While the basic side of stem cell research is prospering, several talks on translating research to therapy were sobering reminders of the challenges ahead.
The June ISSCR conference in Cairns was an upbeat affair, with the stem cell field palpably energized by recent advances in the reprogramming of somatic cells, the report of the first cloned primate embryonic stem (ES) cells, improvements in human ES cell differentiation, and new strategies to harvest both embryonic cells and tissue-specific cells.
Much of the progress was expected and incremental, but real.
Much of the progress was expected and incremental, but real. Arguably most exciting was the advance on the breakthrough reported last year by Kyoto University's Shinya Yamanaka converting mouse fibroblasts into cells that passed many tests of ES cells. Now, conversion of fibroblasts into induced pluripotent stem cells produces cells with differentiation potential and epigenetics that MIT's Rudolf Jaenisch describes as indistinguishable from ES cells.
Other advances, notably from University of Pittsburgh's Bruno Péault confirmed findings of versatile, easily cultured cells lurking within the vasculature. The University of Michigan's Yukiko Yamashita expanded her studies on the Drosophila niche to encompass a potentially generalizable mechanism to keep aging stem cells from inappropriate proliferation.
But while the basic side of stem cell research is prospering, several talks focused on translation of stem cells to therapy were sobering reminders of the challenges ahead.
Hans Kiersted (UC Irvine) described his preclinical work on rats with acute and chronic spinal cord injury, which form the basis of the first clinical trial to use federally approved human ES cell lines on human patients that Geron will be starting soon. Kiersted laid out his method to differentiate human ES cells into high-purity oligodendrocyte progenitor populations, which will be transplanted into human spinal cord injury patients. This “first” makes some members of the stem cell field nervous, fearing that a negative outcome will set back the stem cell field, as the Jesse Gelsinger tragedy once dashed the hopes of the gene therapy field, or at least slowed its progress considerably.
When Katerina Le Blanc from Karolinska Institute described experiments whereby mesenchymal stem cells (MSCs) were injected into live human fetuses in an attempt to treat osteogenesis imperfecta, it gave members of the audience pause. Several wondered whether the disease mechanism or the role mesenchymal stem cells could play had been sufficiently investigated to warrant such an experiment on a human fetus.
This dichotomy between clinically oriented and basic researchers will become more pronounced as clinical trials are slated and as bad outcomes are inevitably reported. Basic scientists tend to be conservative about what clinical trials should be attempted, whereas some clinicians would argue one doesn't need to understand the basis of a therapy for it to be effective (case in point, many psychiatric drugs). In the coming year, ISSCR President George Daley plans to prioritize an international council on governance of clinical trials.
The clinical implications of stem cell research go far beyond cell replacement therapies, of course. Rockefeller's Elaine Fuchs presented an elegant paradigm for how a stem cell niche, in this case in the skin, tightly controls whether a stem cell is active or quiescent, and raised the provocative question, echoed by Luis Parada in his talk on glioma stem cells, whether a mutation in a niche can predispose an individual to certain types of cancers, or even multiple types of cancer within one tissue.
There were few talks on cancer stem cells and how stem cell niches contribute to cancer at the ISSCR meeting, but those talks indicate that the field will become key in the coming decade. Stanford's Irving Weissman warned researchers to avoid assumptions. One cannot extrapolate between characteristics of cancer stem cells and healthy tissue-specific stem cells, which may not be cancer stem cells' progenitors.
Other exciting clinical links came from understanding human diseases starting at the level of the gene. Hongjun Song of Johns Hopkins studies neurogenesis in the adult hippocampus, where about 9,000 new cells are produced each day. Stress, aging, and drug abuse decrease neurogenesis, and factors such as Wnt secreted from the astrocytes stimulate neurogenesis.1 Electroconvulsive shock treatment decreases the Wnt inhibitor Frizzled-related protein 3, providing a possible mechanism for how electroconvulsive shock treatment stimulates neurogenesis and improved cognitive function in depressed patients.
Song pursued another link with human disease by studying a Scottish family with inherited schizophrenia. His group mapped the mutation to a cytoskeletal protein associated with centrosomes, that interacts with many other proteins. The normal function of translocatin, he found, is to regulate the morphogenesis and positioning of new neurons in adult hippocampus, and the tempo of their integration of new neurons in the adult brain.
Song's and others' talks map the field's progress from characterizing cells to manipulating and understanding them. Less than ten years after the first human embryonic stem cells were obtained, many scientists are expanding the sources and techniques to produce versatile, patient-specific cells. At the same time, other scientists are figuring out what to do with the cells once they've got them.
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Lie, D.C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 437, 1370–1375 (27 Oct. 2005). 10.1038/nature04108
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DeWitt, N. Stem cell meeting 2007: Routes and roadblocks on the way to cures. Nat Rep Stem Cells (2007). https://doi.org/10.1038/stemcells.2007.52
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DOI: https://doi.org/10.1038/stemcells.2007.52
