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Human Genome News, January-March 1996; 7(5):1

Collaborations Multiply Research, Commercial Benefits

Academic, National Laboratory, Industrial Innovations Yield Chromosome Painting, Merck Gene Index

Collaborations among researchers in academia, national laboratories, and industry are yielding important benefits for genomic research and the broader biomedical research community. Two outstanding examples, the chromosome painting technology and the Merck Gene Index Project, are described below.

Chromosome Painting Reveals Cancer, Other Diseases

In September 1995, a broad patent was awarded to the University of California (UC) for "chromosome painting," a technology that uses FISH to stain specific locations in cells and chromosomes. Chromosome painting was invented by Joe Gray and Dan Pinkel during their tenure at Lawrence Livermore National Laboratory (LLNL), which is managed for DOE by UC. Licensed exclusively to Vysis Inc., the technology will be made widely available through a nonexclusive sublicensing program.

The innovative approach uses specifically tailored, fluorescently labeled probes that hybridize (bind) with genes or whole chromosomes of interest. The patent covers the use of nonfluorescent "blocking DNA" that prevents nontargeted DNA from being fluorescently stained. After the probes are applied, the results can be seen in a standard fluorescence microscope. Gene amplifications, deletions, or abnormal rearrangements in individual cells are revealed so that missing or extra pieces of chromosomes can be identified. Such genetic abnormalities often provide the first signs of cancer and other diseases.

"We have used these techniques to elucidate genetic changes in a broad range of human diseases including breast, prostate, and colon cancers," said coinventor Gray. "They also appear to have substantial usefulness in prenatal and neonatal detection of genetic diseases such as Down's syndrome, as well as in detecting genetic damage after exposure to radiation and other toxic agents."

According to John Bishop, president of Vysis, the patent is a cornerstone in developing a new generation of tests that not only detect cancer and genetic diseases but provide valuable information regarding disease prognosis and predisposition. Larry Fox, vice president of Technology and Business Development, added, "The use of this technology for the detection of disease is currently in its infancy and will emerge in the next 10 years into a multibillion-dollar market."

Continued development in this area of technology is one of the major goals of The Resource for Molecular Cytoge-netics, established in 1993 and funded by DOE, NIH, and Vysis. The Resource is a partnership between the University of California, San Francisco (UCSF), and Lawrence Berkeley National Laboratory (LBNL), which is also managed by UC. The Resource integrates the technical capabilities of the LBNL Human Genome Center with cancer genetics expertise at UCSF and the Life Sciences Division of LBNL. According to Gray, "The Resource serves as a source of new hybridization technologies, computer-aided fluorescence microscopy capabilities, and probes optimized for molecular cytogenetic studies."

The international molecular cytogen-etics community has already begun to tap successfully into The Resource. A public database featuring available probes, along with a request form, can be accessed via WWW (http://rmc-www.lbl.gov).

[David Gilbert, LBNL, david_gilbert@macmail.lbl.gov]

Merck Gene Index Project

In September 1994, Merck & Co. and Washington University announced plans for a publicly available collection of expressed human gene sequences based on high-quality cDNA clones from normalized libraries. Since then, the project has contributed over 220,000 sequences to the public database dbEST, amounting to over 75% of the reported human ESTs in that database. Merck plans to use these sequences to organize the characterized clones into a minimal set representing each unique identified human gene an index to the genome that will also be made available.

By promoting free data exchange, the project aims to reduce duplicated efforts and speed identification of disease-related genes. Increased accessibility of sequence data and cDNA clones provides starting points for research that will lead ultimately to new targets for drug design, expressed proteins with potential therapeutic value, and discovery of disease-related genes that may become the focus for gene-therapy regimens. Making these basic research tools broadly available to the biomedical community may lead to breakthrough discoveries that will benefit the public by providing opportunities and preserving incentives for gene-based product development.

Collaborators. The Merck-supported sequencing project is conducted at the NIH-sponsored Genome Sequencing Center at the Washington University School of Medicine, St. Louis. Successful large-scale sequencing efforts and demonstrated expertise in EST sequencing and informatics led Merck to select the sequencing center to generate ESTs from both ends of more than 150,000 cDNA clones. The center has contributed to genome sequencing efforts for the roundworm Caenorhabditis elegans, the yeast Saccharomyces cerevisiae, and human. Currently, the center's sequencing capacity is about 14 Mb per year of finished sequence.

For the EST sequencing project, clones are arrayed at LLNL and sent to the center through the Integrated Molecular Analysis of Gene Expression (IMAGE) Consortium [HGN 6(6), 3 (March-April 1995)]. All the arrayed clones have preassigned GDB accession numbers. This standardizing feature helps integrate mapping data obtained from IMAGE clones used in such other projects as the gene map described in (related article).

The sequencing center sizes the clones by restriction digestion and imaging of agarose gels, after which sequencing is attempted from the 5' and 3' ends of each clone. Resulting EST sequences are subjected to quality-control procedures that include removing all vector and nonnuclear RNA sequences as well as any contaminating bacterial or yeast sequences. Sequences are annotated with similarity information, clone source, read orientation, and range of high-quality data and then submitted directly to dbEST. The sequencing center currently processes about 5000 sequences/week and has submitted sequences from more than 131,000 clones, making it the largest public EST sequencing effort.

Other cDNA sequencing collaborators include the NIH National Center for Biotechnology Information, which is publicly distributing sequence data through GenBank and dbEST. The Computational Biology and Informatics Laboratory (University of Pennsylvania School of Medicine) is integrating and checking data for consistency.

Immediate Data Release. Immediate distribution of sequence data to public databases allows all interested parties to access, analyze, and use the information as it is generated. No one has advance access, nor can any of the sequence data from the center be delayed or restricted. In the months following the first data release, dbEST usage increased over 1000%.

The data-release policy already is facilitating downstream projects. A Human Genome Organisation (HUGO) consortium is using the data to generate a high-resolution transcript (gene) map. The HUGO consortium includes the Stanford Human Genome Center and Whitehead MIT Genome Center in the United States; Oxford University, University of Cambridge, and Sanger Centre in the United Kingdom; and Genethon in France. This collaboration will facilitate the candidate-gene approach for mapping disease genes [HGN 6(6), 1-2 (March-April 1995)]. The EST sequencing initiative thus promises to help change the way gene expression is addressed and understood.

Unique Gene Index. A set of high-quality EST sequences and associated clones representing each unique gene is being generated by thoroughly analyzing the 3' untranslated regions from IMAGE clones. These efforts will eliminate low-quality sequences and generate a confidence assessment of each clone's validity as a unique human gene tag. Merck expects a coordinate release of the Merck Gene Index data set and associated cDNA clones as individual clones, clone sets, and high-density gridded filters. All cDNA clones incorporated into the index will be resequenced to verify their identities.

Keith Elliston, Merck & Co., keith_elliston@merck.com

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