An Update on iPS Cell Technology

“Look here,” said the Medical Man, “are you perfectly serious? Or is this a trick – like that ghost you showed us last Christmas?”

H.G Wells
The Time Machine

Most people in touch with current events, in particular, developments relating to science and medicine, have observed the growth of the industry called regenerative medicine. The field was born with the first isolation of human embryonic stem cells in 1998. These cells when propagated under laboratory conditions have the potential for the first time in history of being transformed into all the cell types of the human body. Therefore, the vision of this emerging industry is to invent a new field of medicine wherein the hundreds of cell types of the human body are manufactured to repair or regenerate tissues worn out from aging, trauma, or disease. Some salient examples would be cells that have the potential to regenerate heart muscle after a heart attack (something the heart cannot do on its own), or cells capable of rebuilding the brain destroyed in a stroke, or skin cells lost in a body burn, pancreatic cells missing in diabetes, retinal cells for macular degeneration, and so on.

Some of these cell types can already be manufactured on an industrial scale and could likely be used in all people without transplant rejection. These commercial opportunities are therefore the low-hanging fruit, coveted by biotechnology and large pharmaceutical companies. Examples of these off-the-shelf products could include: cartilage for osteoarthritis, retinal cells for macular degeneration, and cells designed to target cancers to deliver a toxic payload that destroys tumors. All of these are, logically, the front-runners in BioTime’s product development pipeline.

But what about all the other cell types in the body where transplant rejection is an issue? Here is where cloning technology enters the scene. In the late 1990s, some of us in the stem cell field attempted to understand how cloning worked in order to find a way of using an egg cell as a “cellular time machine,” to transform a patient’s cell back into an embryonic stem cell again. So, our goal was to clone stem cells, not people, and in the process find a means of making all cell types available to patients that would be identical and not rejected. We showed that cloning technology could do this in animal models, and amazingly, we even showed that it could reset the telomere clock of cellular aging (Science 288:665, 2000).

Over the following years, we and others began to characterize the molecules within the egg cell that were critical in making all of this actually work. A mere handful of molecules appeared to be the key players. These molecules could be delivered into any cell in your body, such as a skin cell, and they were shown to be able to reprogram the skin cell back in time to an embryonic cell. Because cloning was not actually used (and no embryos were made in the process) they were given the new name “induced pluripotent stem (iPS) cells” to distinguish them from embryonic stem cells, although they are very, very similar. There has been an enormous surge of interest in these cells because they were seen as a noncontroversial means of making the all-powerful stem cells, and because they could potentially allow medical science to make any cell type identical to a patient, thereby eliminating the fear of transplant rejection. BioTime scientists invented some of the key early patents while at Advanced Cell Technology. That intellectual property was later licensed to BioTime and is being used by our subsidiary ReCyte Therapeutics for the development of patient-specific vascular cells for the treatment of age-related heart disease.

Recently, however, dark clouds have begun to gather over the landscape of iPS cells produced using the viral technologies of the Japanese researcher Dr. Yamanaka and the U.S. researcher Dr. James Thomson. First there was the report from scientists at Advanced Cell Technology that cells made from iPS cells appeared to age prematurely. We at BioTime showed that indeed, the widely-studied iPS cell lines did indeed have prematurely aged telomeres (the clock of cellular aging) but we showed that it was possible by sorting through the cells to find cells with sufficient telomerase activity to rewind the clock (Regen. Med. 5(3):345-363). Dr. Homayoun Vaziri (the first author on that paper) and I have published a review on the topic available at or from PubMed under the title, “Back to immortality: the restoration of embryonic telomere length during induced pluripotency.”

Then there were reports that iPS cells produced using the viral technologies of Drs. Yamanaka and Thomson had a large number of genetic mutations compared to normal cells such as human embryonic stem cells. More recently, the laboratory of Dr. Yang Xu at the University of California, San Diego reported in the journal Nature that cells made using Yamanaka’s iPS cell protocol were rejected in mice.

We can safely conclude that this rejection of the cells reported by Dr. Xu’s group is not a problem with embryonic stem cells since the researchers saw no such rejection when embryonic stem cells were used. In addition, it is unlikely that the problem is with the reprogramming process per se since we and others had previously shown that cells reprogrammed by nuclear transfer (cloning technology) showed no evidence of rejection (Nat Biotechnol. 20:689-696). So, in summary, as of today the commonly-used protocols of Drs. Yamanaka and Thomson to generate iPS cells appear to: 1) poorly reset telomere length, 2) cause an abnormally high level of genetic mutations, and 3) at least in the case of Yamanaka’s procedure, to produce cells that are rejected in animal models. Therefore, improvements in iPS cell technologies that solve these difficulties will have a significant competitive advantage.

The most logical path for companies aiming to lay a firm technological foundation for product development in regenerative medicine is to manufacture the majority of their initial products using master cell banks of well-characterized GMP grade human embryonic stem cells, aiming at products that can be used in all patients such as those targeting arthritis, retinal disorders, and cancer (off-the-shelf applications). Then, for products to be derived from reprogramming, we believe that the best path is for researchers to more closely mirror the pathways used in cloning such as with the ReCyte™ technology that do not use retroviruses.

ReCyte is different in numerous respects from the iPS cell techniques used by most laboratories. ReCyte uses the molecules commonly used in the derivation of iPS cells but they are delivered via the cellular extracts designed to rapidly reprogram not only the DNA but also other components within the nucleus of the cell. Like iPS technology, the resulting technique does not require embryo formation, but unlike traditional iPS cells, the technique has the advantage of more closely matching nuclear transfer.

The medical man in H.G. Well’s story The Time Machine was rightly skeptical concerning the existence of a machine to transport a human being forward or backward in time. But a cellular “time machine,” that is, the technologies to reprogram human cells back to an embryonic state, is a demonstrable reality today. The competitive advantages of our ReCyte reprogramming technology over traditional iPS cell methods are only just now beginning to be appreciated by the life science community. We therefore plan to aggressively develop the ReCyte platform in 2011, demonstrating the uniqueness of our method, and collaborating with the regenerative medicine community to accelerate its commercialization.

Please see my blog of July 26, 2010 titled “ES and iPS Cells: Which Holds the Future of Biotechnology?” for more background on the history of ES and iPS cells..