05 Jan Induced pluripotent stem cells steal limelight from embryonic stem cells
Madison, Wis. – Recent stem cell headlines are all about how adult cells can be reprogrammed into induced pluripotent stem (iPS) cells, 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 (ES) cells, which raises a question:
Have ES cells lost their luster since scientists figured out how to reprogram adult cells back to the primordial stem cell state?
iPS cells have certain advantages over embryonic stem cells. For instance, reprogramming was recently used by Harvard professor Kevin Eggan to derive iPS cells from patients with ALS (Lou Gehrig’s disease) and by University of Wisconsin-Madison professor Clive Svendsen, 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.
With iPS technology, scientists can specifically create stem cells from people with certain diseases, which cannot easily be done with ES cell technology because they generally don’t know the health status of an unborn embryo. Therefore, iPS technology creates a powerful research tool that will enable researchers to study disease processes for which they previously had limited access.
“Clinical trials” using iPS cells
The benefits of iPS cells don’t stop there. Madison-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 pharmaceutical companies for drug and toxicity testing; Chris Kendrick-Parker CDI’s chief commercial officer, believes the company soon will switch exclusively to using iPS cells to develop heart and other cell types for sale to pharma and researchers.
“We have a large-scale research activity to create a vector-free methodology for no integrated DNA (in the iPS cells),” said Kendrick-Parker. The company is now filing patents but Kendrick-Parker was not at liberty to say whether CDI has developed a DNA-free method for inducing iPS cells. However, he did say that the company is “looking at all options.”
The advantage of iPS cells is that they can be used to produce adult tissues from people representing different ages, ethnic types, and sex as a way to model 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, he explained that CDI and other companies will use iPS technology to make a large 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 & Co. 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 treat disease? They have been widely touted as the great ethical hope for stem cell therapy because 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. 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 and incomplete. The genome clock is not completely reset and this likely plays a role in the health problems that cloned animals have – Dolly the sheep had arthritis and was euthanized due to a progressive lung disease. This raises the possibility that tissues developed from reprogrammed iPS cells might not function normally.
Forsberg also 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. However, it is unlikely that the Food and Drug Administration would approve such an individualized protocol because the agency likes strict 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 way from the clinic. In fact, ESCs will likely find clinical use before iPS cells do.