Our overarching research vision is to harness the natural behavior of human cells in order to understand and improve health. The challenge in achieving this goal is identifying how cells’ natural behaviors (e.g., proliferation, migration) are constrained by molecular signaling. In other words, how are cells engineered? What principles are fundamental to their design?
Cellular Processing and Communication during Tissue Growth
We first started addressing these questions in the context of a biological phenomenon integral to human life: how cells respond to limited oxygen, or hypoxic response. Hypoxic signaling, fundamental to life on oxygen-rich Earth, requires a delicate balance of complex molecular interactions in order to maintain the health of cells. Overactivation of these pathways leads to aberrant growth associated with cancers and inflammation, while limited functional activation of these pathways can decrease human tissue’s natural ability to self-repair after a wound, brain injury or stroke.
Code-Breaking: When we started studying hypoxic response in the context of brain microvascular growth and the progression of leukemia, we soon realized it’s not a single molecule, or even one set of pathways that was the key to breaking the code of cellular communication. It’s uncovering the complex coordination of many dozens if not thousands of pathways which would enable us to understand how human cells communicate during tissue growth. The scope of the problem required a new set of instruments to inform discoveries. We began building. To study cellular communication, we develop methods that capture dynamic features of patient cellular data and live cell assays. We couple these methods with modeling that allows us to make predictions about single cell behaviors and cell-cell interactions. Our basic science findings are enabling us to identify potential new therapies for cancer and ways to regenerate the neurovasculature after stroke and other neurological damage.
Modeling & Experiments
At heart an engineering design problem, the complexity of understanding the design of human cells across spatial scales requires an interdisciplinary solution, combining expertise from mathematics, computer science, neurovascular biology and cell biology. We work at the interface of these fields, and develop integrated experimental and computational methods to uncover human cell design principles in the context of hypoxic response and co-regulated pathways.
We provide our methods, software, and data as resources to the scientific community, along with applying them for our own studies. Methods we’ve published can be found on the lab’s website, Github page, or by directly contacting us.
Cells of the Brain Microvasculature
Methods developed in the lab enable us to address the following questions about human cell design; and test hypotheses about tissue formation: (1) What ways do diverse (and at times competing) biochemical, spatial and electrical cues integrate to define a cell’s state? (2) How do cells interact with each other to form tissue? (3) Can we use knowledge gained in answering these two questions to guide clinical decisions? We focus on addressing these questions in cells of the brain and bone marrow – tissues where hypoxia plays a particularly critical role in health and disease.
Regeneration and Regulation of Brain Cells & the Neurovasculature
Neural progenitor cells, multipotent cells capable of forming neurons in adult brains, are some of the main cell types involved in the brain’s self-repair mechanisms after injury or disease. We study how these cells develop from pluripotent stem cells, and continually communicate with each other and neighboring cells of the brain microvasculature to differentiate into functional neuronal networks. Four synergistic projects fall under this theme: (1) Characterization of Neural Progenitor Cells’ Formation into Electrically Active Networks (Mahadevan et al., 2018; Video Clip, 2015); (2) Neural Lineage Tracing; (3) Cytoskeletal Patterning of Endothelial Cells as a Function of Neurotrophic Factors (Mahadevan et al., 2018); and (4) Multiscale Models of Microvasculature Formation (Noren et al., Sci Signaling, 2016; Long et al., J Theor Biol, 2013; Qutub et al., IEEE EBMS 2009). Related work focuses on understanding cancerous growth in the brain as a function of metabolic signaling pathways and changes in metabolism (Ranganathan et al., 2018; Lin et al., PLOS Comp Bio, 2015;Video Clip 2015).
Global Molecular Pathway Analysis
The paradigm that healthy cells transform into cancerous cells through a key minimal set of functional traits was introduced by Hanahan and Weinberg over 15 years ago. These traits or “hallmarks of cancer” include cell processes like evading apoptosis, sustained angiogenesis, and ability to replicate. Hanahan and Weinberg defined the hallmarks conceptually based on synthesizing and interpreting a large body of cancer studies. Our goal has been to discover whether a quantitative basis for functional hallmarks exist. To do so, we’re analyzing healthy and cancerous cells, to interpret computationally and experimentally, patterns in their post-translational signaling and metabolism. We’re asking: can hallmarks of health be defined to reflect a minimum set and sequence of possible molecular signaling pathways that either sustain cell health, or lead to malignancy? Can these new hallmarks quantitatively predict cancer patient outcomes?
A strength of focusing the lab’s projects on human cells and working closely with our clinical collaborators is that the basic science can lead to near-term changes in medicine. For example, the global proteomic analysis of leukemia patients’ cells is uncovering how unique combinations of signaling pathway utilization leads to different therapeutic responses for standard chemotherapies. As another example, while studying the fundamental mechanisms of how neural progenitor cells communicate as they form neuronal networks, we’re starting to ask how that cellular communication changes with age and during cognitive decline. Algorithms from the lab have been applied to design clinical trials, biomedical researchers from hundreds of cities worldwide have used our cloud-based software to interpret data, and potential new drug targets have been identified for patient cohorts.