Novel cell line gives clues to pathogen actions

Scientists at the Whitehead Institute for Biomedical Research have developed an unusual line of human cells they have used to explore which genes help disease pathogens such as viruses and bacteria do their dirty work.

The findings by the researcher team at Whitehead could one day lead to novel ways to prevent or treat the disease the pathogens cause.

Human cells normally have 23 pairs of chromosomes, with one half of the pairs coming from the father and the other half from the mother. There are 22 pairs of chromosomes known as autosomes and a pair of sex chromosomes. Women have two X sex chromosomes and men have one X and one Y chromosome. The cells lines created in the laboratory of Whitehead researcher Thijn Brummelkamp have only one each of the autosomes, except for a pair of chromosome 8, plus one X and one Y chromosome.

The Whitehead team then systematically disabled, or "knocked out," each of the genes on the chromosomes in the experimental cell line and studied how they responded when exposed to pathogens. The genes carry the information cells use to produce protein molecules.

"We were surprised by the clarity of the results," says Jan Carette, a postdoctoral researcher in the Brummelkamp lab and the first author of report on the research published in the journal Science. "They allowed us to identify new genes and proteins involved in infectious processes that have been studied for decades, like diphtheria and the flu."

For example, the Whitehead team believes it has uncovered the genes involved in the early stages of the interaction of pathogens and the host cells they invade. The work of using knocked-out cells to screen for human diseases is only beginning, according to Brummelkamp, who has been studying the actions of individual genes since coming to Whitehead in 2004 from the Netherlands Cancer Institute, in Amsterdam. The Whitehead Institute for Biomedical Research is part of the Massachusetts Institute of Technology.

"Having knockout cells for almost all human genes in our freezer opens up a wealth of biological questions that we can look at," Brummelkamp said. "In addition to many aspects of cell biology that can be studied, knockout screens could also be used to unravel molecular networks that are exploited by a battery of different viruses and bacteria."

The research was funded by the Portuguese Foundation for Science and Technology, in Lisbon, and the Sydney Kimmel Foundation for Cancer Research, in Baltimore.