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Two Papers May ‘Open Door’ to Human Trials for Man-Made Stem Cells, Pfizer Says

Results of two widely reported studies showing that human fibroblasts can be reprogrammed into pluripotent stem cells exhibiting the essential characteristics of embryonic stem cells may help “open the door” for stem cells to play a role in clinical research, according to one official from drug giant Pfizer.
John McNeish, a senior director of global research and development at Pfizer, also cautioned that the methodologies outlined in the papers must overcome several hurdles before they can be used in drug development.
The studies could also eventually be a boon for tool vendors in the stem-cell space because the reagents used to isolate, characterize, expand, and differentiate the so-called human-induced pluripotent stem (iPS) cells are the same as the ones used with human ESCs, according to Joydeep Goswami, vice president of stem cells and regenerative medicine at Invitrogen.
Writing in last week’s Science and the current Cell, researchers in the US and Japan claim that their human-induced pluripotent stem cells have normal karyotypes, express telomerase activity, express cell-surface markers and genes that characterize hESCs, and have the potential to differentiate into advanced derivatives of all three primary germ layers.    
McNeish said the findings “are really going to open up the door for patient-specific pluripotent cells that can be used everywhere from idea generation down to identifying the correct genotypes for clinical trials.”
He said he suspects that iPS cells will soon begin replacing bona fide embryonic stem cells in drug discovery just as stem cells have recently begun replacing traditional cellular material in drug discovery.
“I think that within a year, we could easily see a lot of information about the potential of these cells to differentiate into clinically relevant cell types and opportunities for their application within drug discovery,” said McNeish.   
But McNeish, who did not participate in either study, also cautioned that the human-induced pluripotent stem cells still require a lot of basic research, characterization, and molecular profiling before they can play a role in human studies.

“I think that within a year, we could easily see a lot of information about the potential of these cells to differentiate into clinically relevant cell types and opportunities for their application within drug discovery.”

In addition, the researchers, who used 293FT cell line vectors and molecular biology tools made by Invitrogen, must learn how scalable their technology is and whether the resulting cells can be formatted for HTS assays, he said.
At least one of the scientists agreed. According to Ron Stewart, bioinformatics team leader at the WiCell Research Institute and an author on the Science paper, one issue to consider is that the viral vectors used by both groups to introduce the four factors to transform the fibroblasts also integrate into the genome, and therefore have the potential to introduce mutations.
He also pointed that one of the four transforming factors used in the Cell research, c-Myc, has tumorigenic potential. Subsequently, Yamanaka’s team announced that it had been able to generate iPS cells from mouse and human fibroblasts without Myc. Their work was published online in Nature Biotechnology.
Eve Herold, director of public policy, research, and education at the Genetics Policy Institute, said that these issues will have to be resolved. “The upshot is that this work is proof-of-principle,” she said.
Herold, who did not participate in either study, said that the findings do not mean that researchers can quit studying embryonic stem cells. “What I am hearing from the scientific community on this is that it is too soon to shut down ESC research because we know that when we use true ESCs we have normal cells; we do not have a cell population like iPS cells, one fifth of which are destined to become cancerous.”
Another hurdle is that the iPS cell lines portrayed in the Science and Cell papers have not been replicated for as many passages as human ESCs, said R. Alta Charo, a professor of law and bioethics at the University of Wisconsin at Madison.
In addition, the cells have not been tested for as many variations on direct differentiation as hESC cells.
“More work must be done to check iPS cells against the hESC gold standard before they become the source materials for drug-discovery assays,” Alta Charo said.
She added that she was “surprised by the relative lack of public excitement” that pharmaceutical companies showed when the studies were published, especially over the potential of iPS cells to make drug discovery ”cheaper and safer and faster.”

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