A still faster method for finding good drug targets, and even beginning to test potential drugs, forgoes model organisms and heads directly for the cells themselves. The technology is known as “cellular phenotyping,” where “phenotype” is the genetic lingo for how a particular gene manifests itself in an organism-from blue eyes, for instance, to a propensity for certain cancers. In a cell, those traits might translate into the presence or absence of a particular pigment or a tendency toward irregular size and shape. Because vast numbers of cells can be grown quickly and tested in parallel, cellular phenotyping not only speeds the process of elucidating a gene’s function, it opens the possibility of testing thousands or millions of potential drugs aimed at a particular target all at once. “You have to query the cell,” says Brent Stockwell, a chemist at the Whitehead Institute. “Ideally, you would start with diseased cells and then look for chemicals that would simply convert them back to normal cells.”At Aurora Biosciences in San Diego, CA, for instance, researchers have created methods to measure in living cells the performance of the primary types of proteins that are known to be defective in diseases-and their accompanying cellular circuitry. Proteins called ion channels, for example, carry charged molecules back and forth across the membranes that surround cells and play key roles in maladies ranging from heart disease to diabetes to depression. That makes ion channels prime drug targets, but they are difficult to study because they only work when they’re actually embedded in the membranes of living cells.
Aurora’s technology to measure ion channel function uses a pair of fluorescent dyes that can be poured onto human cells growing in culture and then affix themselves to the cell membrane, one on the outside and one on the inside. Once attached, explains Paul Negulescu, senior vice president of discovery biology at Aurora, the dyes will respond to changes in the electric field across the cell membrane, which are controlled by ion channels. If the channels are conducting ions as they should be, then one of the dyes will glow. If they aren’t, then the other dye will turn on. To study a particular ion channel that might make a good drug target in treating a particular disease, says Negulescu, Aurora researchers can genetically engineer test cells to produce that channel, or in some cases work with cells that mimic the disease. They use an automated process to put the cells into thousands of separate wells on an “assay plate” and add the dyes; they can then test thousands of potential drugs per plate, perhaps 100,000 a day, looking for the ones that modulate the channel in a way that might cure the disease with a minimum of side effects.
Since Aurora first developed the technology, many of the major pharmaceutical companies have either licensed it or hired Aurora to develop custom variations of it. Aurora has also formed a consortium with Bristol-Myers Squibb, Merck, Pfizer and the Parke-Davis division of Warner Lambert to develop the technology further. In July, Vertex Pharmaceuticals acquired Aurora for about $600 million, in the hopes cell phenotyping will help bring more novel drugs into the pipeline and, says Vertex CEO Joshua Boger, help to more quickly unravel the biological workings of drug candidates already in development.
Ultimately, the more biological information pharmaceutical companies can acquire-and the faster they can acquire it-the more likely it is they’ll survive in the postgenomics world. “At the end of the day,” says biotech pioneer David Goeddel, who helped develop some of the industry’s first drugs, “those that have the best understanding of the biology are going to have the best success getting drugs out.”