- Research Overview
- Chemical Biology and Medicinal Chemistry
- Chemical Biology and Medicinal Chemistry Overview
- Discovering Enzyme Substrates and Functions
- Discovering Protein Ligands to Probe and Alter Function
- Discovering Enzyme Activators
- Analyzing Mechanisms of Drug Resistance via Chemical Biology
- Analyzing Enzyme Conformational Dynamics, Substrate Binding, and Catalysis
- Effective Drug Targeting of Pathogens via Medicinal Chemistry
- Computational Chemistry and Biology
- Computational Chemistry and Biology Overview
- Modeling protein regulation via allostery and post-translational modifications
- Visualizing and integrating bioinformatics and biomolecular data
- Modeling membrane permeation to optimize pharmacokinetics
- Determining enzyme function by predicting substrate specificity
- Physical Biology
- Protein and Cellular Engineering
- Protein and Cellular Engineering Overview
- Monitoring enzyme activity and disease biomarkers
- Generating human proteome antibodies via phage display and directed evolution
- Globally analyzing and dissecting apoptosis
- Proximity tagging of protein-protein interactions
- Investigating cellular interactions in tissues
- Creating fluorescent probes targeting the genome and key bio-pathways
- De novo design of catalytic and membrane proteins
- Probing and modulating membrane proteins
Investigating cellular interactions in tissues
Examples of our research and methods include:
Total synthesis of complex self-assembling tissues
Researchers here are developing new ways to rapidly and precisely build detailed, complex, three-dimensional human tissues in vitro, including structures that self-assemble with programmed composition, thus controlling which cell-types interact and the spatial arrangement of groups of cells for experimental alteration and analysis.
Such tissue building is comparable to total synthesis, the process in organic chemistry in which complex biologically active molecules are built from more basic chemical building blocks. Just as creating physically similar but slightly altered molecules (structural analogs) helps reveal structure-function relationships and new chemical principles, so constructing tissues from specific cell types should yield new insights into tissue organization and cellular interactions.
Using the human mammary gland as a model, department scientists engineer self-assembling tissues with programmed cell-type composition. Initial connectivity is directed by coating cell surfaces with short segments of DNA strands with complementary base pairs. The results of these initial combinations are then grown in gel matrices to provide a physiologically relevant 3-D spatial context.
Researchers here are working toward building a functional human mammary gland. They are starting with modular substructures, such as the lining of the milk ducts, made of two cell types in layers, and working up a hierarchy of complexity incorporating the ducts with blood vessels, immune cells, and connective tissue.
These models will provide new insight into how normal human tissues assemble during development, and conversely, how they break down in diseases such as breast cancer. Indeed, the synthesized models will use healthy cells and, for certain studies, their malignant derivatives, in structures controlled down to the positioning of individual cells. This will enable analyses of how cellular heterogeneity, injury and/or disturbances in the relay of signals among different cell types contribute to breast cancers.
Our applications of such cellular engineering include:
Building breast tissue to study effects of cell heterogeneity
Department scientists build mammary microtissues with programmed cellular heterogeneity in the cancer-related Ras protein to investigate the effect of such differences on coordinated cellular processes such as tissue structural formation, i.e., morphogenesis. (A hallmark of most tumors is increased cellular heterogeneity.)
A study found that in such growing mosaics (in which about one in five of the cells expressed over-activated Ras) abnormal cells were extruded, protruded, or exited from the tissues, exhibiting behaviors commonly associated with invasive tumors. Homogenous tissues, even comprised of all abnormal cells, did not. Thus heterogeneity in cells’ Ras activity, rather than total Ras activity, appears to be necessary in the development of some of the abnormal behaviors.