Profiles of Pioneers: Class of 2004–2009
George Q. Daley, M.D., Ph.D.
Children’s Hospital Boston/Harvard Stem Cell Institute
“There is no doubt in my mind I felt liberated by the Pioneer Award funding to take many more risks, and inspired to ask bold questions. As I look back on the past five years, they have been the most productive of my scientific career. The Pioneer Award made for scientific heaven!”
What explains the curious and powerful cellular property of pluripotency: the ability of a stem cell to differentiate into all tissues of the body? Knowing the details of this process could allow researchers to drive various body cells to differentiate into desired tissue types "on command."
Dr. George Q. Daley describes his Pioneer Award plans as a “fishing expedition” to catalog all of the genes and molecular pathways that enable pluripotency, followed by a trial-and-error approach to coax somatic cells to become pluripotential by adding pluripotency genes.
He thought that these experiments would not be received well by reviewers, but he also thought that the work was important enough to pursue.
Daley’s original goal was superseded by work from the Japanese scientist Dr. Shinya Yamanaka, who defined a cocktail of transcription factors that could induce pluripotency in mouse skin cells. Yamanaka labeled these cells induced pluripotent stem cells, or "iPS" cells.
However, using Pioneer Award funds, Daley immediately advanced the new findings and succeeded in generating human iPS cells. Then, Daley achieved a landmark goal: He created person-specific stem cells from patients with a variety of genetic diseases, including adenosine deaminase deficiency-related severe combined immunodeficiency, Shwachman-Bodian-Diamond syndrome, Gaucher disease type III, Duchenne and Becker muscular dystrophies, Parkinson’s disease, Huntington’s disease, diabetes mellitus, Down syndrome/trisomy 21, and the carrier state of Lesch-Nyhan syndrome. This achievement will likely change the way we study diseases in the lab and may one day usher in an era of regenerative cell-based medicines.
Science magazine recognized the development of patient-specific stem cells as the 2008 “Breakthrough of the Year.” Daley says that this research achievement came years earlier than he would have predicted had he not obtained Pioneer Award funding.
He adds that the Pioneer Award allowed him to pursue highly speculative aims, some of which “failed miserably,” such as his quest to drive embryonic stem cells to become oocytes, an approach he imagined might enable reprogramming via somatic cell nuclear transfer into oocytes. But several other novel research thrusts enabled by his Pioneer Award funding fared better. For example, Daley used his award to investigate how different types of stem cells form in mouse embryos, using a technique called microRNA profiling.
In these studies, he found that some microRNAs weren't made in embryos until late in development and then discovered that a protein called Lin28 was responsible for suppressing these microRNAs. This work has opened the door to an entirely new field of inquiry linking Lin28 to iPS cell production, germ cell formation and even cancer. A full third of Daley's lab is now working on aspects of Lin28—an unexpected but welcome outcome.
Park I-H, Zhao R, West JA, Yabuuchi A, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008;451:141-6.
Viswanathan S, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science 2008;320:97-100.
Lu C-W, Yabuuchi A, Chen L, Viswanathan S, et al. Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos. Nat Genet 2008;40:921-6.
Park I-H, Arora N, Huo H, Maherali N, et al. Disease-specific induced pluripotent stem cells. Cell 2008;134:877-86.
Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 2009;41:843-8.
Viswanathan SR, Mermel CH, Lu J, Lu C-W, Golub TR, Daley GQ. MicroRNA expression during trophectoderm specification and blastocyst development. PloS One 2009, in press.
West J, Viswanathan SR, Yabuuchi A, Takeuchi A, Cunniff K, Park IH, Sero JE, Perez-Atayde A, Frazier AL, Surani MA, Daley GQ. A role for Lin28 in germ cell development and germ cell malignancy. Nature 2009, in press.
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