Greetings from Belgium, land of beer, chocolate, moules frites and organic chemistry. I’m at the 11th Belgian Organic Synthesis Symposium (BOSS) in Ghent, and it has a line-up to die for: Hartwig, Du Bois, Enders, Shibasaki, Fuerstner and Trost, to name but a few.

The event kicked off with Erick Carreira giving a full day of talks, covering the many aspects of his work, from total synthesis to hardcore catalyst design. He was initially almost thwarted by microphone feedback reminiscent of the sound effects from Close Encounters of the Third Kind (only louder). For some reason, even in the 21st century, conference organizers can’t get microphones to work properly. But once the sound problems were overcome, the talks were great. There are very few people that I’d happily listen to all day, but Carreira is one of them.

While talking about his work preparing an analogue of Amphotericin B, Carreira mentioned something that has become a theme of the conference – the continuing importance of total synthesis. There has been much touting of metabolic engineering – genetically modifying organisms to produce analogues of natural products – as an alternative to total synthesis. But as Carreira points out, it takes years to work out biosynthetic pathways in an organism, and then to modify that organism to knock out part of a pathway to produce just one analogue of a metabolite. Chemists can do the job in much the same time (or in less time, depending on the complexity of the molecules), and can also introduce chemical groups that simply don’t occur naturally – which is vital for drug discovery.

Carreira certainly wasn’t dismissing metabolic engineering out of hand – he acknowledged that the field is advancing all the time, and that it undoubtedly has a bright future for making complex organic molecules. But we’re also getting better and better at organic synthesis, so there will always be room for both chemical and biological strategies. Carreira’s 35-deoxy- analogue of Amphotericin B was invaluable in helping to unravel the biological mechanism of action of the parent compound – something that biologists have so far been unable to do alone. So here’s to a future of collaboration with our colleagues in the life sciences.

Andy

Andrew Mitchinson (Senior Editor, Nature)

An edited version will appear on the site on later this month.

Differentiated cells can be reset to an embryonic-stem-cell-like state, but doing so requires using retroviruses to insert a suite of genes into a culture of cells. Because the viruses insert their cargo at random into the genome, infected cell populations from the same individual are genetically different, and it’s hard to know whether differences between the resulting stem cell lines are due to this genetic variation, the epigenetic state of the original cells, or chance events. Worse, the current use of retroviruses renders the cells unusable for clinical applications.

Now researchers led by Rudolf Jaenisch at the Whitehead Institute in Cambridge Massachusetts show a convenient way to generate genetically identical cell populations that can be converted to induced pluripotent stem (iPS) cells by adding a drug . What’s more, they show that cells from multiple organs can be successfully reprogrammed.

In previous work, Jaenisch and other laboratories had reprogrammed cells using genes that turn on in the presence of a drug called doxycycline. This allowed them to study how long transgenes need to stay active for reprogramming to occur. To prove that the cells with drug-inducible reprogramming genes were pluripotent, researchers mixed the cells with mouse embryos to create chimeric mice.

In this paper, the researchers show that cells from multiple organs within these chimeric mice can be efficiently reprogrammed with the addition of doxycycline: reprogrammed cells include neural progenitors, mesenchymal stem cells, and keratinocytes as well as cells taken from muscle, intestinal epithelium, the adrenal gland, and the hematopoietic lineage.

iPS cells generated from different tissues taken from the same mouse are genetically identical, allowing researchers to examine the effects of cell types and retroviral insertion sites. For example, the researchers were able to reprogram intestinal epithelium derived from one iPS cell line, but not another, suggesting that reprogramming requirements vary between cell types. In particular, the expression of transgenes seemed to vary with both cell type and site of insertion in the genome.

The reprogramming rate for `secondary iPS cells’ was 4 to 8 fold higher than for the production of primary iPS cells, presumably because cells in the mice already had the favorable number of proviruses inserted at appropriate sites of the genomes. Still the overall reprogramming rate is low, only between 2% and 4%.

The researchers believe this could be because the drug-inducible transgenes may be more or less responsive to doxycycline even within genetically identical cells and also because reprogramming depends on stochastic events, several of which are required for complete reprogramming.

A source of genetically identical cells will help researchers home in on these and other variables and greatly simplify the search for methods to create clinically acceptable reprogrammed cells.

Wernig, M. et al. A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat. Biotechnol. doi:10.1038/nbt1483 (Advance online publication July 1, 2008)