A world first
It has been almost 12 years since James Thomson published his groundbreaking paper in Science providing details on how he and his colleagues had managed to isolate embryonic stem cells from human blastocysts, and maintain them indefinitely in culture. This work provided the foundation upon which future therapies could be built. Stem cells are once again in the spotlight as we begin to transcend conventional medical therapies into unchartered waters. Earlier this week, Geron Corp. initiated the world’s first embryonic stem cell-based clinical trial in patients suffering spinal cord injury. In this phase 1 study, oligodendrocyte progenitor cells (GRNOPC1) derived from human embryonic stem cells will be investigated for their safety, and potentially for their ability to remyelinate neurons and stimulate nerve growth in the spinal column of patients.
The stem cell community is no doubt experiencing a whirlwind of conflicting emotions in the face of this progress – excitement and relief, that a new milestone in stem cell-based therapy has been reached; hope, that the patients may indeed benefit from the treatment; and fear, that the study may have arrived too early and could prove unsafe in its course. While the outcome of the study remains uncertain, what is more clear is that its results will have far reaching effects and set the tone for stem cell transplantation therapy for years to come. No doubt, the study will agitate the already heated interchange between stem cell proponents (researchers, advocates, and otherwise) and those staunchly opposed due to ethical and moral objections. It seems it may not be long before one side or the other has new material to buoy its argument.
A recently published letter in Cell Stem Cell, focusing on induced pluripotent stem (iPS) cells, discusses a transplantation approach that may help the scientific and medical communities maximize the value of early stem cell transplantation studies in humans, like that of Geron’s.
Moving iPS cells to the clinic: It has been well established in the scientific community that if induced pluripotent stem (iPS) cells are to be of therapeutic value in the clinic they must be free of any genetic factors used in the reprogramming process. If left behind, reactivation of any of these ‘stem cell’ genes could result in tumor formation following transplantation. In line with this goal, the Canadian research community was taken aback last year when Dr. Andras Nagy of Mount Sinai Hospital in Toronto managed to create human iPS cells using a jumping gene which allowed for complete excision of reprogramming factors (this was also some of the first work illustrating that iPS cells could be generated without viruses, find it here).
In a recent letter in Cell Stem Cell, James Ellis of the Ontario Human iPS Cell Facility reinforces the importance of transgene-free iPS cell lines like Nagy’s for future therapeutic use. In addition, Ellis points out that in the absence of cell tracking technology in early autologous transplantation procedures in humans we will have difficulty in knowing whether transplanted cells survive, localize to pathological sites, or exert positive or negative effects on the recipient. Gene therapy is an example of a field that would have benefited early on from basic information related to clinical outcome. An NIH review of gene therapy trials published in the mid-90’s noted that of over 100 approved clinical protocols virtually none had demonstrated definitive clinical efficacy. To ensure that stem cell transplantation protocols do not meet the same end, Ellis proposes that transgenes be investigated for their ability to act as reporters to facilitate monitoring of therapeutic cells following transplantation. It’s only early days, but this is excellent foresight.
In other Canadian research news we find therapeutic value in natural compounds..
It’s in the skin: Studies show that a ‘Mediterranean diet’ reduces the incidence of certain age-related diseases such as heart disease, cancer, and dementia. Efforts to deconstruct this effect have put scientists on to polyphenols, a class of compounds found in abundance in Mediterranean foods with pronounced anti-oxidant and protective activity. One highly potent polyphenol, resveratrol, happens to be found in the skins of grapes (another reason to enjoy wine). Dr. Remi Quirion and his colleagues at McGill University previously showed that polyphenols bind receptors in the brain. This observation led them to believe that resveratrol may exert positive effects on the skin. Indeed, experiments revealed that resveratrol has specific binding sites in human skin tissue and is able to reduce the incidence of apoptosis in toxicity models. The molecule is currently being investigated by many groups around the globe for use in life extension, prevention of cancer, and a number of other disease-related applications.
Extracts for insulin: After scanning a library of 1319 marine invertebrate extracts using a high-throughput platform, researchers identified a number of compounds that modulate insulin and pdx1 expression in human pancreatic islet cells. In order to confirm up-regulation of relevant genes, pancreatic islet cells were transfected with a dual-reporter lentivirus containing eGFP driven by the insulin promoter and mRFP driven by the pdx1 promoter. Each compound was examined for four parameters, including insulin promoter activity, pdx1 promoter activity, nuclear morphology, and cell number. Bivittoside D was identified as a positive regulator of insulin gene expression. This study is the first example of a high-throughput, high-content, multi-parameter screen in living pancreatic beta-cells, and was led by Dr. James Johnson of the Department of Cellular and Physiological Sciences at the University of British Columbia.