Whitehead Institute researchers have replaced the gene c-Myc and its retrovirus with a naturally occurring signaling molecule called Wnt3a. When added to the fluid surrounding the cells being reprogrammed, Wnt3a promotes the conversion of adult cells into Induced Pluripotent Stem cells.
Currently, IPS cells can be created by reprogramming adult cells through the use of viruses to reintroduce four genes (Oct4, Sox2, c-Myc and Klf4) into an adult cell's DNA. These four genes were employed by Yamanka's team to reprogram human skin cells last November. Thomson's team at Wisconsin, in independently creating the same result, used NANOG and LIN28 instead of c-Myc and Klf4. Later, Dr. Thomas Zwaka at the Baylor College of Medicine found that another gene, Ronin, could substitute for Oct4 and perhaps some of the other genes as well. Oct4, Sox2 and Nanog have been thought to be the major regulators of embryonic stem cells. According to Zwaka, Ronin may be as important as these three.
The reintroduced genes override the adult state and convert the cells to embryonic-like IPS cells. But, as you know if you've been reading these posts, there is a problem, actually two:
- The viruses employed in the process, called retroviruses, are associated with cancer because they insert DNA anywhere in a cell’s genome, thereby potentially triggering the expression of cancer-causing genes, or oncogenes;
- C-Myc is a known oncogene whose over-expression can also cause cancer. For IPS cells to be employed to treat human diseases such as Parkinson’s, researchers must come up with safe alternatives to reprogramming with retroviruses and oncogenes.
“A naturally occurring signaling molecule is a good start toward using external cues instead of genetic manipulation to reprogram cells,” said Alex Marson, MD/PHD student in Rudollph Jaenisch's lab (Jaenisch is a major player in Stem Cell Research). “But we still need to eliminate the need for retroviruses for the three other genes.”
Although the technique is promising in mouse cells, its potential applications in humans have not been studied, emphasized Rudy Jaenisch, who is also a professor of biology at MIT. He asks, “Is the same pathway acting in the human system and can Wnt molecules be used to reprogram human cells? We don’t know, but I think those are very important questions to investigate.”
As we move on through this new work, perhaps it's time for a refresher course on basic terms here at Stem Cell Digest. So here goes: Genes are working information units of DNA. DNA is contained in every cell's nucleus and carries the genetic information of the cell. DNA consists of thousands of genes. In fact, The human genome contains more than 25,000 genes. The function of each gene is to serve as a recipe for building a protein molecule.
Since DNA never leaves the nucleus and protein molecules are formed outside the nucleus, a system is required to get gene information outside the nucleus. To accomplish this, genes are copied into RNA which then in turn is decoded (translated) into proteins in the cytoplasm (the fluid that fills the cell surrounding the cell nucleus). In other words, long sequence RNA works as a sort of a messenger service to carry a duplicated sequence of DNA. This RNA string is used as a template to build protein molecules, sometimes called the building blocks of the body. Muscles and hair are mostly made up of proteins.
To continue our brief definitions, MicroRNA is a short strand of RNA that downregulates gene expression. RNA interference, or RNAi, on the other hand, works to stop gene expression.
We'll have more to come in future posts on the important work being done at the Whitehead Institute and the Jaenisch Lab.
Adapted from the Whitehead Institute announcement and other sources.