Advisory Board on Regenerative Medicine

According to the Advisory Board, patients who have suffered recent heart attacks are the main target of clinical trials of adult stem cells taken from bone marrow, muscle, or skin to repair heart tissue. The cells are taken from the patient’s own body or from a donor, and are transplanted via catheter into an affected artery or injected directly into damaged heart muscle.

Although their long-term efficacy is questioned, such therapies so far seem to be safe and could be on the market in about five years. But they will tend to be complex and costly, and will likely only be performed by interventional cardiologists at specialized centers, not at community hospitals.

The Advisory Board thinks that regenerative procedures like these will be applied to other solid organs besides the heart and will likely transform the practice of medicine. We agree, but we think most of the action will be not in essentially unmodified adult stem cells such as those taken from bone marrow. Rather, regenerative medicine will use either embryonic stem cells (ESCs) extracted from human embryo blastocysts or adult cells such as skin cells reprogrammed or “de-differentiated” back to an embryonic-like state. The latter are called “induced pluripotent stem cells” or iPSCs. ESCs and iPSCs are “undifferentiated” and have the potential to be turned (“differentiated”) into any adult cell type, from neuron to toenail cell.

Venture Capital Backs iPSCs

One reason for optimism in the future of regenerative medicine is the reversal of the Bush administration restrictions on federal funding of ESC research. Another is what looks like a “gold rush” of venture-financed startups rushing into unexplored iPSC territory. A chemist at the Scripps Research Institute described the extraordinary energy going into iPSC research as “a really rare phenomenon .… a sensation, really.”

The interest and energy is not devoted solely to iPSC therapies. While some hope to use iPSCs to create new disease models for research, or to study tissue development, or to develop tissues for tissue engineering and implantation, iZumi Bio (with US$20 million in venture capital) is developing a bank of iPSCs from patients with various diseases and then using the cells to screen drug candidates for development.

Because the cells come from real patients, they also come with documented medical histories, enabling researchers to study the progression of a disease, how the cells (and therefore the patient) will respond to different drugs, exactly what symptoms they will show, and when.

Meanwhile, Harvard Stem Cell Institute has created more than 20 disease-specific iPSC lines for Parkinson’s, type 1 diabetes, and other conditions. iZumi is focusing initially on ALS, spinal muscular atrophy, Parkinson’s, and calcific aortic valve disease. It expects to have “proprietary therapeutics in development in the fifth year—by 2012,” according to CEO John Walker.

Bear in mind that a viable method of creating iPSCs only surfaced about a year ago. In contrast, at least partly as a result of the Bush restrictions, it has taken more than a decade since ESCs were first isolated for the first ESC therapy (for acute spinal-cord injury, developed by Geron) to go to clinical trial.

Need for Better iPSCs

But there remains much work to do to make the process of producing iPSCs reliable and efficient, and to get them to differentiate to a desired adult state reliably and efficiently.

The finding last Summer that the tumor suppressor gene p53 controls somatic cell reprogramming removes one problem. The de-differentiating efficiency of cells genetically engineered to lack p53 increased at least 10-fold compared to control cells. In mouse experiments, this method did not give rise to cancers.

Nevertheless, a study published in February this year comparing the ability of iPSCs and ESCs to turn into neurons found that iPSCs differentiate “less efficiently and faithfully” than ESCs. The study’s senior author said that while ESCs behave predictably, iPSCs do not. “That means that at this point there is still some work to be done to generate ideal induced pluripotent stem cells for application.” Even so, he thought that the issues preventing iPSCs from emulating ESCs were technical and would be overcome.

An experiment that could help researchers understand fundamental differences between ESCs and iPSCs and overcome those technical difficulties was conducted recently in China, where researchers also created live mice from iPSCs. After being injected into “tetraploid” embryos (which develop a placenta and other essentials but cannot develop further by themselves) the iPSCs began to divide and the embryo began to grow.

Twenty days after 624 such embryos were implanted in surrogate mothers, 22 live mice were born, a success rate of only 3.5 percent. Some of them died soon after birth and others had (undisclosed) physical abnormalities. However, 12 of the survivors were eventually mated and all produced offspring with no sign of tumors or abnormalities, even unto the third generation as the researchers continued to mate the offspring of the offspring.

Speaking of China: It has been claimed that iPSCs created (in 2009, in China) from adult pigs could assist research into human disease and the breeding of pigs for organ “xenotransplants” for humans. We don’t understand why anyone would want to use porcine iPSCs for anything other than porcine health, when physiologically and ethically safer human iPSCs are available for human health research and therapies.

Heart Cells To Go

For example, Cellular Dynamics International (CDI) sells heart cells (“iCell Cardiomyocytes”) produced from iPSCs derived from a person’s own blood or other tissue. One great advantage—for research, drug discovery, drug toxicity/response testing, and regenerative therapy—is that the cells can be made “in quantity and on demand,” as CDI’s CEO put it. For about $1,000, a customer receives a tiny vial containing 1.5 million to 5 million heart cells of all the different types.

Used together with genetic tests for sensitivity to drugs (such as one available to test a patient’s sensitivity to the blood thinner warfarin), iZumi’s and CDI’s cells could be used to predetermine very precisely the risk to a patient of a given drug/dose. Those companies’ ability to mass-produce human iPSCs also means that drug developers can cut years of research by using high-throughput testing of thousands of different drug compound candidates to see which work and are safe for the cells.

The Future of medicine

For the time being, then, the value of iPSCs is in disease modeling, pathway identification, and drug screening and development, rather than in therapy. Even so, they may one day “transform medicine into something we’re only just beginning to imagine,” according to Technology Review’s Lauren Gravitz.

Actually, we have been imagining this transformation for most of recorded human history, and have imagined none more feverishly than rejuvenation.

Reversal of Premature Aging

We age because our chromosomes break down when their end caps, called telomeres, wear off. The chromosome loses bits of telomere every time its cell divides, and the cell gets old and infirm, and eventually it dies. Patients with a rare premature aging disease called dyskeratosis congenital lose telomeres much more quickly than other people. But in a recent experiment, iPSCs that began as skin cells taken from dyskeratosis patients regained telomeres that had been lost to the cellular division process.

Note that this was done in the petri dish, not in the patients. It is not yet a cure. But the discovery could lead to cures for this and other telomerase-related diseases, as well as to treatments for the aging process itself. The source article does not say so, but it would seem logical that if some cells can be rejuvenated—as evidently they can—then theoretically all the cells that make up a person could be rejuvenated also.

iPSCs to Liver Cells

At least, future patients with diseased livers can expect to be able to have them rejuvenated. Liver cells produced from iPSCs could one day produce healthy liver cells to replace diseased cells. Among other things, this would eliminate the need for scarce liver transplants.Large numbers of relatively pure liver cells, produced “relatively easily” in petri dishes, have been found to be capable of performing many of the functions associated with healthy livers. Injected into mouse livers, the iPSC-derived human liver cells successfully produced human liver proteins.

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One day, this will all be here. The transformation of modern medicine into postmodern medicine—regenerative, genomic, bionic, and digital—has begun and is accelerating. Because it is accelerating, the future is closer than we think.