Daley’s talk on induced pluripotent
stem (iPS) cells for disease modeling drew a rigorous portrait
of a cell type that has drawn intense scientific interest since they were first created 4 years ago. For as much promise as the cells offer, the road to their safe application will be arduous, Daley
Daley said the goal of 21st century medicine “is to be able to harness cells as medicines,” but warned that customized, patient-specific stem cells remain a distant therapy
What they do offer now is an alluring opportunity to investigate
disease processes at the cellular
iPS cells derived from the cells of people with genetic diseases, which can be used for testing and modeling, “allow a fresh approach to time-honored questions,” Daley said. In amyotrophic lateral sclerosis, for example, scientists have been able to learn details about what causes the death of motor neuron cells in ALS, thanks to iPS cells. Such work may lead to new drug targets.
Scientists have known for years that Down syndrome
has one somewhat beneficial correlate—it appears to confer reduced lifetime incidence of solid tumors. Daley showed how iPS cells are illuminating this protective effect.
|Harvard’s Dr. George Q. Daley said the goal of 21st century medicine “is to be able to harness cells as medicines,” but warned that customized, patient-specific stem cells remain a distant therapy at present.
In studies of telomerase function, reprogramming
via iPS has shown reactivation of the enzyme. Asking themselves whether such revitalization
is “an essential feature of reprogramming,”
Daley’s team demonstrated that iPS cells can be made from patients with the disease dyskeratosis
congenita, despite the fact that these patients lack normal telomerase enzyme, and that telomeres initially shorten after reprogramming
but then mysteriously lengthen; RNA expression gets boosted as well.
Turning to mitochondrial diseases, which result when whole segments of an organism’s mitochondrial
genome are deleted, Daley showed that iPS cells purge such deletions over time, restoring normality to the cell.
“With these forays into disease biology, we can expect more unanticipated insights,” Daley said.
Interested in hematopoietic (blood-cell forming)
stem cells, Daley and his team used traditional
human embryonic stem cells to study Fanconi’s anemia, which he said is difficult to study with iPS cells because the affected cell type is “resistant to reprogramming.” Knocking
down Fanconi gene expression in human ES cells revealed useful new views of the hematopoietic
defects in FA.
Members of his lab also showed that embryonic stem cell lines from embryos affected by Fragile X syndrome behave differently from iPS lines reprogrammed from skin fibroblasts of individuals
affected by FX, Daley said.
Regarding when clinical applications may be successful, he cautioned, “There are many issues to solve before any cell therapy [in humans] can be attempted.”
Asking whether iPS cells are equivalent to ESC, Daley and his team discovered that the answer, generically, is yes, “but in practice they are really
quite different,” he said. iPS cells can get “frozen”
in intermediate steps as they are cultured and can exhibit “a residual measure of gene expression from donor tissue.
“These cells seem to have a ‘memory’ of the tissue
of origin,” Daley continued. About 98 percent
of the cells’ function seems to be reset, but the 2 percent remaining is a concern, as it does not reset to an ESC-like state.
“This is not an indictment of iPS cells,” Daley noted, “but a refinement of our understanding.”
The residual “memory” can be erased by drugs or by serial passage of the cells from generation to generation, he explained.
“Somatic cell nuclear transplant might be a more ready method to reach pluripotency than iPS,” he concluded. “Nuclear transfer may yet teach us important lessons about how to make better iPS cells.”
To see the full lecture, visit http://videocast.nih.gov/summary.asp?Live=9447.