Understanding Mammalian Cellular Diversity
Comprehending how mammalian cells with apparently identical genetic background acquire their extraordinarily specific, stable and yet extremely diverse phenotypes poses one of the most daunting challenges of modern biomedical research. Until the molecular principles that govern branching and maintenance of the basic cellular lineages in the embryo and in the mature organism become clear, it will not be possible to fully address persistent questions in developmental biology, regenerative medicine, cancer biology, and the pathophysiology of degenerative diseases.
Embryonic stem (ES) and ES-like cells (induced pluripotent stem cells, iPS) afford ideal model systems for unraveling the complex molecular networks that give rise to cellular identity. They are relatively easy to generate and maintain in culture and are amenable to manipulation with the growing repertoire of molecular research tools now in the hands of cell biologists. More importantly, they have the property of pluripotency, meaning that they can differentiate to many cell types in the body, even to germ cells. Several groups believe that a small core set of regulatory factors, including Pou5f1 (encoding the Oct4 protein), Sox2 and Nanog, maintain ES cells in the pluripotent state by acting on a limited number of target genes. This fundamental concept has generated enormous excitement in the biomedical community, leading to successful reprogramming of somatic cells to an ES-like state. Yet, recent discoveries in our laboratory suggest that the complement of factors needed to direct ES cell pluripotency is considerably larger than originally thought.
Embryonic stem (ES) and ES-like cells (induced pluripotent stem cells, iPS) afford ideal model systems for unraveling the complex molecular networks that give rise to cellular identity. They are relatively easy to generate and maintain in culture and are amenable to manipulation with the growing repertoire of molecular research tools now in the hands of cell biologists. More importantly, they have the property of pluripotency, meaning that they can differentiate to many cell types in the body, even to germ cells. Several groups believe that a small core set of regulatory factors, including Pou5f1 (encoding the Oct4 protein), Sox2 and Nanog, maintain ES cells in the pluripotent state by acting on a limited number of target genes. This fundamental concept has generated enormous excitement in the biomedical community, leading to successful reprogramming of somatic cells to an ES-like state. Yet, recent discoveries in our laboratory suggest that the complement of factors needed to direct ES cell pluripotency is considerably larger than originally thought.
Molecular control of stem cells
This project seeks to clarify the molecular function of Ronin, a member of the THAP (Thanatos-associated domain-containing apoptosis-associated proteins) gene family, and its biochemical role in specific cell types as they change fates. We propose that Ronin (and other THAPs) mediate promoter-promoter interactions to regulate gene transcription in a cell type-specific manner.
This project seeks to clarify the molecular function of Ronin, a member of the THAP (Thanatos-associated domain-containing apoptosis-associated proteins) gene family, and its biochemical role in specific cell types as they change fates. We propose that Ronin (and other THAPs) mediate promoter-promoter interactions to regulate gene transcription in a cell type-specific manner.
Cell competition
In this project we are studying how early embryogenesis and pluripotent stem cells are protected against genetic parasites through a primitive immune system. Retrotransposons can seriously damage the genome of the nascent embryo and cause sporadic diseases and infertility. Here we will explore a new sensing mechanism that involves early embryonic cells “sniffing” one another for endogenous retroviruses and the removal of cells that failed to silence their genetic parasites. Our line of investigation will provide new targets for genetic diagnosis and interventions targeting pregnancy loss, birth defects and childlessness.
In this project we are studying how early embryogenesis and pluripotent stem cells are protected against genetic parasites through a primitive immune system. Retrotransposons can seriously damage the genome of the nascent embryo and cause sporadic diseases and infertility. Here we will explore a new sensing mechanism that involves early embryonic cells “sniffing” one another for endogenous retroviruses and the removal of cells that failed to silence their genetic parasites. Our line of investigation will provide new targets for genetic diagnosis and interventions targeting pregnancy loss, birth defects and childlessness.
Developing new models for Parkinson’s disease
We have discovered methods to enhance the self-organizing properties of differentiating pluripotent cells to promote the proper development of mid-brain structures. Ultimately, we are creating patient-specific ex vivo models of PD using the methods we are developing to generate midbrain organoids from patient iPSCs. This will allow us to get a handle on the factors relevant to each individual’s unique manifestation of the disease. We are also conducting parallel screens in this system for neuroprotective small molecules.
We have discovered methods to enhance the self-organizing properties of differentiating pluripotent cells to promote the proper development of mid-brain structures. Ultimately, we are creating patient-specific ex vivo models of PD using the methods we are developing to generate midbrain organoids from patient iPSCs. This will allow us to get a handle on the factors relevant to each individual’s unique manifestation of the disease. We are also conducting parallel screens in this system for neuroprotective small molecules.
Quantum biology
In this project we explore non-classical (quantum physical) properties of early embryonic cells and neurons. The idea is that the current view that cells organize activities (like signal transduction or subcellular communication) via random walks among the staggering range of possibilities is incredibly unlikely. We propose instead a quantum mechanics-based relationship between molecular assemblies and elements of cell behavior. We are currently testing the prediction that cells harbor highly specialized structures that act in a quantum-computer like fashion to orchestrate cell function at a higher level.
In this project we explore non-classical (quantum physical) properties of early embryonic cells and neurons. The idea is that the current view that cells organize activities (like signal transduction or subcellular communication) via random walks among the staggering range of possibilities is incredibly unlikely. We propose instead a quantum mechanics-based relationship between molecular assemblies and elements of cell behavior. We are currently testing the prediction that cells harbor highly specialized structures that act in a quantum-computer like fashion to orchestrate cell function at a higher level.
