PHILADELPHIA — Fifty years ago, UK researcher John Gurdon demonstrated that genetic material from non-reproductive cells could be reprogrammed into an embryonic state when transferred into an egg. In 2006, Kyoto University researcher Shinya Yamanaka expanded on those findings by expressing four proteins in mouse somatic cells to rewind their genetic clocks, converting them into embryonic-like stem cells called induced pluripotent stem cells, or iPS cells.

In early October, Gurdon and Yamanaka were awarded the 2012 Nobel Prize in Physiology or Medicine for their discoveries. Now, thanks to some careful detective work by a team of scientists led by Kenneth Zaret, PhD, at the Perelman School of Medicine, University of Pennsylvania, researchers can better understand just how iPS cells form – and why the Yamanaka process is so inefficient, an important step to work out for regenerative medicine. Zaret is associate director of the Penn Institute for Regenerative Medicine and professor of Cell and Developmental Biology.

The findings, which appear in the Nov. 22 issue of the journal Cell, uncover cellular impediments to iPS cell development that, if overcome, could dramatically improve the efficiency and speed of iPS cell generation.

“These studies provide detailed insights into how reprogramming factors interact with the chromatin of differentiated cells and start them down the path toward becoming stem cells,” said Susan Haynes, PhD, National Institute of General Medical Sciences, which partially funded the work. “Dr. Zaret’s work also identified a major structural roadblock in the chromatin that the factors must overcome in order to bind DNA. This knowledge will help improve the efficiency of reprogramming, which is important for any future therapeutic applications.”

Human iPS cells are generated by expressing four DNA-binding proteins – Oct4, Sox2, Klf4, and c-Myc (O, S, K, and M) – in human non-reproductive, or somatic cells, such as skin cells. These factors have generated intense interest in the stem cell and medical communities, not least because they offer the promise of embryonic stem cells with none of the messy ethical and moral dilemmas. Just as significantly, patient-specific iPS cells from individuals with genetic disorders can be used to study disease origin and to develop drugs for a range of conditions such as Huntington’s and Parkinson’s diseases.

Yet, the process of generating iPS cells is highly inefficient. It can take a month to fully reprogram somatic cells into iPS cells, and as few as one in 10,000 cells that take up the four factors will successfully convert. What’s more, some studies indicate that, for all their plasticity, iPS cells are not precisely equivalent to embryonic stem cells. Zaret, with Penn postdoctoral fellow Abdenour Soufi, PhD, and bioinformatician Greg Donahue, PhD, decided to find out why.

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