Cellular Networks - from Robust Function to Catastrophic Failure

Our lab studies the response of cellular networks to changing environments in health and disease. While the structure of regulatory pathways is studied extensively, far less is known about network re-organization under time-varying stimuli. Yet this under-explored dimension has broad implications – time-variant stimuli can culminate in extreme outcomes, from detrimental signaling catastrophes to anticipatory stress responses. We combine experimental and theoretical approaches to dissect network functionality and uncover its unique points of failure. We aim to exploit the network structure to therapeutically target subpopulations of diseased cells within a healthy host. 


CHARACTERIZING THE DYNAMICS OF SIGNALING NETWORKS IN HEALTH AND DISEASE

Cells need to process and integrate different, fluctuating and potentially contradictory external signals before mounting a suitable response. This challenge is facilitated by dense and highly dynamic regulatory networks that operate within cells and have been optimized during millions of years of evolution. Our lab aims to characterize the information processing preformed by canonical MAPK signaling cascades in healthy human cells, and to uncover how it malfunctions during diseases like Cancer. Our studies explore how a stimulus is perceived by individual cells. We monitor aspects as emerging group behavior and population outliers that are thought to underlie the resilience of some tumors to targeted therapy. Our lab collaborates with diverse groups to test the effects of newly synthesized inhibitors on cellular behavior and to integrate our findings on the level of the whole organism.

Isogenic population of human cells responding to targeted therapy. Individual cells activate alternative response programs (red and blue fluorescent reporters).

Isogenic population of human cells responding to targeted therapy. Individual cells activate alternative response programs (red and blue fluorescent reporters).


Inhibition of cancer cell growth with targeted drug therapy is restricted due to rewiring of regulatory networks. A subpopulation of cells that have adapted to the drug within a two day treatment is marked by a green dye indicating that they are actively proliferating.   

Inhibition of cancer cell growth with targeted drug therapy is restricted due to rewiring of regulatory networks. A subpopulation of cells that have adapted to the drug within a two day treatment is marked by a green dye indicating that they are actively proliferating.   

UNCOVERING THE MECHANISMS OF CELL ADAPTATION TO TARGETED THERAPIES

In recent decades substantial progress has been achieved in designing drugs for targeted cancer therapy, yet resistance remains a major challenge that limits the overall clinical impact. While most efforts are dedicated to characterize the genetic mechanisms of resistance that evolve after months of therapy, emerging evidence suggests that cells can also adapt within much shorter time scales by rewiring their signaling and regulatory networks. Research in our lab aims to elucidate the dynamics of network rewiring that takes place during drug adaptation and to test the potential of dynamic dosing strategies to mitigate adaptation. By doing so we hope uncover potential points of failure in network dynamics that can be exploited as an Achilles’ Heel to re-sensitize diseased cells to commonly used drugs.


Cell growth monitored by time-lapse microscopy of yeast cells reveals alternative dynamics of growth. While some pairs grow in synchrony (i). most pairs quickly de-synchronize from each other (ii).  

Cell growth monitored by time-lapse microscopy of yeast cells reveals alternative dynamics of growth. While some pairs grow in synchrony (i). most pairs quickly de-synchronize from each other (ii).  

ELUCIDATING THE EVOLUTIONARY DESIGN PRINCIPLES UNDERLYING CELLULAR CIRCUITS

A major challenge of biological research is to identify the common design principles that are shared between diverse organisms and cell types. Our lab uses model microorganisms as a toy system for approaching fundamental questions in Evolution and Cell Regulation. In these studies we combine experimental and theoretical approaches to examine how existing regulatory circuits function and compare their performance with alternative circuits that we design and construct in the lab. This Synthetic Biology approach allows us to elucidate the evolutionary constraints shaping existing regulatory networks. The emergence of asymmetric cell division during evolution is one fundamental question that fascinates our lab. In this line of research we use yeast cells as a model system that naturally divides asymmetrically in order to quantitatively evaluate the benefits and potential costs of asymmetric cell division.


designing and constructing our own hardware

We design and construct the hardware platforms we use for controlling light and fluidics. 

We design and construct the hardware platforms we use for controlling light and fluidics. 

A common goal of many of our projects is to study cell regulation in dynamically changing environments. This line of research requires the use of novel technologies, as microfluidics and optogenetics, amenable for creating time-varying stimuli profiles. Our lab implements a DIY approach and develops its own platforms for delivering dynamic inputs. We design the hardware required for many of our experiments and construct them using “Maker” tools as laser cutters, 3-D printers and programable micro-controllers. This DIY (do it yourself) approach allows us to custom-engineer the toolset required for delivering dynamic stimuli with high temporal resolution and to uncover the time-varying inputs that drastically alter cell behavior. We welcome collaborations with other bio-hackers and are establishing an open access maker-space for this type of work.