In a paper to be published online in the March 2008 issue of Nature Biotechnology, now available online, researchers from San Diego-based biotechnology firm Novocell Inc. reported that they have managed to generate insulin-sensitive pancreatic beta cells from embryonic stem cells.

"Human embryonic stem cells can now be considered a source to produce functional islets," Novocell Chief Science Officer Emmanuel Baetge told Bioworld Today. Novocell's goal is to use such cells in transplantation therapies for diabetic patients.

The paper, senior author Baetge added, "puts the third leg on the stool" of Novocell's work on human embryonic stem cells; it follows two other papers in which Novocell scientists inched closer to the goal of functional islet cells.

In their most recent paper, which was published in 2006, the Novocell scientists showed that after transplantation with so-called definitive endoderm cells derived from human embryonic stem cells, mice "made pancreatic endocrine cells with fairly high efficiencies . . . but they weren't fully functional," Baetge explained. The cells showed several characteristics of immature islet cells. Most importantly, they released insulin, "but not in response to glucose. That was a major deficit that they had," Baetge said.

In the current paper, the researchers switched their strategy to transplanting earlier-stage pancreatic endocrine cells - with success. The cells exhibit properties characteristic of functional adult pancreatic beta cells, including expression of critical beta cell transcription factors and enzymes that process insulin.

In a critical test of the cell's functionality, when the researchers used a toxin that selectively destroys mouse islet cells while leaving human islet cells intact, mice that had been transplanted with the pancreatic endocrine cells did not develop diabetes, showing that the transplanted cells turned into a sufficient source of insulin for normal glucose metabolism.

Just a few weeks ago, Belgian researchers reported that they have managed to identify and isolate adult stem cells that can make pancreatic beta cells. Asked how that affects Novocell's approach, Baetge said, "We are certainly sticking with our embryonic cells," adding that the Cell paper "in a way, validates the embryonic stem cell approach."

The methods used to generate adult stem cells, he explained, were "extreme" and involved ligating the pancreatic duct - something that is certainly not going to become the standard of care for diabetic patients no matter how many stem cells it creates. (The authors of the Cell paper nevertheless are more optimistic about their finding prospects for clinical relevance. In their paper, they call the progenitor cell "an obvious target for therapeutic regeneration of beta cells in diabetes" and propose "investigating the feasibility of . . . isolating facultative beta cell progenitors and newly formed beta cells from human pancreas in order to expand and differentiate them in vitro and transplant them in diabetic patients.")

Both papers do agree on the key importance of isolating those cells that express neurogenin 3. Baetge said that the interventions used in the Cell paper to identify adult progenitor cells switch on "the same process [of beta cell differentiation] that happens embryonically - in fact, it's the process that happens in our cultures."

Novocell also has developed an encapsulation technology whose goal it is to enable cell transplantation without the need for chronic immunosuppression.

Baetge said that the company plans to work on purification of the cells and scale-up of the process, which will allow the company to go forward with IND-enabling studies. If all goes well and the company finds a partner for the program, Novocell expects to file an investigational new drug application in 2011, he said.