Since the completion of the Human Genome Project, DNA microarrays have become a significant laboratory research tool. The microarray industry is now poised for explosive growth into other areas including clinical diagnostics/toxicogenomics, environmental analysis, antiterrorism monitoring, comparative genomics, and forensic testing. Most industry analysts would agree with a recent Frost & Sullivan report that puts the current size of the DNA microarray market at nearly $600 million . In their report, Frost & Sullivan predict that total DNA microarray revenue will reach $937 million by the end of the decade with a compound annual growth rate of 6.7%. Estimates regarding the DNA microarray industry could go higher if one considers that Affymetrix alone posted $222 million in product revenue in 2003 and if it were to continue to post growth at 10% compounded annually for the next 6 years (a low rate when compared with its previous 5 years) Affymetrix could anticipate product revenues of $430 million by the end of the decade . When one considers that close to 50% of the array market, by volume, was done by do-it-yourselfers in 2003, shrinking to less than 25% in 2006, and not with commercially purchased arrays, and that Affymetrix accounts for 80% of commercial array sales, the total market for DNA arrays could be well over $1 billion by 2010 . The continued conversion from the home-grown variety of arrays to the commercial arrays, as economy of scale and qualitative considerations takes hold, could greatly drive these numbers. Additionally, the array industry as a whole, including DNA, protein, cell, and tissue arrays could exceed $5 billion by 2010 .
Though these estimates are impressive, they still fail to take into account the explosive industry growth that could occur, should microarrays take off in any of the four emerging growth areas, namely clinical diagnostics, toxicogenomics, environmental monitoring, and bioterrorism. Current estimates put the DNA-based (nonmicroarray) diagnostics industry at more than $1 billion (2002) with expectations that it will reach $3 billion by 2008 . Toxicogenomics, with a current market of only $120 million (2003), is expected to grow to almost $259 million by 2008 . But the real financial incentives are coming from the U.S. government's commitment to combating terrorism. There is an expectation that DNA microarrays will be used in every aspect of counterterrorism from surveillance to exposure diagnosis to treatment monitoring. The stakes are high and so are the funding opportunities for microarray technologies. For example, funding at the CDC for initiatives regarding public health preparedness and response to bioterrorism topped $49 billion in 2004 . To add to these numbers, the budget proposed by President Bush for 2005 includes a 10% increase to Homeland Security funding and an increase in the Health and Human Services budget for bioterrorism preparedness to over $5 billion from just $300 million in 2001 . Included in the 2005 number is money for Project Bioshield with a $2.5 billion budget proposal before Congress (up from $900 million in 2004) and an estimated $5.5 billion secured for the project over the next 10 years and a new $129 million biosurveillance initiative. The proposed funding for the NIH tops $28 billion in 2005 with $1.7 billion set aside for bioterrorism research. There is also a $567 million allocation for defending food and agriculture systems. In many of these areas DNA microarray technology could prove useful pending further development. It is clear that federal initiatives offer great financial incentives for those in the DNA microarray industry to push this technology forward.
Of these "new frontiers" for DNA microarrays, early commercial applications and market adoption is expected in the area of molecular diagnostics. Diagnostic arrays could be used to profile tumor subtypes to identify patients who would respond to a particular drug treatment a priori, for treatment decisions or for inclusion in clinical trials, and might also be used to follow a patient through treatment to see if the tumor is responding [9-13]. One recent study using DNA microarrays to diagnose non-Hodgkin's lymphoma (NHL) illustrates this point . In 2000, there were 22,553 deaths from NHL subtypes, and 54,900 patients were newly diagnosed. Of the various subtypes of NHL, diffuse large B-cell lymphoma (DLBCL) subtype is the most common. Within this subtype, only 35-40% of patients can be cured with chemotherapy, the remaining 60-65% with DLBCL will die from the disease. Current techniques, such as histopathology and molecular markers, are unable to distinguish between responsive and nonresponsive DLBCL tumors. However, using DNA microarrays to profile gene expression, researchers were able to classify DLBCL tumors into several subclasses and to further link those profiles with patient prognosis.
The application of microarrays to the study of toxicogenomics is already moving into the commercial realm. Affymetrix and Roche have teamed up with a $70 million multiyear partnership to develop commercial array applications. Their first product is the Amplichip™ CYP450 microarray launched in June 2003 in the U.S. and, in fall 2004, received its CE mark for launch in Europe . The CYP450 chip is used to identify variations in two genes (CYP2D6 and CYP2C19) that play a major role in the metabolism of various drugs. Revenue expectations are high, and corporate sources are hoping for $100 million annually by 2008 from this single product, though the pair expects the P450 array will be only one of several pharmacogenomic tests in the platform . However, the FDA has already begun to question Roche's classification of the Amplichip as an ASR (analyte-specific reagent), which did not require review prior to launch . The FDA is investigating whether the claims made by the company for the chip would require it to be designated as a medical device that would then be subject to FDA review and likely array platform standardization requirements for both test procedures and data analysis. Currently, the device is approved for research use only, and is not indicated for clinical diagnosis, though Roche is pursuing IVD (in vitro diagnostic device) status for the Amplichip. Regardless of its designation, toxicogenomic chips are in demand not only for clinical patient profiling but also from drug industry researchers to enable them to identify toxic compounds earlier in the R&D timeline, saving time and money. Meanwhile, there are those in market research who anticipate that over the next year, the use of microarrays for toxicogenomics could grow by approximately 33% among existing users .
The combination of molecular diagnostics and toxicogenomics studies are leading the way toward personalized medicine where treatment plans would be tailored to an individual's response and potential for side-effects based on the personal genetic expression pattern. There is a growing eagerness for such personalized medicine. In a recent, though small, survey, 43 participants were asked how much more they would be willing to pay for tailored drugs that better matched their body type and have fewer adverse reactions . Of the 43 questioned, 27 said they would pay 10% or more for such personalized medicines. There are, however, significant barriers to the widespread adoption of microarrays in clinical diagnostics such as reimbursement, education, awareness of the test's utility, nonuniform testing procedures, data interpretation, and intellectual property rights covering specific genes that limit their inclusion in such tests .
Federal funding of environmental and antiterrorism surveillance has helped to stimulate the development of commercially viable microarray-based detection products. In order to be competitive, biosurveillance devices must become more accurate, faster and cheaper as outlined by panelists at a bioterrorism session at the Biotechnology Industry Organization (BIO) Convention in Washington, D.C. (June, 2003). For example, current air monitoring tests cost about $40 and are truck-mounted but will need to be made both cheaper and smaller according to Cindy Bruckner-Lea
(staff scientist, U.S. DoE Pacific Northwest National Laboratory). It is in this context that DNA microarrays could prove useful if the analysis device could be miniaturized. Recently, BioLog Corporation has been awarded an NIAID grant to develop their Phenotype MicroarrayTM for bioterrorism agents, and a group at Lawrence Livermore National Laboratory has constructed a Multi-Pathogen Identification array that proved to be 91% accurate and able to detect as little as 10fg of B. anthracis DNA in a sample . Microarrays can also be used to aid in determining if there has been a terrorist attack at the patient level. Because an outbreak of flu might present symptoms similar to an outbreak caused by exposure to a biowarfare agent, there is a real need to be able to quickly determine the source of a patient's symptoms. One can imagine a scenario at local emergency rooms during such an outbreak where physicians would have to make a rapid assessment about public threat levels and will need diagnostic tools to do so. With this in mind, Dr. Maria Salvato at the Institute of Human Virology, University of Maryland Biotechnology Institute is employing DNA microarrays to identify gene expression profiles that correspond to a flu infection vs. infection from a more serious threat . There are many other potential applications for microarrays in combating terrorism that have not been discussed here.
DNA sequencing is also becoming an important growth area for microarray technology and has applications in both terrorism surveillance and public health monitoring. For example, the recent severe acute respiratory syndrome (SARS) outbreak highlighted the need for rapid genetic level identification of the virus, as well as an immediate need for an easy-to-use, accurate screening tool for patient diagnosis. There was really no time to develop a traditional antibody-based diagnostic test in light of the rapid spread of the virus from Asia to North America and Europe. The ability to quickly identify the strain of the outbreak through comparative sequencing could lead to a better understanding of how the virus spreads and how best to treat patients. Monitoring mutation patterns and rates among other viruses such as HIV, polio, and rhinoviruses might enable researchers to create better vaccine or drugs that target specific variants.
In summary, there are many areas in which DNA microarrays will have a significant impact. From bioterrorism, cancer profiling, or to monitoring global flu outbreaks, there are a wide range of opportunities and significant increases in both public and private funding to stimulate microarray technology development.
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