Protein Legacy From Celibate Cells

With no thoughts of having children, monks and nuns and worker bees can dedicate themselves to a life of selflessly serving others. Now, researchers have put abstinence to work in mammalian cells: When prevented from dividing, the cells crank up their protein output 30-fold. Reported in this month's issue of Nature Biotechnology, the advance should be a boon to pharmaceutical companies that use mammalian cells as factories for therapeutic proteins.

Most cells in culture spend much of their energy replicating DNA and growing so that they can split into two daughter cells. James Bailey of the Swiss Federal Institute of Technology in Zurich and his colleagues hoped that by halting cell division, they could channel extra energy into making commercial proteins. (Although researchers have been using a similar technique with bacteria for years, mammalian cells have proven trickier to control.) The team targeted two genes, called p21 and p27, that help to delay the onset of division until the proper time. By increasing production of those genes, the researchers thought, they might be able to prevent cell division altogether.

The team outfitted hamster cells with a circular piece of DNA, called a plasmid. They included genes for three proteins: p21, C/EPBa to prevent the p21 protein from breaking down, and SEAP--the secreted protein they wanted the cells to produce. After 3 days, the cells had stopped growing and were churning out 10 to 15 times more SEAP than were cells that only overexpressed p21. In another experiment, the researchers included both p27 and a gene that prevents aging cells from committing suicide. These engineered cells produced 30 times more SEAP than did cells that were able to divide.

The advance comes just in time, says chemical engineer Eleftherios Papoutsakis of Northwestern University. Doctors are finding more and more therapeutic uses for proteins that can be made only in mammalian cells, such as erythropoietin--a red blood cell growth factor used to treat anemia--and antibodies against cancer. With an increased demand for such proteins, production "will soon face a dramatic bottleneck," he says. "We need all the help we can get."

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