Click photo for a larger view. “Our study showed that during normal life, beta cells are generated by proliferation of pre-existing beta cells.”

I believe the paper is cited so frequently because it touches upon a significant controversy in the field of pancreas biology, with implications for future therapies for diabetes, namely the cellular origins of pancreatic beta cells. Our finding that most beta cells are generated by self duplication contrasted with the widespread belief that beta cells originate from adult stem cells. The reminder that terminally differentiated cells have a dramatic proliferative capacity has implications also for the role of adult stem cells in other tissues.

Apart from the basic discovery about the origins of beta cells, we have introduced in the paper a novel, unbiased method for determining the cellular origins of a tissue of interest, termed "genetic pulse-chase." This method, based on cre-lox technology, can now be applied for determining the in-vivo roles of adult stem cells in other organs.

The significance of the paper in layman’s terms: a future cure for type 1 diabetes, where the body destroys its own insulin-producing beta cells, will likely be based on transplanting patients with beta cells. Since cadaveric beta cells suitable for transplantation are very rare, major research efforts are devoted for generating a large supply of beta cells in the laboratory. The starting material for such experiments can in theory be freshly isolated beta cells, adult stem cells, or embryonic stem cells. Our study showed that during normal life, beta cells are generated by proliferation of pre-existing beta cells. This finding casts doubt on the popular view that adult pancreatic stem cells are key for generating new beta cells, and in fact challenges their mere existence. Therefore, efforts for generating new beta cells might be more productive if focused on expanding differentiated beta cells, or on controlling the differentiation of embryonic stem cells.

In 2001 I came to Harvard University as a post doctoral student with Doug Melton because I wanted to study stem cells in a top laboratory. My plans were to work on adult pancreatic stem cells and their potential contribution to beta cell regeneration. But before doing that, we just wanted to formally confirm that pancreatic stem cells do exist and indeed contribute significantly to the generation of new beta cells. Two years later we were quite surprised to discover that the major source for new beta cells is in fact pre-existing beta cells, not adult stem cells.

The paper can contribute to the ongoing debate over the use of human embryonic stem cells (hES). Opponents of hES argue that adult stem cells present a scientifically sound and morally acceptable alternative to embryonic stem cells. Our study casts doubts on the potential of adult stem cells for diabetes therapy, and suggests that pre-existing beta cells or human embryonic stem cells offer a better chance for a cure. Since approaches for expanding differentiated beta cells have not been successful so far, it is possible that human embryonic stem cells will remain as the only solution for curing type 1 diabetes.