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Vol. LXII, No. 17
August 20, 2010
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Harvard’s Daley Updates NIH on iPS Cells

On the front page...

There are probably only a handful of scientists whose visit to campus in the arid offseason of the Wednesday Afternoon Lecture Series, which normally takes July and August off, could draw a crowd. Harvard stem cell research authority Dr. George Q. Daley is one of them.

The WALS folks dreamed up a midsummer, Monday afternoon version of the lecture on July 26 and, by 3 p.m., Masur Auditorium was packed with curious summer interns and a modest legion of tenured investigators who were either back from, or had not yet gone on, vacation.

Daley, a professor of hematology and director of the stem cell transplantation program at Children’s Hospital Boston, did not disappoint. His résumé alone pointed to a man who could speak authoritatively about the future of 21st century medicine: summa cum laude graduate of Harvard Medical School (only the 12th person to win that honor, in 1991), graduate work with Nobel laureate Dr. David Baltimore, HHMI investigator, member of the NIH Director’s Pioneer Awards inaugural class in 2004, A-list quote supplier when stem cells are a topic in any major newspaper, among many other honors.

Continued...


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 argued.

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.

What they do offer now is an alluring opportunity to investigate disease processes at the cellular level.

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.
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. NIHRecord Icon

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