© 2016 by the Paszek Research Group

Lab Research

We image some of life's tiniest structures.  We love to think about the biophysics of glycans, because so few others do. We consider that disease could have a physical basis.  We hope that our work will make a difference.  Here is a sampling of our research efforts.

Engineering the cellular glycocalyx

 

Receptors on the cell surface control the flow of information from the cell's local environment to its decision making pathways.  When receptors and their target pathways malfunction, disease can result. This fact underlies why receptors account for more than 50% of our current drug targets.  A grand challenge that persists in biomolecular engineering is to coerce specific states of receptor activity that instruct autonomous tissue-level responses or can revert diseased tissue back to health. Virtually all attempts at addressing this challenge have emphasized altering the milieu of biological factors that bind receptors, engineering the structure of the receptors themselves, or targeting the downstream signaling pathways that receptors trigger. 

 

Our group takes a different approach and instead focuses on engineering the local medium within which receptors diffuse, assemble, activate, and signal.  Analogous to optimizing the solvent for thermodynamic and kinetic control over a chemical reaction, we target the dense, cell-surface structure called the glycocalyx, where receptors reside and function. Towards this goal, we are building a genetically encoded toolbox for engineering the structure and chemistry of the glycocalyx.  We believe that this biotechnology will be an important development in the early stages of physical inquiry in glycoscience and glycoengineering.

Genetically encoded toolbox
Metabolic reprogramming

 

Metabolic reprogramming is a hallmark of cell fate transitions.  When a stem cell becomes specialized or a normal cell transforms into a cancer cell, there are distinct changes in how cells process nutrients and resources.  We now understand some of the reasons why metabolism is altered in cancer cells.  Nutrients are preferentially diverted into pathways that make building blocks to construct new cells.  These building blocks include special sugars for the synthesis of more glycocalyx. We believe that having more glycocalyx biomass has big consequences for the cancer cell - it may help them grow, spread, and resist conventional therapies. 

 

We are now investigating these consequences as part of a national consortium of researchers mobilized through Cornell’s new Center for the Physics of Cancer Cell Metabolism.  Our group’s hope is that by targeting the cancer-specific metabolic program, we can choke glycocalyx production to make cells less aggressive and more responsive to conventional therapies. 

The glycocalyx: a metabolically regulated structural material

Optical imaging development – resolving life’s organizational code

The glycocalyx has long been considered a simple “slime” that protects cells from mechanical disruption or against pathogens, like bacteria and viruses.  We reason that it has evolved to do much, much more.  We are investigating the possibility that sugars organize some of life’s most important communication machinery on the cell surface. Testing this hypothesis requires us to overcome a major technical bottleneck. Traditional light microscopy has a resolving limit of about 200 nanometers, much too large to discern the tiny molecular details of the glycocalyx and other cellular nanostructure.

 

To tackle this problem, our group is developing custom microscopy methods that use interfering patterns of light to pinpoint molecular features in cells with greater accuracy.  We build these systems with high-speed optoelectronics from the ground up, including the development of our own microelectronics, firmware, and software.  The instruments and electronics are being developed as part of a multi-investigator collaboration on campus.  We also are actively developing new reagents and protocols to take advantage of other breakthroughs in optical imaging, including Expansion Microscopy and Single Molecule Localization Microscopy.  While our personal motivation is to apply these tools for physical glycoscience, we hope that they will be broadly applicable in the biosciences.

Custom interference microscope
Biomaterials design and mechanobiology

 

Cell sense physical information from the environment when they pull on their surroundings.   They process this information to help make important decisions, including whether to live, reproduce, and assemble into a tissue.  We are actively investigating how to encode physical directives into biomaterials to control complex cellular and multicellular programs.  A primary goal is to understand how surface chemistries can be tuned to program the desired deformability of biomaterials and emergent cell behaviors.  We are actively collaborating in this work with our colleagues in Theoretical and Applied Mechanics.

Biomaterials with physically encoded messages
Computational models

 

Theoretical models help us to test our hypotheses and generate new hypotheses.  We actively collaborate with leading theoreticians on campus to develop new models that describe the equilibrium and kinetic behavior of the glycocalyx.  A key goal is to relate transport phenomenon to the emergent spatial organization and mechanical response of the glycocalyx. Future efforts will incorporate principles from classical polymer physics.  These models will help us to understand how physical forces  can direct the organization of the cell's communication machinery.  We also hope to gain insight into how cells switch from an anchored to migratory state in metastatic cancer.

Glycocalyx
model