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Living Array Speeds Gene Research

Cells do all the work in a novel biochip that might shorten the path to safer drugs.

Microarrays of living cells could provide a shortcut to the development of safer drugs and a fuller understanding of the human genome. The new lab technique, developed by a research team at the Whitehead Institute for Biomedical Research in Cambridge, MA, is outlined in the May 3 issue of Nature.

Testing Goes Whole Cell

DNA chips-fingernail-sized microarrays that can analyze thousands of genes at once-have been around for the last five years. But the new cell microarray takes the idea of massive parallel analysis in a new direction.

David Sabatini and his research team began by printing an array of about 200 DNA samples-each corresponding to a particular gene-onto a glass slide. The slide was then placed in a culture of mammalian cells, which adhered to and covered it. (With conventional DNA chips, genes, rather than living cells, are applied to the DNA on the chip surface.)

The cells that came into contact with DNA absorbed it. By dividing, they formed distinct cell clusters, each manufacturing the particular protein encoded in the absorbed DNA. (Genes are recipes for proteins.) The remaining cells surrounded these clusters, acting as controls. The result is a living array of gene expression, giving researchers a unique test bed in which to experiment with gene and protein behavior.

Loosening the Drug Bottleneck

When a pharmaceutical company develops a drug, the challenge isn’t only to find molecules that do the right things in a test tube. It’s also to make sure that they don’t do the wrong things in patients.

If a drug molecule finds the right protein but inadvertently binds to a host of other proteins as well, that translates into unwanted side effects for the patient. Finding substances that cause few, if any, side effects is a major bottleneck in current drug discovery-one that Sabatini’s cell microarray could loosen.

As a proof-of-concept experiment, Sabatini tested two drugs. One targeted a protein found inside a cell. The other targeted a cell-membrane protein (most drugs bind to proteins on a cell’s membrane). In both instances, he reported that the binding properties of drug molecules could be clearly observed in a cell microarray.

Sabatini says a single microarray could express a large percentage of the human genome. By adding to it a drug whose function or side effects are unknown and observing the binding pattern, one could, in a single day, come up with results that would otherwise take months to accumulate.

Many labs are counting on protein chips to do just that, when-and if-a commercially viable product enters the market. However, proteins are notoriously unstable and difficult to purify outside their natural environment. Moreover, membrane proteins, which drug companies care most about, can’t exist apart from the cell membrane.

Sabatini’s cell array “makes the protein for you,” he says. “You don’t even have to purify it. And it’s made in the right place, so if it’s a membrane protein, it goes right to the membrane.”

“This technology could have a big impact on high-throughput screening for new drug candidates and new drugs,” says Yale biologist Ron Breaker. “It’s a great example of what array technologies can achieve-the miniaturization of biological assays and the massively parallel analysis of genes and proteins.”

Sorting Out the Genome

In another experiment, Sabatini’s team again prepared a slide with an array of 200 genes. But this time, rather than simply using each cell cluster as a “drug-testing factory,” they examined the effects of the genes themselves on the cells. (Although they were using genes with known functions, the experiment was conducted as a blind test.)

They observed that certain genes killed the cells, others caused the cells to stick together, and others activated certain signaling pathways in the cells. All these observations were verified when they looked up the function identified for each gene.

The implications of this experiment are potentially far reaching. Within two years, every one of the roughly 30,000 human genes will be copied and catalogued in DNA “libraries.” At the same time, cell microarrays containing up to 10,000 cell clusters each should be possible, says Sabatini.

By printing the contents of a DNA library onto a series of cell microarrays, a researcher could hold in one hand a set of slides on which the entire human genome is being expressed-each cell cluster a microscopic theater displaying the behavior of a particular gene.

Limits to Cell Array Growth

To Joshua LaBaer, director of Harvard Medical School’s Institute of Proteomics, the cell array is “a beautiful technique.” But he cautions that “not all cell types work for the system yet,” and some experiments might require a different method of DNA absorption.

The cells that Sabatini used were grown over many generations in labs and readily absorb genes. But primary cells taken directly from an organism do not. In such cases, DNA absorption can be facilitated by infection with a viral agent.

In addition, the cell array can only disclose a gene’s function on a cellular level. It can’t show how genes affect interactions on a larger scale.

No single microarray technology can provide all the answers. But as the arsenal of microarray techniques increases, we’re that much closer to unraveling the secrets of the genome-one gene at a time.

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