Cytocentric Visionaries: Tim Downing, PhD

This post is part of a three-part series from an interview that Dr. Alicia Henn, Chief Scientific Officer of BioSpherix, conducted with Dr. Timothy Downing. Finishing a post-doc at The Broad Institute of MIT and Harvard this year, Dr. Downing will soon be taking a post at UC Irvine and launching his own laboratory. Our conversation on his perspectives on the in vitro cell microenvironment was edited for brevity and clarity.

We met Dr. Downing at ISSCR 2015 and were impressed by his enthusiasm and his visionary work on the in vitro microenvironment. We invited him here to share his perspectives.

Why is epigenomics so important to iPS and ES biology right now?

TD: Reprogramming is actually a very interesting look into cell identity. I think it’s even broader than reprogramming. It has to deal with why a cell, any cell, takes on a certain fate or phenotype.

Epigenomics adds another layer that compliments transcriptomics, but is also distinct and, in some ways, can be more predictive that gene expression data alone. It gives you more confidence in what you see, and provides more insight into the role epigenetics plays in cell identity.

My work focuses on how the cell microenvironment influences cell behavior and cell fate, via epigenomic modulation. I want to understand how biophysical inputs or biomaterial properties influence cell fate through epigenomic changes.

What key factors have you found so far in the cellular microenvironment?

TD: My experience is in the mechanical or topographical properties of the surfaces that we’re culturing our cells on. We’ve shown that microgroove substrates can have a dramatic effect on histone modifications. And these things tend to be, in turn, related to that cell’s ability to reprogram back to pluripotency when you add the Yamanaka factors OSKM. Other people have looked at things like how substrate rigidity might change cell identity, in particular mesenchymal stem cell or ES cell specification. But other biological factors in the media, like serum proteins, these also have a big influence.

Like chemical moderators?

TD: Small molecules have definitely been shown to boost cell reprogramming. I think the addition of chemical factor is the typical approach and the promise of these methods has been well demonstrated by many seminal works. The approach of finding a small molecule or chemical that can have some effect on cell behavior, especially in terms of epigenetic modifications, I think certainly has its own mainstream.

A small molecule can easily be mixed in your media bottle before you add it to the cells, but it takes the right tools to be able to make certain cell culture surfaces. That capability is not accessible to every lab. I think that’s the limiting factor of why there is not more widespread control of these environmental material property components.

So technical capability is a limitation?

TD: I would say so, and also scale is a big problem. With only a small surface that we’ve fabricated to create a microgroove pattern, it’s hard to scale up to the point where you can get enough material for epigenetic profiling assays.

Is that why more people don’t go beyond flat plastic in vitro?

TD: We’ve been able to find a lot of information with polystyrene, 20% oxygen, 5% CO2. From an investment standpoint, you can certainly run a lab, and make significant contributions to the field with “standard” cell culture practices. But, now we’re getting to a point, technologically, where we don’t have to scale up our materials as much. I think very soon we’re going to see how much value there is in controlling for these environmental factors.

We can go back and look at a pathway in the situation where the cell hasn’t been essentially stressed out from this extreme oxygen environment or where it’s no longer in its native (elongated, for example) shape inside of the body. There is going to be a wealth of information that we’re going to get from now being able to control for all these factors.

The value of being able to culture and expand cells in a tissue culture dish is great, but if we can understand better how this extraphysiologic environment will change cell identity or state, then perhaps we can better predict from drug screenings on a dish how the cells might respond in its prior in vivo context. This is really a major part of the greater vision for this work.

Our conversation with Dr. Downing is continued in the next post, where we talk in more depth about controlling for microenvironmental changes to cells in vitro.

If you would like to be considered for a Cytocentric Visionary feature, please contact us here and tell us how your work fits the Cytocentric Principles.

 Tim Downing interview: Part 1, Part 2, Part 3