Work in the Maas Laboratory focuses in two areas, both of which revolve around the problem of how vertebrate organs form. The first research area, embodied in a large, new and highly interdisciplinary research Consortium approach called SysCODE, or Systems based-Consortium for Organ Design and Engineering, is aimed at organ regeneration. The second and more long-standing research area involves mechanistic investigations into Pax and Hox genes, their respective gene networks, and the genetic control vertebrate eye, craniofacial, pancreatic and kidney development.
We have recently undertaken a very exciting NIH U54 research grant called SysCODE: Systems-based Consortium for Organ Design and Engineering. The project involves a Consortium of 23 outstanding scientists from BWH, Harvard Medical School, Harvard University, Children's Hospital, MIT, Boston University and Vanderbilt University who will integrate their respective scientific disciplines to regenerate critical organ parts from stem cells. This $24M, 5-year effort, funded under the auspices of the NIH RoadMap Interdisciplinary Research Program, is being led by Dr. Maas and entails a major activity of the Maas Laboratory.
The Consortium will focus on regenerating three organ parts: the tooth germ (an attractive target because of its accessibility), the pancreatic islet and the heart valve. The Consortium is organized into four scientific teams: Developmental Genetics, Computational and Genome Science, Bioengineering, and Technology Development, led by Drs. Douglas Melton (Harvard University), David Gifford (MIT), Donald Ingber (Children's Hospital Boston), and Jon Seidman (Harvard Medical School), respectively.
The underlying premise is that current genomic and proteomic technologies can be used to capture information on the regulatory networks that are normally used to direct endogenous organ development. Computational approaches can be used to integrate these different datasets into "molecular blueprints," that can then be used by tissue engineers to regenerate organ parts from stem cells. A unique feature of the Consortium is an interdisciplinary training grant led by Joe Bonventre (BWH) that funds trainees working at the interfaces between the different scientific disciplines. We are happy to speak with interested students and postdocs further about this exciting, groundbreaking research effort.
Work in our laboratory has historically focused on the developing ocular lens, tooth and the other organs mentioned above as model systems for understanding organogenesis. Many organs form via the sequential exchange of inductive signals between interacting tissues, frequently an epithelium and a mesenchyme. We are identifying the molecular components of the inductive signaling mechanisms that operate between tissues during early mammalian organogenesis. For example, across Metazoa, the Pax6 gene resides high in the genetic regulatory hierarchy controlling eye formation.
Insights from Drosophila have provided considerable insight into the nature of the eye forming genetic hierarchy, and it has been possible to extrapolate these findings to mammals. We have used naturally occurring mouse mutants and knockout mice that lack the function of Pax6, Msx, Eya, Hox and other genes implicated in eye development to begin to order the actions of these genes into a regulatory pathway. We take a multidisciplinary approach to this problem, including the application of experimental embryology, molecular biology, biochemistry, and human and mouse genetics. An exciting principle to emerge from this work is that the genetic regulatory pathways controlling eye development are not only evolutionary conserved, but are also utilized in the formation of different mammalian organs besides the eye.
The central goal of the Maas Laboratory in the context of DGAP (Developmental Genome Anatomy Project) is to use human chromosomal rearrangements to identify genes required for human organogenesis. Merely identifying genes(s) that are disrupted by a translocation or inversion is not sufficient, because more than one gene may be broken, inactivation of a single gene copy may not cause a phenotype and position effects may exist. Therefore, research in the Maas Laboratory is directed to establish that candidate genes disrupted or otherwise affected by a breakpoint are causal for the proband's phenotype.
Two strategies can provide this level of proof: (1) identification of phenotypically similar, independent human cases with mutations in the candidate gene, and (2) recapitulation of key aspects of the proband's phenotype in a model organism such as mouse by targeted mutation of the candidate gene. The raison d'êtreof work in our laboratory is to use these complementary strategies to assign new developmental functions to genes that we identify as being linked to important human birth defects of major medical importance.
For example, in two DGAP cases affecting renal development that involve the genes ROBO2 and NFIA, the respective mouse mutants provide insight into the pathogenesis of human vesico-ureteral reflux, or VUR, and in the case of NFIA, also into disorders of CNS development. In craniofacial development, SUMO1 was identified as a novel oro-facial clefting locus, suggesting a new molecular mechanism for palatal development. Thus, these experiments identify genes that are important in the pathogenesis of human birth defects and elucidate the key developmental mechanisms responsible.