Egli Lab

About the PI, Dieter Egli

 

I was fortunate to be mentored and taught by pioneers in molecular and developmental biology, including Drs. Walter Schaffner, Ernst Hafen, Konrad Basler, and Charles Weissmann. During my PhD in the laboratory of Dr. Schaffner, my primary interest was in double strand break induced homologous recombination in the fruit fly.Realizing that finding cures required the study of human cells, I joined the laboratory of Prof. Kevin Eggan at Harvard University as a postdoctoral fellow funded by a Swiss National Science Foundation fellowship. In Kevin's lab, I studied how oocytes turn a differentiated cell into a pluripotent stem cell. We found that mitosis was a mediator of cell type transitions, in work that was published in the journal Nature. This research was motivated by the concept of 'therapeutic cloning', an idea born when Dolly the sheep was cloned, and when human embryonic stem cells were derived in the late 90ies. The combination of these two powerful technologies should allow the re-generation of any tissue and organ with a patient's own cells. For instance, it should allow the generation of insulin-producing beta cells, the cells that are lost in type 1 diabetes. This was a distant dream in 2005, when no one had made such personalized stem cells, and when no one had reported the generation of beta cells from human stem cells.

 

The path to get to these stem cells appeared straightforward: get human eggs and inject the nucleus of a skin cell, derive stem cell lines and turn the stem cell into a beta cell. However, none of it was as straightforward as it seemed when we set out to do this. Realizing this goal took two postdoctoral fellowships and two PI positions across three different institutions, required insights into the basic biology of human eggs, the acquisition of new skills, and fortunate circumstances. 

 

At Harvard University, our work followed the shocking revelation that earlier claims made by others on cloned human stem cells were false, and had to be retracted. After much initial enthusiasm at Harvard University about these studies, we soon realized that we would not obtain very many eggs due to regulatory hurdles related to funding of the research. In 2008, I moved to the New York Stem Cell Foundation Research Institute in Manhattan as a NYSCF-Druckenmiller postdoctoral fellow. There I showed that human eggs could reprogram a somatic cell to a pluripotent state. The study was published in Nature, and was my first as a senior author. It was named the medical breakthrough of the year 2011 by Time Magazine. In 2014, I was a group leader with a small research team, and we showed that cloned stem cells could be made from a patient with type 1 diabetes, a study that was again published in Nature.  

 

Patients at the Naomi Berrie Diabetes Center had donated the skin cells for stem cell derivation, and we now wanted to know if they could form beta cells. In 2014, I became Assistant Professor at Columbia University and started to build my research group there. The location at the Columbia University Medical Center was ideal to make connections between doctors, patients and researchers. Mice participating in research were also an important factor. We differentiated the stem cells to insulin producing beta cells and grafted them into mice to answer the question whether the patient matched stem cells could make functional, insulin producing beta cells. Indeed mice without their own beta cells could regulate their blood glucose normally because of the grafted human cells, a study that was published in the journal Diabetes.

We made the proof of principle, that therapeutic cloning in humans is possible. It is no longer a distant dream that personalized stem cells cure diseases that we can only manage today.

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Alongside these studies, we performed research on mitochondrial replacement, parthenogenesis, haploid stem cells, disease modeling, and the differentiation of pluripotent stem cells to hypothalamic neurons. 

 

Among the most surprising findings during these studies occurred while I was imaging the first division of the human egg after transfer of a somatic nucleus: chromosomes failed to segregate normally, and formed a chromatin bridge. Further investigation into the molecular mechanism showed that this was caused by cell type specific differences in chromatin affecting DNA replication, studies that were published in Nature Cell Biology. This points towards poorly understood links between genome stability and the identity of a cell. My group is now performing research to understand genome instability during development and during normal and induced cell type transitions.