Science And Technology Advances In Biomarker Research

In the past decade of biomarker research, far and away the most influential driving force was completion of the Human Genome Project in 2003. The impact of this project on biomarker research has many facets beyond establishment of the reference data for human DNA sequences. This mammoth undertaking initiated in 1990 led to the sequence for the nearly 25,000 human genes and to making them accessible for further biological study. Beyond this and the other species genomes that have been characterized, human initiatives to define individual differences in the genome provided some of the earliest large-scale biomarker discovery efforts. The human haplotype map (HapMap) project defined differences in single-nucleotide polymorphisms (SNPs) in various populations around the world to provide insights into the genetic basis of disease and into genes that have relevance for individual differences in health outcomes. A collaboration among 10 pharmaceutical industry companies and the Wellcome Trust Foundation, known as the SNP consortium, was formed in 1999 to produce a public resource of SNPs in the human genome t 6] . The SNP consortium used DNA resources from a pool of samples obtained from 24 people representing several racial groups. The initial goal was to discover 300,000 SNPs in two years, but the final results exceeded this, as 1.8 million SNPs had been released into the public domain at the end of 2002 when the discovery phase was completed. The SNP consortium was notable, as it would serve as a foundation for further cross-tndustry public-private partnerships that would be spawned as a wide variety of community-based efforts to hasten the discovery of genomic bio-markers (see below).

The next phase of establishing the basic infrastructure to support biomarker discovery, particularly for common chronic diseases, came in 2002 through the International HapMap Project, a collaboration among scientists and funding agencies from Japan, the United Kingdom, Canada, China, Nigeria, and the United States [7] . A haplotype is a set of SNPs on a single chromatid that are associated statistically. This rich resource not only mapped over 3.1 million SNPs, but established additional capacity for identifying specific gene markers in chronic diseases and represented a critical reference set for enabling population- based genomic studies to be done that could establish a gene-environmental basis for many diseases [8].

Within a short time of completing the description of the human genome, a substantial information base was in place to enable disease-gene discoveries on a larger scale. This approach to referencing populations to the well-described SNP maps is now the major undertaking for defining gene - based biomarkers. In recent years, research groups around the world have rapidly been establishing genome- wide association studies to identify specific gene sets associated with diseases for a wide range of chronic diseases.

This new era in population-based genetics began with a small-scale study that led to the finding that age-related macular degeneration is associated with a variation in the gene for complement factor H, which produces a protein that regulates inflammation [9]. The first major implication in a common disease was revealed in 2007 through a study of type II diabetes variants [10]. To demonstrate the rapid pace of discovery of disease gene variants: At the time of this writing, within 18 months following the study, there are now 18 disease gene variants associated with defects in insulin secretion [11].

The rapid growth in genome-wide association studies (GWASs) is identifying a large number of multigene variants that are leading to subclassification of diseases with common phenotype presentations. Among the databases being established for enabling researchers public access to these association studies is dbGaP, the database of genotype and phenotype. The database, which was developed and is operated by the National Library of Medicine's National Center for Biotechnology Information, archives and distributes data from studies that have investigated the relationship between phenotype and genotype, such as GWASs. At present, dbGAP contains 36 population-based studies that include genotype and phenotype information. Worldwide, dozens if not hundreds of GWASs are under way for a plethora of health and disease conditions associated with genetic features. Many of these projects are collaborative, involve many countries, and are supported through public-private partnerships. An example is the Genomics Association Information Network (GAIN), which is making genotype-phenotype information publicly available for a variety of studies in mental health disorders, psoriasis, and diabetic nephropathy [ 12] . For the foreseeable future, substantial large -scale efforts will continue to characterize disease states and catalog genes associated with clinically manifested diseases.

As technology and information structures advance, other parameters of genetic modifications represent new biomarker discovery opportunities. The use of metabolomics, proteomics, and epigenomics in clinical and translational research is now being actively engaged. A new large-scale project to sequence human cancers, the Cancer Genome Atlas, is focused on applying large-scale biology in the hunt for new tumor genes, drug targets, and regulatory pathways. This project is focused not only on polymorphisms but also on DNA methylation patterns and copy numbers as biomarker parameters [13]. Again, technological advances are providing scientists with novel approaches to inferring sites of DNA methylation at nucleotide-level resolution using a technique known as high - -hroughput bisulfite sequencing (HTBS). Large - scale initiatives are also under way to bring a structured approach to relating protein biomarkers into focus for disease conditions. Advances in mass spectrometry, protein structure resolution, bioinformatics for archiving protein-based information, and worldwide teams devoted to disease proteomes have solidified in recent years. Although at a more nascent stage of progress in disease characterization, each of these emerging new fields is playing a key complementary role in biomarker discovery in genetics and genomics.

Supporting this growth in biomarker discovery is massive investment over the last 10 years worldwide by public and private financers that has spawned hundreds of new commercial entities worldwide. Private-sector financing for biomarker discovery and financing has become a major component of biomedical research and development (R&D) costs in pharmaceutical development. Although detailed budget summaries have not been established for U.S. federal funding of biomarker research, in a recent survey by McKinsey and Co., biomarker R&D expenditures in 2009 were estimated at $5.3 billion, up from $2.2 billion in 2003 [14].

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