Building Better Bones June 2005 Scientists at Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation have discovered a new chemical, called purmorpahrine, that builds stronger bones by converting stem cells into new bone cells. The chemical works by altering a molecular pathway that controls how cells develop. Scientists hope it can be used to treat bone diseases like osteoporosis. Our bones are in a process of continuous breakdown and re-formation everyday. As we age, the breakdown outpaces the reformation, resulting in the brittle bones of 44 million Americans alone who suffer from osteoporosis. Doctors have looked for ways to reverse these effects and have turned to stem cells to regenerate the lost bone density. However, stem cells can differentiate into many different types of cells, and finding a way to ensure that they become bone cells has remained a mystery. As reported in the September 2004 issue of the journal Chemistry & Biology, Dr. Peter Schultz's group from Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation tested 100,000 chemical compounds searching for the one that turned stem cells into mature bone cells. One was all they found. It's called puromoraphine. To understand how purmorphamine converted stem cells into bone, Dr. Schultz's group used Affymetrix microarrays to monitor gene expression in stem cells after treatment. They found that a cluster of 29 genes were uniquely upregulated by purmorphamine consistently across all time points. The research team used Ingenuity Pathway Analysis and found that most of the 29 genes were related to a well-known pathway, called Hedgehog, that controls development of many tissues types, such as neurons, cartilage and bone cells. The purmorphamine treatment activates Hedgehog signaling in stem cells, which, in turn, activates a number of genes that promote proliferation and differentiation, ultimately leading stem cells to transform into mature bone cells. By using GeneChip® Murine Genome U74Av2 Microarrays the researchers were able to simultaneously evaluate the expression pattern of 12,000 mouse genes after purmorphamine treatment. Coupling this high throughput method with the pathway analysis technique provides a quick tool to explore the effects of a chemical on cells. Schultz' research team showed for the first time that a small synthesized molecule could be used to turn stem cells into a specific cell type like bone. Their work lays the first stage for developing a stem cell therapy to replace irreparably damaged cells causing disease—for instance bone cells for osteoporosis or neurons for Parkinson's and Alzheimer's disease.