I cornered Harvard’s George Daley shortly after this afternoon’s opening symposium at the International Society for Stem Cell Research meeting in Philadelphia, and asked him for some stats and trends at the meeting. He’s the current president of ISSCR. There are 24,000 2,400 pre-registered attendees, he told me. That’s only 24 2.4 times the size of the last meeting I attended. As for trends: “There’s certainly a bit of Shinya-mania,” Daley said. He was referring to the focus on induced pluripotent stem cells (iPS cells), adult human cells reprogrammed to a stem cell-like state thanks to a couple of transcription factors by a Japanese group led by Shinya Yamanaka.

**Note updated numbers. It was a big meeting, but not that big! 24,000 would be getting into society for neuroscience range!

Daley wasn’t kidding. Cruising the poster session this evening, I was intrigued by the dense clump of bodies congregating around a handful of posters in one corner of the exhibit hall. All of them had to do with using variations on the so-called “Yamanaka factors.” Yamanaka used four, but there was a poster talking about using just two (Oct4 and Klf4) on adult neural stem cells with high efficiency. The work, presented by Vania Broccoli of San Raffaele Scientific Institute was drawing a crowd. Next to him Mali Prashant of Johns Hopkins was presenting data on reprogramming using non-integrating lentiviral vectors. John Dimos from Harvard was presenting work on developing models of the neurodegenerative diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) respectively in embryonic stem cells (retrieved from discarded embryos that had been diagnosed as carrying SMA associated mutations), and – you guessed it – induced pluripotent stem cells derived from the cells of adults with ALS. According to the poster, the SMA cells have a distinct phenotype with low numbers of motor neurons compared to other ES cell cultures that can be rescued genetically. The ALS cells are still being worked on. Dimos’ PI, Kevin Eggan, has been trying to do the same work modeling ALS through stem cell cloning, essentially dropping a nucleus into an egg and deriving embryonic stem cells from the resulting embryo. But eggs have been scarce.

Harvard’s Doug Melton, in a plenary talk this afternoon to open the International Society for Stem Cell Research (ISSCR) meeting in Philadelphia, actually didn’t talk about stem cells at all. Rather he discussed new results showing direct differentiation of pancreatic tissue into the elusive and important Beta cells, skipping stem cells altogether.

It was clear from the opening session, that a large part of the conference would focus not on the derivation of stem cells, but rather their re-differentation into useful tissues, which is not so easy as one might think. Take the beta cell for example. Melton has had a long-standing project to derive beta cells from es cells. The potential is obvious. For folks with type 1 diabetes, beta cells can be transplanted with limited success, but are currently in short supply (cells from two cadavers are required for the so-called Edmonton protocol).

After four years of work trying to use chemical compounds to edge stem cells down the developmental path of the insulin producing beta cells, he found two with 70% efficiency in moving the cells the very first step in a process that looks to contain maybe six. So, his group began experiments to short circuit the process. Rather than taking an undifferentiated stem cell, could one take a fully developed adult cell and switch its fate using transcription factors without reverting to stem cells? The answer, ostensibly seems to be yes. Screening for upwards of 1000 factors in 5000 mouse embryonic tissue samples, Melton’s lab identified 28 factors that appeared closely related to beta cell differentiation formation. Paring down brought the number to nine. Using a virus to inject the genes that encode these transcription factors into the pancreas of living mice, they were able to cause exocrine cells in the pancreas to start producing insulin and look just like beta cells in every way they’ve looked. Melton says, it’s “not the case that they’ve just turned on the insulin genes. There’s a panoply of genes turned on and off in response to these transcription factors.” They even started producing VEGF and promoting angiogenesis to get blood supply. The group has been able to reliably convert cells to insulin producing beta cells using just three of the nine genes: Ngn3, Pdx1, and Mafa. Mice in which islets had been chemically ablated achieved some level of blood sugar control, but not that of wild type. And despite waning expression of the three genes they injected, the phenotype of the transformed cells remained for several months. Melton says he wouldn’t necessarily predict a gene therapy approach based on his findings, but if in vitro technologies could be adapted, they might increase the number of beta cells for transplant operations. This type of cellular reprogramming involved here is fascinating. I remember when few believed de-differentiation from adult cells to pluripotent stem cells was possible with out the help of egg cytoplasm. iPS cells proved that wrong. This fate-jumping reprogramming without intervening de-differentiation is even more astonishing.