Cole DeForest is the Dan Evans Associate Professor of Chemical Engineering and Bioengineering and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). He is the leader of a research group that, over seven years, has grown to include nearly 20 postdoctoral students, graduate students, and undergraduates. As an emerging leader in the future-edge field of biomaterials, he is also what you might call a reality-show producer for cells.
Essentially, DeForest and his team manufacture tiny bio-worlds staged to mimic living systems, force an eclectic cast of cells to cohabitate, apply light, heat, and chemicals to stir up drama, then record it all with sophisticated monitoring equipment.
Of course, the work has vastly more value than any semi-scripted content packaged for entertainment. The DeForest Research Group, primarily engineers by trade, partner with biologists and pathologists to study the fundamental processes that drive human development and to identify the root causes of diseases. The discoveries DeForest and his ISCRM collaborators make at the tiniest scales could lead to worldwide improvements in human health.
“At its heart, our group is a tool development lab,” says DeForest. “We design material platforms with tremendous user-customizability that can be applied to tackle many different biological problems. We engineer systems that allow biologists to answer questions they wouldn’t be able to otherwise.”
DeForest hints at an inherent challenge in the search for truths in living systems. Conditions in our cells, tissues, and organs are always changing. Particles move. Cells age. Snapshots will reveal only a sliver of a much more complicated story. Fundamentally, solving biological problems requires tools that allow scientists to observe cellular dynamics in four dimensions.
This fall, DeForest’s quest to arm researchers with new tools to study how the body works, and to understand what goes wrong when it doesn’t, received a major boost in the form of a prestigious five-year, $1.9 million Maximizing Investigators’ Research Award (MIRA R35) from the National Institute of General Medical Sciences (NIGMS). Specifically, the funding will allow DeForest and his ISCRM collaborators to pioneer methods to mimic, exploit, and quantify biological systems in full 4D complexity, accounting for dynamics across space and time in unprecedented detail.
For decades, scientists have cultured cells in two dimensions – an approach that cannot fully capture the heterogeneity found in our bodies. “In biological systems at every scale, no matter how you slice it, you’ll never find something truly uniform,” says DeForest. “There is always biochemical and biophysical variation, both spatially and temporally. Cells move and die, signaling is turned on and off, factors are temporarily secreted in response to others; everything is moving around and undergoing constant change. This is how biology functions in development, disease, and normal aging processes.”
In reality-show terms, the house where the motley cells from all walks of life learn to get along is known as a polymer-based hydrogel, essentially a synthetic micro-world with properties that match the composition of natural tissues. Crucially, the house is not static. Rather, it is highly tunable. That tunability is the secret to mimicking heterogeneity.
“When we say, tune, we mean regulate,” explains DeForest. “Just like adjusting the temperature or lighting in your house might trigger certain behaviors of the people living there, we can cue cells to move, replicate, or differentiate by introducing a combination of signals, like light or heat or chemicals, or by changing the stiffness.”
External signals administered by scientists are known as exogenesis cues. At the same time, the researchers are watching for endogenous cues from cells to better interpret what makes them tick. For example, in one investigation involving multiple ISCRM labs, DeForest used chemical cues to coax a diverse set of heart cells to organize themselves into a heart tube, all the while gathering data on how the cells communicate through time and space.
“Being able to expose stem cells to spatially controlled environmental signals and to show that you could achieve similar differentiation patterns to that accompanying human development hasn’t been done before,” says DeForest, speaking to the significance of unlocking the secrets of cells signaling.
Of course, just like us in our own homes, we rarely respond to one change in the environment at a time. To account for that complexity, DeForest uses a form of Boolean logic – the “or, and, not” paradigm familiar to anyone who has performed an advanced web search – to decode which combinations of signals seem to cue cells to behave in certain ways. In this fashion, they are exploiting the biological heterogeneity present in a living system.
“Different tissues and cells are going to have different chemical and physical signatures, and different biomarkers that define their state,” says DeForest. “Our goal is to come up with systems that interpret this heterogeneity, then act upon it in response to specific combinations of cues.” DeForest adds that such systems have tremendous use for basic scientific discovery, for disease modeling, and for more targeted, controlled drug delivery.
Jen Davis, Associate Professor of Pathology and Bioengineering and the Director of the UW Center for Cardiovascular Biology, collaborates frequently with DeForest. “As biologists, we are driven by questions about how life works and what causes things to go wrong,” says Davis. “Cole and his team give us the tools we need to answer those questions and solve real-world medical problems. Being able to not just observe, but to actually control and quantify biological processes has tremendous translational value.”
A third direction of research funded by the NIH grant involves quantifying heterogeneity in living systems. Exactly how much do conditions in cells, tissues, and organs really change through time and space? “Right now there is no real way to measure that at the protein level,” says DeForest. “The classic proteomics approach has been to identify and quantify all proteins present in a given sample and use that information to make predictions, but these traditional approaches give no definitive information about where and when proteins originated within a heterogenous tissue. We’re developing strategies to identify proteins originating from specific 4D locations, such that we can quantitatively map out protein expression throughout tissues. The resulting information should give us critical data towards accurately recapitulate the natural environment of cells.”
Behavior changes in time and space. Everything acts on the environment, and responds to it. And systems depend on diversity. For the DeForest Research Group, these themes apply on micro and macro scales. On the macro scale, DeForest stresses the importance of being a member of his own living system – the Institute for Stem Cell and Regenerative Medicine.
“Our group is good at innovating strategies to help investigators study and even control biological processes. But we need partners who can apply those tools for them to be truly useful. That’s what makes the connection to ISCRM labs so essential. Many future directions and past successes for our lab involve a different set of ISCRM investigators.”