The Path from Research to Revenues - Microarrays and Diagnostic Testing

Author: Valerie Kellogg – Managing Director USA

The microarray, which at its most basic, consists of a substrate (such as a glass microscope slide) carrying hundreds or thousands of bits of genetic material, was developed in large part by Patrick O. Brown and colleagues at Stanford University.

Strictly speaking, microarrays use fluorescent dye labelling for the detection of hybridization, and are created with robotic equipment (arrayers) that deposit probes on the slides. Nucleic acids representing genes may be either spotted onto or synthesized on a substrate and then tested against a sample. High-density arrays contain many tens of thousands of genes (or bits of genetic material) per chip, whereas medium- and low- density contain on the order of a few thousand to a few dozen genes per chip. The current trend is to classify arrays simply as low or high density.

Microarrays gauge mRNA levels—and thus gene expression. Using microarrays, many different genes or bits of proteins can be studied, enabling expression patterns to be determined in, for example, diseased versus normal tissue or in early-stage disease tissue versus late-stage disease tissue. At the end of the day, the enormous advantage of microarrays is that thousands of tests can be run on a sample in parallel, taking hours instead of days or weeks to complete the testing.

After the array has been hybridized, it is scanned, or “read,” with a reader to obtain an image that shows the amount and intensity of light emitted across the surface of the microarray. The image is then analysed to identify the "spots" where reactions have occurred. Today complete biological data analysis is a team effort involving biological researchers, statisticians, bioinformaticists, database developers, and software engineers.

Proteomics and microarrays

Proteomics, or analysis of the expressed protein content of biological materials (the proteome), offers a relatively new approach to protein expression profiling. Most drugs that are on the market or in the pipeline are designed to target proteins, due to the fact that most biological processes are protein driven. Proteome analysis allows the researcher to obtain information on protein identity, protein-protein interaction, the level of protein expression and profiling, protein variants, etc. One of the more recent developments in proteomics has been the use of disease-specific biomarker protein chips, such as chips for the study of Alzheimer’s disease or of rheumatoid arthritis.

One of the key problems with protein arrays is the fact that proteins are delicate molecules whose function is primarily dependent upon the correct folding sequence; change or corrupt the sequence, and the function either changes or falls apart. Protein structures can be affected by a number of factor, such as temperature and sample preparation, as well as by the very substrate used to create the array. Hence, working to combine proteins and microarrays creates a unique set of technical problems, as well as attractive research opportunities.

Over 130 companies are active in the protein arrays market, having recently introduced protein arrays, or having plans to do so within the next 1-2 years. Ciphergen Biosciences, Inc. (US) manufactures the ProteinChip AutoBiomarker System, intended to aid researchers in discovering protein biomarkers to use in clinical diagnostic assays, and recently launched the IMAC30 ProteinChip Array. Biacore (Sweden) has developed a new SPR-MS functionality for its Biacore®3000, as part of its ongoing collaboration with Bruker Daltonics Inc. The purpose of the alliance is to create a comprehensive and marketable technology solution for functional proteomics studies.

A few of the many types of arrays

A number of these companies are privately-held firms which have successfully sought financing, and are now developing products such as protein arrays, related equipment such as arrayers and readers, diagnostics chips, subscription arraying for research purposes, and pharmaceutical drug lead development.

HBS Consulting predicts that the annual global market size for proteomics and DNA –based diagnostics will be around US$2.67bn by 2005, based upon a 2002 market size estimate of some $400 million, and a current annual growth rate of 48%, zooming to 70% as the technology comes of age. This market is so young that figures depend very much upon what products and product areas are included; it is for this reason that estimates of market size and CAGR vary so widely from source to source. What is indisputable is that once the proteomics technology has proven itself, the market will surge forward, and diagnostics will be one application that will see strong growth in market revenues.

No more pure knowledge: give us products

Microarrays have exploded in the field of biological research. However, there remains significant volatility in the market. The first wave of interest produced databases chock full of information, and pharmaceutical companies scrambled to obtain rights to these databases, or to produce proprietary sets of data in their own laboratories. Too late, after throwing millions of dollars into arrayers and readers, companies realized that all of this data did not easily translate into revenue production in the form of new drugs or other products. They abruptly put the brake on further spending in this area, and many took the position of sitting back to see how the new industry was going to fall out.

In another example, initial strong interest on the part of investors in the promise of proteomics faded when investors realized that marketable products weren’t immediately forthcoming. The timelines to commercialisation of potential products had far exceeded investor expectations. Investors are looking for that promising drug candidate or a diagnostic product that will produce rich revenues, and are reluctant to place their bets on when a viable product may emerge. However, the technology hurdles facing the proteomics and protein microarray companies no longer appear insurmountable, and the investor excitement is again picking up.

Making the transition from academia to revenues

Due to this shift in priorities towards the production of revenues, the use of microarrays is shifting from gene expression and drug discovery into lead optimisation studies and forays into the diagnosis of disease. Experts have long predicted that the microarray will find its greatest usage in the field of diagnostics, and that prediction appears to be an accurate assessment.

When used in diagnostics, microarrays can compare the DNA and protein molecule characteristics from normal tissue and from diseased tissue, such as a breast tumour biopsy sample. In this way, researchers hope to more precisely classify and stage diseases, and therefore better tailor the treatment to what the individual patient requires. Better tailored treatments should mean fewer adverse side effects, a greater treatment success rate, and ultimately decreased treatment costs.

Companies such as Abbott Laboratories, Johnson & Johnson, Boston Scientific, NextGen Sciences, as well as numerous smaller start-ups, are developing test kits for applications such as this. The challenge here is to make the tests accurate and error-free, the results repeatable and ultimately able to be run in a high-throughput manner, and the cost reasonable and reimbursed. Application for product approval will have to be made to regulatory bodies such as the USFDA, before such test kits may be marketed.

The greatest immediate to short term uses of microarrays are to be found in infectious disease, cancer and genetics testing. Cancer diagnostics is not only one of the fastest growing areas, but is also a field that particularly fascinates the investor as well as the general public.

Microarrays can also be applied to pathogen identification. For example, virus identification is being applied in the areas of AIDS and influenza diagnostics. Bacteria product development has focused upon applications such as E.coli (for food poisoning testing), H.pylori (ulcers), Mycobacterium spp (tuberculosis), Salmonella enterica (food poisoning), and Streptococcus pneumoniae (Strep throat). In the parasites area, product development focus has been on the study of Alexandrum cantenella (food poisoning) and Plasmodium falciparum (malaria).

A few of the companies actively pursuing diagnostic uses of microarrays

Government initiatives and industry consortia further research into the human genome, with a long-term view towards the development of products for the detection and treatment of disease. Several of these initiatives are focused in whole or in part upon oncology. The Wellcome Trust Sanger Institute (UK), the National Cancer Institute (US) Cancer Genome Anatomy Program, the Dublin Molecular Medicine Centre, the RZPD (Ressourcenzentrum für die Genomforschung) German Cancer Center, Genome Canada and Singapore’s Institute for Bioengineering and Nanotechnology are only a few of the organizations performing or funding research in the area of cancer diagnostics and treatment, among others.

Meanwhile, medium term opportunities exist in somewhat less-glamorous areas such as the production and sale of custom arrays; the development and marketing of improved high-throughput array readers for use in the research laboratory (while developing the same for clinical use); marketing of arrayers and related equipment to research facilities; and building alliances with pharmaceutical companies for both present-day research and to lay the foundation for future drug and diagnostics development.

In the meantime, companies should plan to take advantage of the coming twist in direction of the diagnostics market as arrays come into their own. The field of clinical diagnostics will be set on its head within a decade, and companies that map out a shrewd strategy now, will then be well positioned to reap the rewards.