Two early online papers in Cell and Sciencexpress, respectively, reported this week that by adding four factors to human fibroblasts via retroviral insertion, researchers have turned them into induced pluripotent stem cells, or iPS cells, that are almost indistinguishable from embryonic stem cells.

The work "changes everything and nothing," James Thomson, senior author of one of the papers, told reporters at a press conference.

The papers represent a breakthrough of rare magnitude in basic research, and have the potential to cut the Gordian knot of ethical and regulatory issues associated with human embryonic stem cells. But Thomson stressed that iPS cells are as unproven medically as human embryonic stem cells, though they open up a plethora of research possibilities and removing the controversy around embryonic stem cells likely will make the field more attractive to scientists and businesses alike.

Thomson said that human embryonic stem cells "unleashed a storm of controversy" when they were first isolated in his lab a decade ago. The new findings, he said, mark "the beginning of the end of that controversy."

For now, the technique is not ready for prime time, at least if one considers prime time to be its use inpatients. The retroviral vectors used to transform the cells present a major safety issue for their use on patients.

Shinya Yamanaka, senior author of the Cell paper, conceded the basic point, telling BioWorld Today via email that "we have to find a way to avoid retroviruses before application in cell therapy."

But, he added, "the most immediate usage of iPS cells is in drug discovery and toxicology. For this purpose, the retrovirus is not a big problem."

The work also has an interesting scientific twist that goes even beyond its fundamental importance to stem cell research: it's not the same four factors in each paper.

In a publication that will appear in the Nov 30, 2007, print issue of Cell, Yamanaka and his colleagues reported that by adding Oct3/4, Sox2, KLF4 and the oncogene c-Myc to adult human fibroblasts via retroviral insertion, they were able to make cells resemble embryonic stem cells in their ability to divide and turn into different cell types. The team had reported the same feat with mouse fibroblasts last year.

The paper in the Nov 21, 2007 issue of Sciencexpress, by Thomson and a group of colleagues also reports on transforming neonatal and fetal fibroblasts into pluripotent cells. Like the authors of the Cell paper, the authors of the Sciencexpress paper - which will appear in the Dec. 21, 2007, print issue of Science - use Oct3 and Sox2 to coax their cells back into an embryonic stem-cell-like state. But instead of KLF4 and c-Myc, the cells in the Sciencexpress paper were transformed with Nanog and Lin28 in addition to Oct3 and Sox2.

The reasons for those minor discrepancies are not clear at this point; a news story accompanying the Sciencexpress paper reported that Japanese scientists saw no effect of Nanog, and did not uncover Lin28 as a pluripotency factor in their initial screening, while the Wisconsin group was not able to induce pluripotency using the factors that led to success in the Cell paper.

Thomson suggested his own group might not have used the four factors identified by the Cell paper in the correct ratios, which appear to be critical for success.

And Yamanaka said that even he had been skeptical initially whether the method that transformed mouse cells would work on human cells, since "human embryonic stem cells are different from mouse embryonic stem cells in many aspects, including morphology and cytokine dependency."

Indeed, initial attempts to use the same four factors that had been successful with mouse fibroblasts did not pan out. "When we cultured fibroblasts in mouse ES cell condition after introduction of the four factors, we could not obtain iPS cells," Yamanaka said.

Only after changing the culture conditions was Yamanaka's team able to get iPS cells. This led him and his team to "speculate that the fundamental transcription network is common between human ES cells and mouse cells, but exogenous factors and intracellular signals to maintain the network are unique in each species."

In response to reporter questions, Thomson strongly defended the continuation of human embryonic stem cell research, calling those cells the "gold standard" against which to measure iPS cells and noting that if the iPS cells proved to be as good as true embryonic stem cells, the research community naturally would switch to them over time.

And Yamanaka noted that the iPS cells create their own ethical problem by the very fact that they are so similar to embryonic stem cells. "It might be possible to generate sperm and eggs from skin cells, via iPS cells," he said. "This might help people with infertility problem, but it will be essential to have a proper regulation regarding the generation and usage of human iPS cells to avoid misusages of this technology."