Gene Expression Laboratory
Roger Guillemin Chair
Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory, studies how genes and molecules orchestrate the development of an embryo.The questions addressed by the laboratory include: How does one cell give rise to millions of cells, and how do they come to be organized into complete structures such as limbs, a heart or brain? How stems cells differentiate and give rise to over 200 cell types that constitute the human body? How certain animals are able to regenerate their tissues and organs, i.e., what are the genetic pathways responsible for epimorphic regeneration, a complex biological process by which animals can regenerate tissues and even entire organs throughout their lifetime after injury or amputation?
Through the years his work has contributed to uncovering the role of some homeobox genes during organ and tissue patterning and specification, as well as the identification of the molecular mechanisms that determine how the different cell type precursors of internal organs are organized spatially along the embryonic left right axis. Overall, his studies have helped to better understand how embryonic stem cells give rise to specific cell types during embryo development, and how these cells interact with one another to form tissues and organs with proper morphology and function. His studies are contributing to give us a glimpse into the molecular basis implicated during organ regeneration in higher vertebrates, the differentiation of human stem cells into various tissues as well as aging and aging related diseases.
In addition to improving our knowledge on early human development, the research activities of Dr. Izpisua Belmonte's laboratory are relevant to understanding the causes that underlie human birth defects, as well as the development of new molecules and specific gene and cell based treatments to cure diseases affecting mankind.
For more information about Dr. Izpisua Belmonte's lab, click here.
Ever since the first adult cells were converted into induced pluripotent stem cells (iPSCs), they have generated excitement as an alternative to embryonic stem cells and a potential source for patient-specific stem cells. Unfortunately, reprogramming adult cells into iPSCs is a slow, inefficient and costly process and carries the risk of cancer, limiting the cells' therapeutic value. Two recent studies in Izpisua Belmonte's lab, however, offer the prospect of safer, faster and more efficient approaches to coaxing cells back in time.
The most widely used technology involves the forced expression of four transcription factors in fully committed adult cells: Oct4, Sox2, Klf4 and c-Myc. Because only a tiny fraction of cells transmogrify into iPSCs that look and act like embryonic stem cells, Izpisua Belmonte wondered whether the process used to reprogram the cells was inducing a response that stopped them from growing. Izpisua Belmonte and his team showed that adding Klf4 and c-Myc, which are oncogenes, activated the pathway for the tumor suppressor p53. In cells genetically engineered to lack p53, reprogramming efficiency increased at least tenfold, clearly demonstrating the important role that p53 played in reining in cells trying to revert back into a stem-like state. Because iPSCs generated with the full complement of reprogramming factors can turn malignant, Belmonte and his team also tried reprogramming mouse cells lacking p53 using only Oct4 and Sox2. The cells readily converted into iPSCs and gave rise to healthy, full-term mice that were able to reproduce, passing the ultimate test for pluripotent embryonic stem cells.
In related work, Izpisua Belmonte's group set out to transform immunologically immature hematopoietic stem cells isolated from umbilical cord blood into iPSCs. They not only successfully converted them using only Oct4 and Sox2, but did so in less time than any previously published methodology. The resulting iPSCs were indistinguishable from human embryonic stem cells and passed all standard tests for pluripotency, establishing the possibility of a comprehensive bank of tissue-matched, cord blood–derived stem cells.