ES and iPS Cells: Which Holds the Future of Biotechnology?

New developments in stem cell technology offer significant promise for the future of medicine. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are the two sides of the coin of regenerative medicine. Many people ask, “Which of these are the most important, and which holds the future of lifesaving medical therapies?” I believe both will be critical in the coming years. To see why, let me share some of our thoughts in the early years of this technology. By tracing the flow of this history I think it will be possible to bring into focus the big picture.

Medicine has long wished for a means of repairing the hundreds of diverse tissues in the human body. Organ transplantation has become one way of doing this, but its use is severely limited by two things. First, the majority of people in need of tissue never find a compatible donor. The reason for this is that it is quite rare to find organs that are a close match to a given patient. Second, cells and tissues from adult tissues are limited in their ability to regenerate. If they could regenerate, we would simply re-grow amputated arms and legs after they were lost, heart tissue would regenerate after a heart attack, and brain cells would repair the damage occurring in Parkinson’s disease.

The History of ES Cells:

In the mid 1990’s when I was at Geron Corporation, we launched a project to isolate cells we thought could revolutionize this field. The concept was that, theoretically at least, there were cells in the first few days of human life that could form all the cells of the human body. The idea was that if we could capture these cells and cause them to proliferate in the laboratory dish as cell lines, that is to say, cultures where we could expand them into millions and millions of cells without them beginning to differentiate into the cells of the body, we could invent a scalable source of any cell type of the human body. Then we could take these all-powerful stem cells and turn on the molecular switches that would cause them to become anything we needed to make, that is, cartilage for the treatment of arthritis, blood cells for leukemia patients, or cells to produce insulin for diabetics, and so on. We found collaborators in Drs. Roger Petersen at UCSF, James Thomson at the University of Wisconsin at Madison, and John Gearhart at Johns Hopkins University School of Medicine and the race was on to create these cells. As a result of this collaboration, the first human embryonic stem cells were derived in 1998.

Therapeutic Cloning:

Then in 1997 came the advent of animal cloning. Cloning is a technique where the DNA removed from an egg cell is replaced with that of one of the cells of the body of an adult animal. When this is done, amazing things happen. Something in the egg cell changes the DNA of the cell from the body, perhaps a skin cell, and transforms that cell back to the embryonic state wherein the cell has totipotency (the ability to become all the cell types in the body). If this cluster of cells is transferred to a uterus, the cells may attach to begin a pregnancy and perhaps a live born animal, the genetic twin of the animal from which the original cells were obtained.

The first mammal to be cloned in this manner came from a breast epithelial cell, and was named “Dolly” after Dolly Parton. Shortly after Dolly was cloned, some of us proposed using cloning technology in the human species, but not to clone human beings, rather to clone ES cells. This was called “therapeutic cloning” as opposed to “reproductive cloning” (i.e. the cloning of a baby) (Nature Medicine 5(9): 975-977). The promising nature of this technology to us was that this technique could potentially allow medicine to do something that has always been outside its reach; namely to make any type of cell or tissue available in any quantity genetically identical to the patient, thereby obviating transplant rejection for human donors. In addition, we had reasons to believe that cloning technology just might act like a cellular “time machine” to reset the clock of cellular aging by restoring embryonic telomere length (the clock of cellular aging). We showed this was indeed the case, at least in the bovine species in 2000 (Science 288: 665-669).

So the vision was to take a cell from a patient, some cell easy to part with like one from a plucked hair follicle, or a blood cell, then to take that cell back in time using the molecules in the egg cell. Again, the goal was to produce young cells of any kind for old people. The goal never was to clone babies and human beings. We then showed preliminary success in cloning human cells at the earliest stages of life, the cloning of preimplantation embryos (e-biomed: J. Regen. Med. 2: 25-31). However, we were not successful in deriving stem cell lines from these reprogrammed cells (and to my knowledge, no one yet has).

There was, of course, a great deal of controversy over therapeutic cloning. While we said that these early clusters of cells are not yet an individual human being (some of my testimony on that subject can be found at, others disagreed and vociferously argued that therapeutic cloning, despite any potential benefit to people suffering from degenerative disease, ought to be illegal.

However, the greatest difficulty, in my opinion, was not this ethical controversy over the legal status of preimplantation embryos. Even some theologians have concluded that human life should be considered to begin at about 14 days after fertilization, way beyond the stages of life used in stem cell technology. An example of this would be Norman Ford’s thoughtful analysis in the book “When did I begin?” To me, the real difficulty with therapeutic cloning was the source of the active ingredient in the whole process: the human egg cell. We would need millions of egg cells a year to meet the need of those in need of regenerative therapy. Since young women need to be the source of these cells, a large percentage of these women would need to display a beneficence not yet observed in medical donation.

iPS Cells:

In the years 1999-2005 a number of patent applications were filed on what one might call a “cloning machine.” The idea was to define the molecules in an egg cell that made cloning work and then construct a robotic platform using these molecules to transport a patient’s cells back in time without making embryos or without using egg cells. We at BioTime now call this proprietary process “ReCyte™.” In 2007 the Japanese researcher Shinya Yamanaka and the University of Wisconsin-based researcher James Thomson published the first papers showing that four master regulatory genes could reprogram cells from the human body back to an embryonic state. Since the cells used did not come from discarded embryos, the reprogrammed cells were no longer called “embryonic stem cells” but were designated “induced pluripotent stem cells” or “iPS cells” for short.

iPS cells have really lit a fire under the scientific community. What is so exciting about these cells is that, like ES cells, they have the potential to make all the cells of the human body, but unlike ES cells, iPS cells can be made identical to the patient to prevent transplant rejection. Moreover, the derivation of iPS cells is essentially noncontroversial, since no embryos or egg cells are involved.

Recently, however, dark clouds have begun to gather over the iPS cell picture. Reports began to surface that iPS cells actually didn’t seem to behave like ES cells. In one report by scientists at Advanced Cell Technology, Inc., the iPS cell derivatives seemed to age prematurely. Then, at BioTime, we reported that in nearly all of the iPS cell lines we studied, the telomere clock of aging was abnormally shortened– that is, cells derived from the iPS cells would indeed be prematurely old. However, we showed that it was possible to reset the cellular aging clock back to the beginning of life by sorting through the cells to find ones 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 recently 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 more recently still, scientists at Harvard reported that iPS cells are abnormal, in that the iPS cells still retain the faint “imprint” of the cells from which they were derived. While this would at worse case likely be a minor problem, it emphasized the need to perfect the iPS process to make it as effective as cloning itself. I describe this as a minor problem because we know that the cells are close enough to normal that they can make a living mouse. In the context of a patient dying for lack of transplantable cells, most scientists believe that some minor abnormalities would be better than nothing at all. But, of course, the goal is to make the perfect cell.

Back to the time machine. The conclusion of all this would be that the egg cell contains molecules, other than the four master regulatory genes commonly used in iPS cell techniques, that makes cloning work so well. Thinking this might indeed be the case, we at BioTime designed ReCyte™ to use a mixture of proteins from egg or sperm-related cells called “EC” cells. We use the proteins derived from the EC cells together with the master regulatory genes of iPS to make what we be believe is currently the optimum reprogramming material to replace the egg cell.

While ReCyte™ is still in development, we believe this proprietary iPS technology may have significant advantages over other techniques. In any event, we believe that it gives us a technology to reset a patient’s cells back to the pristine state of the beginning of life, opening the door to the manufacture of young cells of any type identical to that of the person from whom the original body cells (such as skin cells) were obtained. If that person was suffering as a result of DNA carrying a disease gene such as muscular dystrophy or cystic fibrosis, then that abnormality could be theoretically be corrected in the iPS cells and then those repaired cells could be used to produce cell types free of the disease gene but otherwise identical to the patient. In many diseases like muscular dystrophy, the hope would be that the normal muscle progenitors produced from the iPS cells would be able to proliferate to maintain enough functional muscle to allow a normal life. There are countless other ways the technology could be utilized in medicine.

Off the Shelf vs. Customized Approach:

But what about ES cells? Are they now unnecessary? The answer that I believe most stem cell researchers would agree upon is that both ES and iPS cells will likely be necessary for a long time. The way we see this working is as follows: in order to treat patients afflicted with an acute disease or injury — that is to say, disease or injuries that occur suddenly like a heart attack, stroke, or skin burn — physicians will not have time to order cells and tissues to be made from the patient’s own cells through iPS cell technology. iPS cell reprogramming will takes weeks, not days, to deliver a product for a patient. So, we think that for acute applications, existing cells made from existing ES cells will be utilized. We already have banks of clinical grade human ES cells made for this purpose by our subsidiary ES Cell International Pte Ltd in Singapore. Since these cells are not a genetic match to the patient, the cells will either need to be used in treatments with low risk of rejection such as in the brain, eye, or arthritis where the immune system is not as active, or in cases where the cells are not intended to be permanently grafted such as when they are used to target and destroy tumors. These are indeed the applications we and our subsidiaries are targeting first, and the reason we acquired ES Cell International and its clinical grade ES cell bank. For chronic diseases such as heart failure, diabetes, and osteoporosis, where physicians have more time to find a treatment, we think iPS technology will be the source of the ultimate treatment of choice.

The power of human ES cells to generate a platform for the manufacture of all the cell types of the human body, and iPS cell technology to reprogram human cells back to the beginning of life, even resetting the genetic clock of cellular aging, is the foundation of the emerging field of regenerative medicine. Frankly, the power of these technologies stretches the imagination. It is hard to imagine the full potential of the technology, and we do not yet know where all the bumps in the road to the use of these technologies in medicine will reside. BioTime’s aim, and I believe the aim of most researchers around the world, is to accelerate the translation of these technologies from the lab bench to the hospital bedside in the hope that we will one day lift the burden of suffering off our fellow human beings by using these new regenerative medicine technologies to improve the quality of life, and perhaps even to extend life in old age..