The Emerging Metabolomics Industry

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By Ashwin Singhania

Over the last decade, genomics and proteomics have been used as tools to discover potential drug targets and to better understand the complexities of biology. To complement research in these areas, a new field, metabolomics, is emerging. Like the other “omic” sciences, metabolomics generates large volumes of data in an attempt to better understand biological systems. Instead of focusing on genes or proteins, the science examines the substrates and end products of enzymatic reactions: metabolites. These low molecular weight compounds are directly responsible for the phenotype (the observable characteristics) of a biological sample and thus provide a direct link as to what causes various biological states, such as disease states.

Popularly, particularly in North America, the term “metabolomics” has been equated with the term “metabonomics,” a term coined by Jeremy Nicholson, PhD of Metabometrix Ltd. (London, UK). The distinction between these two terms is still evolving, though many feel that metabonomics implies research on a system-wide level as opposed to the cellular level. Regardless of the nomenclature, metabolomic research has been more popular in Europe, with the largest emphasis being on plant metabolomes, or the set of all metabolites in a system. However, there is a movement in North America towards establishing metabolomics as an integral part of the drug-discovery process as well as in developing novel diagnostic tools. There are two Canadian firms with an interest in providing tools that can be used for analysing and interpreting the results of metabolomic research. As we have seen in genomics and proteomics, bioinformatics and interpretation will be paramount to the science’s success.

Though efforts to survey the entire metabolic profile of a biological sample are a relatively recent phenomenon, endeavours to identify and quantify one to dozens of metabolites have been ongoing for several decades. Originally, such research was performed to characterize substrates and byproducts of chemical reactions, such as those involved in glucose metabolism. More recent research has been aimed at identifying metabolites that correspond with particular disease states as an approach to drug discovery.

In 2002, the estimated worldwide market for metabolomics was $38 million US. By 2007, it is estimated that the market will grow to over a quarter billion dollars at a compound annual growth rate of 46 per cent (Fig. 1). The market for metabolomics is composed of three basic segments: providers of tools that are used to perform metabolomic research; software and informatics providers for data collection and analysis; and companies that are performing the research for in-house drug development or as contract services. While the companies that are using metabolomics for internal or contract research purposes will grow to constitute the majority of the metabolomics market, the bioinformatics segment will grow the fastest due to the fact there are few available platforms and there is tremendous room for growth, both in terms of the number of competitors as well as in the sophistication of the product offerings. It is estimated that this segment will experience a compound annual growth rate of nearly 80 per cent.

Though the sophistication and sensitivity for analysis tools has been and is still improving, the tools for metabolomic research are largely already in place. The most common techniques for determining the metabolic profile of a sample are mass spectrometry (MS) and nuclear magnetic resonance (NMR). The data generated by these analytical tools are then collected and analysed by powerful bioinformatic suites to determine the metabolic content of a sample.

While the framework and the tools for metabolomics have existed for years, the approach and aim of this research has only come into focus over the last five to 10 years. It is now possible to determine the presence and concentration of hundreds to thousands of compounds simultaneously. A central focus of the metabolomic effort has been achieving economies of scale and the automation of all processes, from sample preparation to data analysis.

The Role of Data Management

The market for metabolomic software and data analysis tools is growing rapidly. Some pioneering pharmaceutical companies have begun to integrate metabolomic research into their drug-discovery processes, yet the proper tools to analyse the results of this research are often not in place. There are a handful of companies that have specifically developed products that can be used as data-handling tools that organize and perform data-mining functions to reduce the complexity of gathered data. In some cases, data from genomic, proteomic, and metabolomic research can be analysed concurrently to draw relationships between genes, proteins, substrates and end products.

One company hoping to help fill the need for advanced bioinformatic tools is Phenomenome Discoveries Inc. (Saskatoon, SK). The company has developed a patent-pending MetArray analysis suite that is one of the most comprehensive metabolomics bioinformatics platforms in the industry. The software uses MS analyses to investigate and validate all known metabolites as well as link these metabolites to known pathways. MetArray can also create pathways de novo from novel metabolites and can determine the molecular formula for these compounds. Phenomenome is also able to perform the front-end of the analysis by using its proprietary MetEx (Comprehensive Metabolome Expression Analysis) technology. This technology analyses samples using Fourier transform ion cyclotron resonance mass spectrometry, the highest resolution technology available (Fig. 2). The company continues to form collaborative research partnerships.

A second Canadian firm with a vested interest in metabolomic bioinformatics is Chenomx Inc. (Edmonton, AB). The company has developed Eclipse, a software platform that is able to interpret the NMR output produced from biological samples, such as blood or urine. The software performs statistical analyses between data sets and uses a flexible and customizable user interface. Beyond data analysis, Eclipse facilitates the automation of sample handling. The company has partnered with large pharmaceutical companies, including Pfizer Inc. (New York, NY) to bring its technology to the drug-discovery laboratory.

Although the market for metabolomic software is expected to grow rapidly, many of the pharmaceutical companies that would be prime candidates to license metabolomic software are instead choosing to develop these technologies in-house. This will allow these pharmaceutical companies to specifically tailor analytical products to their own needs. Fortunately for companies that focus on metabolomic bioinformatics, there are many pharmaceutical companies in this business climate that have neither the necessary financial nor personnel resources to develop such analytical tools.

Metabolomic Drivers and Applications

The greatest driver of metabolomic technologies is their potential widespread application in the drug-discovery process. Metabolomics can help pharmaceutical companies stretch their research and development dollars by improving the efficiency of target discovery and validation, mode-of-action discovery, and toxicology studies.

Through prior emphasis on genomic and proteomic research, many pharmaceutical companies possess a deep portfolio of potential drug targets. By comparing the metabolic profiles of a diseased sample against a normal sample, metabolomics can help these companies validate and prioritize their potential targets. Without metabolomic data, it is only possible to know which genes are up-regulated and down-regulated. Information on specific metabolites, namely the substrate or product of the gene/protein of interest, helps determine to what extent the overall activity of a particular reaction is augmented or diminished.

However, the greatest potential cost-savings benefits are in the toxicology studies that can emerge from metabolic profiling of samples that have been exposed to potential drugs. Samples that are treated with an investigational drug can be compared to an untreated sample. The differences in their respective metabolic profiles have the capacity to provide pharmaceutical companies toxicological insight early in the discovery process. Specifically, metabolite concentrations can indicate which pathways are disrupted and whether or not accumulation of certain metabolites would have a toxic effect. By eliminating programs that are likely to have high side-effect profiles early in the process, pharmaceutical companies can focus their research time and money towards more promising programs. This, in effect, will help create greater efficiency in the drug-development process.

The Future of Metabolomics

Although the metabolomics industry is growing quickly, it is starting from a small base. The uptake of the technology, particularly by larger pharmaceutical companies, has been relatively slow when compared to the introductions of genomics and proteomics. Many companies are skeptical of the benefits of metabolomics, especially after they felt that genomics and proteomics have created more questions than they have answered. Initial successes using this technology are causing this skepticism to fade, yet full adoption will not be achieved until higher-profile successes are seen.

With the pharmaceutical uptake of metabolomic technologies will emerge the need for software and bioinformatic suites that are able to draw increasingly complicated relationships. Such product offerings will establish a more complete relationship between metabolites and their phenotypic effects. The companies that are developing these products are seeking to include predictive and modelling capabilities into their data-analysis tools. These additions will help discover new pathways by linking the concentrations of known and novel metabolites to one another.

The metabolomics industry is still emerging with relatively few companies occupying this space. In North America, there are currently fewer than 15 companies with a primary interest in metabolomics. The outlook for this technology is bright and growth will be most noticeable in North America as pharmaceutical companies continue to partner with companies that have expertise in metabolomic research and bioinformatics. Expect the analytical power of the technology and sophistication of the software to continue to develop.

Ashwin Singhania is an associate at Front Line Strategic Consulting (San Mateo, CA). Phone: 650-525-1500
E-mail: info@frontlinesmc.com
Web site: www.frontlinesmc.com