October 29, 2020

The Niche

Knoepfler lab stem cell blog

Jaenisch’s 5 key action items for the ES and iPS cell field

This morning on day two of the World Stem Cell Summit here in Pasadena, Rudy Jaenisch of the Whitehead Institute gave the scientific keynote address.

It was a fabulous talk.

Jaenisch, accurately described by Bernie Siegel as a true giant of the stem cell field, outlined the key issues facing the field of highly pluripotent stem cells including ES cells and iPS cells. One of the things I enjoyed so much about Jaenisch’s talk was the way he has a laser focus on the most important issues from a perspective of using stem cells to improve human health.

I could write pages about what was in this talk, but let me summarize it into key action items.

1) A critical challenge for the stem cell field is that every stem cell is different. Even if one takes genetically identical cells and starts growing them under different conditions, the cells become different in important ways such as tumorigenicity. One important factor is oxygen tension but I believe that there are many more factors.

2) Why are mouse stem cells so different from human stem cells? Generally mouse stem cells are easier to work with and have characteristics such as high cloning efficiency and manipulability that could be very helpful for regenerative medicine, while human cells lab behind. Understanding these differences should provide new ways to establish and grow human ES and iPS cells that have more desirable properties for regenerative medicine.

3) What are the 3 main goals of iPS/ES cell research? To study human diseases in a dish, to screen for new drugs for targeted therapies, and (the one most people think about) to produce customized cell therapies.

4) Huge question–what is a good ES or iPS cell? If we do not know what makes for what Jaenisch calls a “good” ES cell or iPS cell, then we cannot find it, right? I would say one characteristic is low tumorigenic potential coupled with high pluripotency. However, we do not have all the answers to this mega question. So in a way we have kind of gotten ahead of ourselves. My postdoc Bonnie and I recently did a commentary, Inducing iPS cells to escape the dish,  in Cell Stem Cell on the issue of what is a good iPS cell and how can we make them more clinically useful.

5) Why are iPS cells produced in extremely similar ways exhibiting very different properties? It turns out that the stoichiometry of the reprogramming factors meaning their relative levels as proteins is at least one key reason.  What this also means is that unless any given iPS cell line is clonal (meaning derived from a single cell), then even within any single iPS cell line there are going to be very different cellular properties. Even under clonal conditions the cultures are likely to undergo what we call “drift” meaning different subpopulations will emerge with unique properties. Of course this issue of heterogeneity has enormous clinical implications.