Pluripotency Surges Ahead: A Grad Student’s Perspective on the Keystone “Stem Cell States” Symposium

By Justin S. Becker

At the base of Steamboat Mountain in Colorado, a remote winter paradise on the verge of thaw, a community of scientists held a specialized meeting in late March for the nexus of two of the hottest fields in biology: Stem Cell Research and Epigenetics. Stem cells are the rare population of progenitor cells, found in the early embryo or certain adult tissues, that have the power to develop into multiple types of cells in the body. Harnessing this potency of stem cells has tremendous potential for the therapeutic replacement of damaged or diseased tissues, so-called “regenerative medicine.” Since all the cells in our bodies have the same DNA sequence, the transition from stem cells to more specialized cells occurs not by adding or removing genes, but rather by turning genes “on” or “off” in terms of the their activity in making proteins. These persistent changes in gene activity take place “above” or “beyond” the DNA sequence itself, and hence are termed “epi”-genetic.

The scientific conference in Colorado, organized by Keystone Symposia, was titled, “Transcriptional and Epigenetic Influences on Stem Cell States” – a mouthful to be sure, but one that expresses the researchers’ common interest in how stem cell potency is governed on the genomic level. Thanks to support from Kerafast, I could take part in this exciting symposium, hear talks from some of the most renowned stem-cell biologists in the world, and give a poster presentation on my own research in the field. I was able to meet and talk science with many of my scientific idols, including Rudolph Jaenisch, Jacob Hanna, Rick Young, Stephen Dalton, Bradley Cairns, and others. I made connections with like-minded graduate students and post-docs, including trainees from Boston and the West Coast, from Canada and the UK, from Munich and Israel. The scientific conversations were rich and taught me to lot, whether they took place in the coffee or meal breaks between presentations, or afterhours on the ski lifts or at the bar. Needless to say, it was a highly stimulating way to spend the week, not to mention a tremendously fun one as well.

A major theme that stuck out to me over the course of the meeting, as I listened to the many breakthroughs described, was the rapid progress that has been made in understanding the biology of the early embryo. The earliest stages of development of a mouse or human embryo are of great interest in the field of stem cell biology, because it is this point when stem cells are “pluripotent” – meaning they have the capacity to give rise to all types of tissues in the body. Three separate research groups discussed new methods for converting traditional human embryonic stem cells—that is, pluripotent cells that can be maintained in a plastic dish—back to an even earlier “naïve” phase of development, a stage previously thought to be inaccessible for human cells in vitro. Though much remains unknown about the properties of the new cells, a hope is that they will have enhanced potential for generating mature tissues of therapeutic importance. Two other speakers reported discoveries of methods for dramatically enhancing the conversion of differentiated cells (such as skin cells) back to the pluripotent state. These conversions or “reprogramming events” are traditionally very inefficient, but these groups discovered ways to alter the epigenetic state of the starting cells such that the reprogramming proceeds in many more cells and at a faster rate. Other investigators, meanwhile, have succeeded in analyzing the earliest cell divisions of the mouse embryo, revealing with unprecedented resolution the changes in cellular structure and gene activity that occur as the embryo develops in vivo.

This rapid growth in our understanding of pluripotency is a tremendous achievement, but it also casts in sharp relief the areas in which progress has been slower. As the isolation or production pluripotent stem cells improves, our ability to direct the stem cells toward various mature lineages – of the kind that would have function for therapeutic transplantation – has lagged behind. There exists a variety of methods for the in vitro generation of specific kinds of differentiated cells, but a unifying theme among these methods is that the cells produced do not completely resemble their natural counterparts, and as a result, such cells are generally unfit for clinical transplantation. Some of the biggest advances reported at the Keystone meeting helped to underscore, rather than solve, this problem. Specifically, a few research groups reported new, sophisticated methods for analyzing the gene activity signature of particular cell populations, and they found that the differentiated cells generated in vitro had signatures of either an immature cell state or of the wrong cell type altogether. On the bright side, this close-up view of the precise epigenetic deficiencies of these cells should inform efforts to improve their quality.

It was a privilege to be able to attend this major conference at what feels like a transition point in the stem-cell field. I was able to learn about numerous scientific developments that will inform my own research, and in the process I gained a firmer sense for the “gaps” in the field that warrant greater attention. I returned feeling inspired, and anxious to get back in the lab.

Justin S. Becker is an MD-PhD combined degree candidate in the laboratory of Kenneth S. Zaret at the University of Pennsylvania Perelman School of Medicine.