A faster way to chart pathways to genetic discovery

On June 26, 2000, Celera Genomics and the Human Genome Project announced two far-reaching developments in the understanding of human genetics. Celera Genomics researchers have completely assembled the human genome, meaning they have determined the correct order of the 3.12 billion rungs on the double helix ladder that is our genetic code. The Human Genome Project now has a working draft of the entire human genome, showing where genes are located on our 23 chromosome pairs.

These complementary developments have been called "the end of the beginning" and "the starting line, not the finish line." With this information in hand, scientists and researchers now begin the long, difficult work of analyzing and annotating the genome, which means deciphering the function of each gene. This will likely take several years, but eventually we will know which genes are useful for treating diabetes, Alzheimer's disease, cancer, and more.

Changing the nature of medicine

A disease is a complicated mechanism that produces a whole set of biological events in the body. Researchers call that chain of events a "disease pathway" and charting its course is one of their primary goals. Already, abnormalities in single genes have been linked with cystic fibrosis and sickle cell anemia, while mutations in multiple genes have been associated with cancer and diabetes. Once researchers know the pathway they can then focus on finding the best point on the path to intervene.

Understanding the function of each gene in the cancer pathway, for example, is important for developing both diagnostic tests and treatments. Once the functions are known, specialists can design drugs for the specific purpose of inhibiting or activating particular genes in the pathway. Identification of cancer-associated genes can also lead to the development of specific diagnostic tools potentially allowing easier and speedier diagnosis of particular types of cancers.

Cracking the code

Researchers are using computers and automated analysis equipment to look at more pieces of the genetic puzzle simultaneously. One way to understand which genes do what is called "gene expression monitoring," which is the process of measuring the activity level of genes during specific stages of cell activity. Those stages typically involve cells that are healthy, diseased, or have been treated with a drug or other substance.

Relatively new devices called "DNA microarrays" are accelerating such tests by allowing analysis of thousands of genes simultaneously. A microarray is composed of a microscopic set of specific DNA fragments attached to a glass, plastic or silicon slide in a grid-like pattern. These fragments are called "probes" and they will react with samples -- usually from diseased or treated cells -- that are added to the slide. For each experiment, here is the basic process:

Agilent Technologies laser-induced fluorescence scanner for DNA microarray analysis.

• start with an off-the-shelf chip containing a well-understood set of probes that represent specific genes, or create a custom microarray with specific probes of interest
• add the sample material to the array of probes on the slide and allow the sample to bind specifically to the various genes represented on the chip
• read the amount of each gene present in the sample by putting the microarray into an automated system such as the Agilent Technologies laser-induced fluorescence scanner
• analyze the results with software that can process thousands of reactions at a time

This last step is called bioinformatics, which is the use of powerful computers and sophisticated algorithms to process the large volumes of data produced in complex experiments. As the number of genes represented on the DNA microarray increases, the process gets faster but the data management and analysis problem gets bigger. Agilent offers a solution: the Rosetta Resolver™ expression data analysis system combines hardware, software and database architecture to enable storage, retrieval and high-level analysis of massive volumes of gene expression data.

"Number of arrays per day" is one measure of progress, and the ability to do more gene expression analysis every day helps accelerate the discovery process. However, just as crucial is having the right microarray for each experiment. This is possible through Agilent's Technology Access Program (TAP), which provides preferential and early access to DNA microarray technology. Researchers can access this technology by subscribing to an integrated service program that includes custom, on-demand microarrays. Through rapid, affordable iteration of array design and manufacture, TAP subscribers can quickly arrive at gene expression solutions optimized to meet their needs.

Better treatments sooner

Computer-generated fluorescence image of a scanned DNA microarray from the angiogenesis research project. Colors represent cell stage and gene activity level (inset shows detail).

Tools such as bioinformatics and custom DNA microarrays promise to reduce the time it takes to chart a complete biological pathway. As an example, a group at Agilent Laboratories, our central research facility, is collaborating with a team in the Cardiology Department of Stanford University to gain a more detailed understanding of angiogenesis, the process by which blood vessels form. Angiogenesis is critical to the development of blood vessels as well as the progression of cancer, arthritis, and numerous inflammatory diseases. This makes it an attractive target for new medical treatments.

The Stanford team has isolated thousands of genes that may play a role in angiogenesis and Agilent has created custom DNA microarrays containing probes for that collection of genes. Those microarrays will reduce the time required to validate which genes are involved in angiogenesis and then explore the various connections between these genes. From that, the next step is to order the genes into the specific, complex pathways of angiogenesis. The resulting gene set will advance the understanding of the molecular mechanisms of angiogenesis and will pinpoint ideal targets for specific therapeutic initiatives.

For more information

Agilent is committed to providing the highest caliber tools to enable new discoveries in life sciences. To learn more about our products, solutions and services, please visit the DNA microarray and Chemical/Biochemical sections of the Agilent Web site.

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