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An Interview with Patricia Labosky

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By Carla B. Mellough

 

A little bit of background about this month’s featured Investigator.

patricialaboskyI was born in Niagara Falls, NY. Both of my parents were physical education teachers in the secondary school systems in Niagara Falls and Lewiston-Porter, NY. Education has always been a critical part of my life and background. I was a bookworm and often thought I was effectively hiding the fact that I was reading in bed with a flashlight and a towel shoved under my bedroom door! I grew up and was educated in Youngstown, NY, graduating from high school as the valedictorian. I received a BA in Biology from the University of Pennsylvania in 1985 then my PhD in 1992 in the Department of Biology at Wesleyan University in Middletown, CT where I worked with Dr. Laura Grabel on the role of homeobox transcription factors in differentiation of embryonal carcinoma (EC) cells in vitro. One of my life changing/career shaping events was being a student in the ‘Molecular Embryology of the Mouse’ course at Cold Spring Harbor in 1990. Exposure to all of the great minds and exciting ideas in that class was mind-boggling. I was the only student in the class, the rest were postdocs and faculty members. This experience confirmed for me that I wanted to study, learn and understand mammalian embryology. I then joined the laboratory of Dr. Brigid L.M. Hogan at Vanderbilt University as a postdoctoral fellow. My work there focused on the derivation of stem cells from primordial germ cells and the role of winged helix genes in early embryogenesis. After accepting a position as Assistant Professor in the Department of Cell and Developmental Biology at the University of Pennsylvania in 1997, I continued my work on the role of winged helix genes in patterning the vertebrate embryo. I was recruited to Vanderbilt University Medical School in 2006 where I took the position of Associate Professor in the Center for Stem Cell Biology and the Department of Cell and Developmental Biology. Our work is focused on the molecular mechanisms required to maintain pluripotent stem cells and normal development of multipotent neural crest cells.

 

What was your original motivation for pursuing a career in scientific research?

I remember distinctly sitting in high school Biology class and Mr Strong, our teacher, told us that every cell in our body had the same DNA, so it was a real mystery how a cell in the eye knew how to do its job while a cell in the liver did something entirely different. That to me was a real “a-ha!” moment, and so simple yet so complicated. In college I had a couple of professors, Dr Steve Roth, especially, that I would just love to listen to in lectures. It became clear to me that these essential questions in cell and developmental biology were important to me, and the way I wanted to focus my career.

 

laboskyimage1What was it about the Fox family of transcription factors that initially grabbed your interest, leading you to focus much of your work on this?

Remember that this was back in the day when it was novel and a bit of a surprise that all these invertebrate genes were conserved in vertebrates. And transcription factors were viewed as the ultimate powerful master regulators in development. So when Hiroshi Sasaki in Brigid Hogan’s lab discovered all these Fox genes (back then they were called “mf” for “mouse forkhead”) it was terribly exciting. And I think the most exciting thing for me was to first see how their expression patterns were so exquisitely distinct. We also had the tools to start to explore function and this opened so many doors. However, my interest always circled back to early stem cells so when I found one of these genes that allowed me to ask precise questions about stem cell properties, that’s when I got really excited.

 

Much of your work has focused on the study of the transcriptional control of the neural crest and ES cells. In your opinion, what has been your most exciting discovery, and why?

This is a really hard question. One answer is that we have shown quite nicely a molecular conservation of stem cell properties. We’ve shown that extremely disparate stem/progenitor types in the embryo and in vitro critically depend on a single transcription factor (Foxd3) for survival, self-renewal and multipotency. We have yet to determine how this works at a genetic regulatory network level and this is one of the things we are actively pursuing now.

 

How easy or difficult do you find it to keep abreast of the vast volume of new literature in the field?

This is a challenge and one that directly relates to how to spend/organize time. But keeping up is always hard. Online resources make it much easier to not “miss” a paper and I find that attending national meetings is also a huge help. I do read a lot, but I also want to make sure people in my laboratory are reading and getting all of this information, too. So one way we manage this is that we have one lab meeting per month dedicated to a journal review. We divide up journals, everyone has 2 or 3 and we report on the articles of interest in each of those. We also report titles that we think might be relevant to someone else in the group. This keeps everyone fresh and more than once helped us solve problems in the lab and given us some great ideas to follow up on.

 

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How important is a collaborative approach in your research and how multidisciplinary has this been/is this becoming, in your experience?

I think this is extremely important. We have benefited greatly from having neighbours and colleagues who are interactive and open to new ideas and ways to approach things. Vanderbilt has an extremely interactive community where this behaviour is rewarded in many ways. We have weekly group meetings with researchers in our Stem Cell Center and in our Program for Developmental Biology (obviously partially overlapping) and this has led to a fruitful cross-fertilization on many levels. It has allowed us to expand our use of select technologies and ask better scientific questions. It also provides a fantastic training environment for students and postdocs.

 

What would your words of advice be to young researchers trying to find their way in the stem cell field and obtain funding in this highly competitive field and under the current economic climate?

I would tell them to learn embryology - in any model system, not just mammalian embryology. The embryo knows how to make a pancreas or a specific type of neuron. Although directed differentiation protocols clearly cannot recapitulate embryology exactly, it’s obvious that the ones that work the best take clues from the embryo and use this knowledge to generate cells of interest.

 

It seems that the barrier is always being raised for the achievement of success in publishing manuscripts and obtaining funding. What effect do you think this has on the research that is being undertaken and the way in which it is conducted?

Publishing papers has always been a challenge. But, I think the funding difficulties have slowed overall progress considerably and created an incredibly non-level playing field. I also think it has driven many young people away from research science as a profession.

 

laboskyimage3How do you think the current funding situation will affect the progression of stem cell research in the short and/or long term?

It’s a real concern that smaller labs are having a very hard time getting funding and this contributes to the un-level playing field I mentioned above. These labs are essential not only for primary research, but also for training excellent students and postdocs. I came from a smaller graduate program and I feel I was trained extremely well to think critically and attack problems technically and creatively.

 

There has been a huge shift in public thinking about the use of stem cells for research and to ameliorate human disease. In your opinion, what are the main barriers that still remain for the clinical translation of hESC? How do you foresee these being overcome?

I think the main barriers to effective clinical use of hESCs (or hiPSCs) are still tumor formation and efficiency of directed differentiation. This is not a new concern. We still don’t understand the pathways regulating self-renewal and multipotency, and until we do, I think those problems will always be there.

 

A number of recent articles implicate that induced pluripotent stem cells (iPSC) may be more dissimilar to hESCs than was initially thought and thus cast some doubt over the applicability of iPSC for the treatment of human disease. In your opinion, how important do you think these differences are?

I think the differences between iPSCs and ESCs are critical to understand, but they are really not surprising. There have always been differences between ESC lines and especially ESC lines from different strains of mice. My work with Brigid Hogan showed in 1994 that EGC lines were not like ESC lines in terms of genomic imprinting (epigenetic status). These differences are not insurmountable, and in fact they might even be useful once they are more fully understood.

 

In your opinion, what do you consider to be the most important advance in stem cell research over the past 5 years?

iPSCs, no doubt.

 

What are your hopes for the future stem cell research and clinical translation in your specialist area?

My hope (and expectation) is that I will see ESCs (or iPSCs) in clinical use during my lifetime, safely and effectively!