Dr. Paul Tesar on Becoming a Scientist, his Research Goals, and his Newly Published Work

For the second in our series of researcher interviews, we bring you some thoughts from Dr. Paul Tesar, a member of the inaugural class of NYSCF Investigators.

Dr. Tesar has recently become Assistant Professor and Director of the Pluripotent Stem Cell Facility at Case Western Reserve School of Medicine where he works on directed differentiation of stem cells into oligodendrocytes to study diseases such as multiple sclerosis.

We talked to Dr. Tesar about his experiences in becoming a scientist and also discussed his most recent manuscript to be published tomorrow in Cell Stem Cell titled “Isolation of Epiblast Stem Cells From Preimplantation Mouse Embryos.” The full text is now featured on the Cell Stem Cell website and is currently available for free: http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(11)00049-X

Did any experiences in your childhood shape your interest in science and medicine?

Even from a young age I have always had a curiosity with how things work. Unfortunately for a countless number of radios, televisions, microwaves, computers, and lawn mowers, I spent a lot of time growing up (and still do today) disassembling things down to their core components in order to understand how they function. My mom is a nurse so I was exposed to science and medicine from a young age and I became fascinated with understanding the mechanisms that underlie the development and function of the human body.

Can you talk about some of the things you have learned about leading a research team since starting your own group at CWRU?

Since starting my new lab a year ago I’ve learned that being successful in science goes well beyond being ‘smart.’ Even in academia, leading a productive research team requires managerial and marketing skills for which most scientists have never received any training. Leading a lab is like running any other successful organization whether it is a large corporation, a small local restaurant, or a professional sports team. This involves assembling, managing, and motivating a great set of people (the research team), having exquisite quality control of the product (results & papers), marketing the product (presentations), sustaining a source of income (grants), environment (having great local resources and collaborators), constantly planning for the future (creative & innovative new experiments), and enjoying what you do.

Can you explain your research in terms the public can understand?

My lab is interested in understanding how different cell types in the nervous system are initially formed during development and how they are maintained throughout adult life. The hope is that by understanding these basic questions we will be able to prevent or repair damage caused by disease, aging, and injury.

What disease are you specifically working on and how did you choose that disease?

Research in my lab has the potential to impact a number of devastating neurodegenerative and mental health conditions such as Parkinson’s disease, ALS, Huntington’s disease, and autism. Currently, we are focusing on disorders that impact myelin – the insulating coat that surrounds neurons (the wires of the body). Loss of myelin, which is produced by a cell type in the brain called oligodendrocytes, results in an impairment in the body’s ability to send signals along the neurons. The incapacitating effects of myelin defects are typified by motor and sometimes cognitive deficiencies and readily apparent in diseases such as multiple sclerosis and cerebral palsy as well as a group of disorders called leukodystrophies which includes diseases such as Pelizaeus-Merzbacher disease and vanishing white matter disease.

What impact could your research have on these diseases?

Our goal is to develop innovative strategies to restore function in patients afflicted with myelin-based disorders. Therapeutic approaches may require either the transplantation of stem cells capable of remyelination or direct activation of stem cell populations already present in the body. Research is currently hindered since cells in the developing and adult human brain are not readily accessible to direct interrogation in the laboratory. Our current work utilizes stem-cell based approaches to generate pure and scalable populations of human oligodendrocytes and neurons to study in the laboratory. The hope is that we can then translate our findings into the clinic and restore function to patients afflicted with myelin-related disorders.

Can you tell us a bit about the background of your manuscript published today in Cell Stem Cell?

In 2007 we first reported the isolation and properties of mouse epiblast stem cells (EpiSCs) from post-implantation mouse embryos (Tesar, et. al. 2007) and this provided a major impetus for a number of studies evaluating the mechanisms that regulate a cell’s acquisition of one of two distinct pluripotent states (mES-like or epiblast-like). We showed previously that standard human ES cells are distinct from mouse ES cells and, paradoxically, share defining features with the post-implantation epiblast state. Since human ES cells and mouse ES cells are both derived from the pre-implantation embryo yet exist as different states in vitro, we analyzed the impact of extrinsic and intrinsic mechanisms on the acquisition of distinct pluripotent states when starting from pre-implantation mouse embryos.

What were you able to accomplish in this work?

In the current manuscript we show that both the mouse ES cell and EpiSC state can be routinely derived from the pre-implantation blastocyst. The acquisition of these states, however, is dependent on extrinsic signals provided in the culture medium as well as strain-intrinsic genetic elements in particular mouse strains. The derivation of EpiSC lines from pre-implantation embryos provides novel insight into the mechanisms regulating the acquisition pluripotent states in both mice and humans. Additionally, these results overcome a major barrier in the field by providing a reproducible means by which EpiSCs can be derived without the extreme technical demands of dissecting post-implantation embryos.

How does this affect the field of stem cell research?

Our current results significantly enhance understanding of the pluripotent ground states of the widely utilized pluripotent cell culture systems (ES, EpiSC, iPS, etc). A clear understanding of the lineage and properties of these pluripotent cells is providing us with a previously unobtainable level of control over developmentally relevant protocols to reproducibly differentiate pluripotent cells into functional cell types for study and potential therapy.