Most of the ways scientists turn one type of cell into another, or into more basic stem cells, depend on adding genes to the original cells. But this gene insertion approach has drawbacks. Its intricate steps are time-consuming, and there’s always a chance the added gene could land somewhere on a chromosome that activates a cancer-causing gene.
The new approaches—both published online today in Cell Stem Cell—take a less invasive route. The key, explains Gang Pei, a biochemist at the Shanghai Institutes for Biological Sciences in China, and a co-author on one of the studies, are so-called small molecule chemicals that can slip into a cell, enter the DNA-containing nucleus, and alter the activity of a gene. Pei and his team probed thousands of chemicals to identify those that could convert one cell type into another and found a specific recipe of molecules that essentially switched off skin cell genes in human cells and turned on neuron genes. When the group added seven small molecules denoted as VCRFSGY (valproic acid, CHIR99021, Repsox, Forskolin, SP600125, GO6983, and Y-27632), to a petri dish of human skin cells, the cells transformed into mature, functional neurons over the course of a few weeks.
VCRFSGY works in stages. The initial four chemicals, VCRF, start by changing physical traits, acting on a gene called Tuj1, which is specifically active in neurons. But VCRF alone leaves the cell in an unhappy medium: not a true skin cell and not yet a neuron either. The rest of the chemicals—SGY—round out the conversion by amplifying the neuronal development initiated by VCRF. Not only did the resulting cells look like neurons, they acted like them, too: They were able to fire action potentials, a key component that underlies the basics of neuron communication, the team reports.
In the second study, another group of researchers based in China accomplished the same task in mouse cells, using a different chemical cocktail. The fact that two different chemical combinations are able to transform skin cells into neurons suggests that this technique can compete with gene insertions for cellular reprogramming, says HongKui Deng, co-author on the mouse cell study and cell biologist at Peking University in Beijing.
Molecular and cell biologists say the technique could become an important player in personalized medicine, specifically in using a patient’s own cells to develop therapies for their disease or even to provide a source of transplantable cells for treatment. Indeed, Pei’s team showed that skin cells from an Alzheimer’s patient could be coaxed into neurons that expressed several telltale markers of Alzheimer’s disease. These results lay the groundwork for future Alzheimer’s research, giving scientists a safe and accurate platform to test the effects of possible new drugs, Pei says.
These cell-transforming collections of small molecules could really help transform medicine as well, says Jenny Hsieh, a molecular biologist at the University of Texas Southwestern Medical Center in Dallas, who was not involved with either study. “We’re just scratching the surface here.” www.glorybios.com