Recent stem cell headlines are all about how adult cells can be reprogrammed into induced pluripotent stem cells (iPS), which was recently hailed as the biggest scientific breakthrough of 2008. All of this attention to iPS cells and hardly a word about embryonic stem cells (ESCs)—have ESCs lost their luster since scientists figured out how to reprogram adult cells back to the primordial stem cell state?
In reality, iPS cells have been around longer than ES cells. In cloning the sheep Dolly in 1996, Scottish scientist Ian Wilmut took a single adult cell and injected its nucleus into a sheep egg from which the nucleus had been removed. The cellular environment of the egg reprogrammed the nucleus of the adult cell so that it was able to give rise to Dolly.
Last year, the laboratories Jamie Thomson at the University of Wisconsin-Madison and of Shinya Yamanaka, from Kyoto University, reported that this reprogramming could be done by simply expressing only three or four genes in an adult cell. More recently reprogramming has been used by Harvard professor, Kevin Eggan, to derive iPS cells from patients with ALS (Lou Gehrig’s disease) and by UW-Madison professor, Clive Svendson, to derive iPS cells from patients with another neurodegenerative disease, spinal muscular atrophy (SMA). Both iPS cell lines were then used to grow the defective neurons in the lab giving the scientists their first access to the very cells that caused the respective neurodegenerative diseases. This creates a powerful research tool that will enable researchers to study the disease process and find ways to halt it.
“Clinical trials” using iPS cells
The benefits of iPS cells don’t stop there. Madison, Wisconsin-based Cellular Dynamics International (CDI) recently produced one of the world’s first commercial stem cell products, ESC-derived cardiomyocytes. These are functional heart cells that CDI produces and sells to pharma companies for drug and toxicity testing. But CDI also has a robust research effort to efficiently produce iPS cells, possibly without having to introduce exogenous genes into the adult cells.
“We have a large scale research activity to create a vector-free methodology for no integrated DNA (in the iPS cells),” said Chris Kendrick-Parker, Chief Commercial Officer at CDI. The company is now filing patents and Kendrick-Parker was not at liberty to say if CDI has developed a DNA-free method for inducing iPS cells. However, he did say that the company is “looking at all options.”
Kendrick-Parker believes that CDI will soon switch exclusively to using iPS cells to develop heart and other cell types for sale to pharma and researchers. The advantage of iPS cells he said is that they can be used to produce adult tissues from people representing different ages, ethnic types and sexes as a way to model the human heterogeneity in tissue culture. This way, “drug companies can actually recapitulate (in tissue culture) what happens in clinical trials,” Kendrick-Parker said.
For this to happen, Kendrick-Parker says that CDI and other companies will use iPS technology to make a library of iPS cells from a wide range of people in order to reflect the genetic heterogeneity of the population.
Most investigational or even post-market drugs fail due to liver or cardiotoxicity in a subset of people, which is “why pharma is so interested in these (iPS-derived) models,” said Kendrick-Parker. The cells should allow drug makers to identify organ-specific toxicities before clinical trials begin, thereby saving much time and money bringing a new drug to market, only to have it fail. For example, having iPS-derived cardiomyocytes from a large patient population might have identified, early on, the cardiotoxicity of Vioxx, saving Merck & Company a great deal of money getting the drug to market and in subsequent litigation fees.
iPS cells in the clinic?
But what about using iPS cells to directly treat disease? After all, they have been widely touted as the great ethical hope for stem cell therapy since they don’t involve destroying human embryos.
Currently, iPS cells are made by expressing a few genes in an adult cell, which turns back the cells' developmental clock to an embryonic-like state from which they can become any of the body's 220 different cell types. Yet, the genes used to reprogram adult cells are, themselves, associated with cancer, so iPS cells made this way will not be used clinically.
However, last November, Thomson opined that in about six months, it will be possible to make iPS cells without having to resort to oncogenic gene expression. While this will eliminate the immediate problem to using the cells clinically, they still face significant hurdles before being used to treat specific diseases. In fact, Thomson also suggested that there may be problems with iPS cells, saying that there are “dark clouds on the horizon”.
Eric Forsberg, Director of the WiCell Research Institute, explained that reprogramming of adult cells is extremely inefficient, meaning that for some reason, it is only the rare adult cell that can be successfully re-programmed. This suggests that other unknown factors affect the ability of each cells’ genome to be reset to an embryonic state.
Researchers also know that reprogramming is incomplete. The genome clock is not completely reset and this Incomplete reprogramming likely plays a role in the health problems that cloned animals have—Dolly had arthritis and was euthanized due to progressive lung disease. This raises the possibility that tissues developed from reprogrammed iPS cells might not function normally.
Forsberg pointed out that the extent to which a person’s genome is reset can vary from person to person and this could mean that each person will require an individualized reprogramming regimen in order to create iPS cells for therapeutic use. But, it is unlikely that the FDA would approve such an individualized protocol—they like uniformity and conformity in therapeutic protocols, not different protocols for different people
Thus, while iPS cells provide enormous potential for learning how human disease develops and progresses and for cost-effective development of new and safer drugs, they are still a long ways from the clinic. In fact, ESCs will likely find clinical use before iPS cells do.
Great post Steven. Well done producing a very easy-to-read overview of iPS cells. I dugg! it.
--Lee
www.celltherapyblog.com
Posted by: Lee Buckler | January 19, 2009 at 12:48 AM