Their findings may help scientists understand cancer process
Benjamin Franklin's maxim that the only certainties are death and taxes may yet be obsolete on one count. A team of Brown researchers has disrupted the natural progression of division and death in human cells, endowing the cells with an extended life span.
Reporting in the journal Science, the researchers describe how they can temporarily thwart the aging process by removing a gene, dubbed p21, from ordinary human cells cultivated in the lab. Cells without the gene divide up to 30 additional generations before they die.
The researchers are associate professor John Sedivy, former postdoctoral associate Jeremy Brown and graduate student Wenyi Wei. They modified a gene "knockout" method that is routinely employed to genetically engineer mice for scientific research, and used the technology to remove the p21 gene from human cells. The "knockout" method used by the Brown researchers allows for precise, specific changes in manipulating human cells.
"For obvious ethical and medical reasons, we can't make a knockout human, and we're not going to clone a human, so this is as close as we can get," said Sedivy, who conducts cancer research in J. Walter Wilson Lab. Because cancer cells appear to possess an infinite life span, the finding may provide insight into how human cells are immortalized into tumor cells, a very important step in understanding the cancer process, he says.
Moreover, the finding has broad implications for fighting diseases because it would allow scientists to study genetically varied human cells without the need to alter human beings to produce such cells. In scientific research, the preferred method of studying a gene's role is to remove it, eliminating its function. Knockout mice, for example, are used as models of human disease, such as cystic fibrosis, which can be induced in mice by removing one or more of their genes. Potential gene therapy treatment for cystic fibrosis involves implanting nonreproductive, or somatic, cells into people with the disease to introduce the missing genetic material.
However, mice and humans differ in important ways.
"Mice are not a good model for researching many diseases in humans," said Sedivy. "Rodents, for example, make poor models for studying human cancer. That's another good reason to be able to manipulate human cells genetically."
Indeed, the Brown research may have important gene therapy implications. "There is no reason we couldn't take cells from a patient, alter them, and put them back in that patient," Sedivy said. "That's exactly what a lot of gene therapy trials are doing now, but they are using less sophisticated methods." Sedivy and Yale collaborators have an NIH grant application pending to explore use of their "knockout" process for gene therapy.
The Brown research also makes inroads into one of the least understood biological fields: the molecular mechanisms of human aging. Sedivy says there are two general aging theories. First, that people grow old and die because their bodies simply wear out. Second, that a genetic program determines how long we live. Even if a person does everything possible not to wear out his or her body, a genetic program may still kick in and the person will age and die.
"There is something to be said for the theory that we age because the machine just wears out," Sedivy said. "But very compelling evidence exists that there may be a genetic program such as a molecular clock that's on in all cells in the body, irrespective of how you've taken care of yourself." His research may have implications for tinkering with the aging process.
"These findings are the best evidence yet that senescence, the mechanism behind growing old, is a real thing," Sedivy said. "We think we are looking at the molecular mechanism that actually determines senescence. Our goal is to understand and describe that mechanism."
Sedivy hopes the research may allow scientists to draw a picture of exactly how human cells age and die. The aging process is much more complicated than the activities of one gene, he says.
"We probably have to alter a bunch of genes before human cells become immortalized. But we think this finding is an important incremental step, because there are probably not a lot of genes involved, maybe a half-dozen at most."