has struck deals with a wide range of partners seeking access to the company's databases. Since the start of 2000, subscribers to these databases have included Bayer, Biogen, Corixa, Elitra Pharmaceuticals, and Vertex Pharmaceuticals.

Gene Logic. Gene Logic offers the GeneExpress gene expression database. This reference database comprises three modules: BioExpress, a broad survey of both normal and diseased human tissue samples for target discovery and validation; ToxExpress, a survey of human and experimental-animal tissue samples treated with known toxic compounds for predictive toxicology assessment; and the soon-to-be-launched PharmExpress, a survey of human and experimental-animal tissue samples treated with known therapeutic compounds. PharmExpress is intended for optimization of testing and refining of current drug candidates. Gene Logic uses Affymetrix's GeneChip technology to generate the GeneExpress data.

The GeneExpress suite incorporates bioinformatics software that allows data mining, analysis, and visualization. It also incorporates information from public databases.

Gene Logic, the third most active dealmaker, customizes its gene expression information products to meet the needs of individual customers. Customers for Gene Logic's gene expression databases and data management software include such companies as Pfizer, Aventis, Merck, SmithKline Beecham, Schering-Plough, and Wyeth-Ayerst.

Emerging players
Several other companies are emerging as important players in the array field. Nanogen, for instance, is developing one of the most intriguing new technologies—microelectronic arrays—based on advances in molecular biology and semiconductor microfabrication techniques. These arrays contain microelectrodes that can generate an electric current to draw probes, samples, and reagents to specific locations on the array. This approach allows faster hybridization than traditional arrays and permits a greater degree of control over the hybridization process.

Clontech Laboratories (part of Becton Dickinson) and Research Genetics (part of Invitrogen) are two other notable players. Clontech started by offering macroarrays (which have a lower probe density than microarrays, among other differences) and began providing microarrays earlier this year. The company's macroarrays have been a popular with smaller research groups because these arrays use instruments already found in most molecular-biology laboratories. Clontech also has glass-slide-based microarrays that contain their own fluorescent labeling kits.

Research Genetics is also aiming to provide cost-effective tools for researchers. Because its GeneFilters arrays are reusable, they are being promoted as an affordable option for laboratories that have not used microarrays in the past because of the expense.

More recently, even newer players like Motorola and Corning have entered the array field. This trend illustrates growing awareness of the usefulness of array technology, says CHI president Phillips L. Kuhl. "It's becoming that much more widely recognized as a technology that is having a dramatic impact and that is presenting more opportunities than may have been realized previously."

Outside of the array field, Third Wave Technologies' Invader assay is emerging as one of the key alternatives to TaqMan—the most commonly used approach for more specific quantification of individual genes.

A future of opportunity, with some challenges
The maturity of technologies used for gene expression analysis—and the promising results achieved so far—are building up expectations that many more, and more insightful, results are ahead. There is every reason to believe that these expectations will be fulfilled and that the technologies and tools like those we have discussed will identify real drug leads, as well as powerful new diagnostics.

However, certain challenges remain for companies in the array field. For example, for arrays to achieve optimal use in industry and academic laboratories, reliability and ease of use will have to improve and costs will have to decrease. Companies in the field are taking steps to address these challenges.

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