Daniel A. Hammer

Research Interests

                 Cell adhesion. In cell adhesion, our primary focus has been on the dynamics of adhesion mediated by blood-borne cells in the microvasculature. This type of adhesion is ubiquitous in physiology – it is displayed by leukocytes to enter tissues during inflammation, stem cells to home to bone marrow to regenerate tissues and during transplants, and metastasizing cancer cells to enter secondary tumor sites. We have developed novel experimental and theoretical tools to measure and manipulate this type of adhesion.

                 To understand adhesion, we have developed a suite of computational techniques that allow us to model the adhesion of cells to surfaces. This method, called Adhesive Dynamics, combines stochastic simulation of bonding dynamics with an accurate mechanical description of a cell. We have developed a diversified suite of Adhesive Dynamics algorithms, which allows simulation of the rolling and stopping of leukocytes, the docking of viruses to cell membranes, and the collective adhesive behavior of many cells. Our current efforts are focused on developing AD algorithms in which we embed signal transduction networks within cells, and the outside-in flow of chemical information leads to intermolecular conversions that result in changes of adhesion. We are using these new algorithms to understand how chemokines control the stopping of leukocytes and the trafficking of lymphocytes to lymphoid organs.

Cell Motility. After leukocytes dock at inflammatory sites, they change shape and crawl to their targets. These cells are amoeboid, crawl quickly but exert small forces. In collaboration with Micah Dembo (Boston University) we have used traction force microscopy (TFM) to image the forces that neutrophil leukocytes exert during chemotaxis and chemokinesis. We have found that neutrophils exert their largest stresses in the rear, that cells undergoing chemotaxis exert larger stresses than chemokinesis, and that changes in direction are preceded by changes in the uropodial force center at the rear. We are now exploring how the internal molecular machinery of the cell is related to the force generation using knock-out mice and engineered cell lines.

Polymersomes. We have extended the theme of cell mimicry to make novel cell-like materials from polymers. In collaboration with Frank S. Bates (CEMS/Minnesota) and collaborators from Penn, we have used di-block copolymers that self-assemble in water to form the lamellar phase, and made closed shell vesicles from them. Called polymersomes, these vesicles have superior and tunable properties that make them suitable for imaging and drug delivery, especially when compared to phospholipids vesicles. A particularly exciting application has been to make emissive polymersomes, in which porphyrinic molecules synthesized by Mike Therien (Chemisry, Penn) are embedded in the membrane. These vesicles can emit light in the near infrared and are suitable for deep tissue imaging. We are pursuing applications of these polymer vesicles to drug delivery in cancer, tracking of dendritic cells during immune processes, and construction of leuko-polymersomes – polymersomes with the adhesive properties of leukocytes – which can be used for treating inflammatory diseases.

Viral  infection. We are interested in the molecular mechanisms by which viruses attach to and infect cells. We have performed detailed computer simulations to study the mechanisms of HIV docking. Aside from the obvious clinical importance, HIV is an interesting biophysical chemical system that employs trimeric attachment proteins and uses two distinct receptors for entry. We are studying how the assembly of bound trimers, which are required for entry, is dynamically regulated. Further, in an effort to elucidate the optimal cell receptor composition for viral entry, we are studying the relationship between receptor density and receptor type and the dynamics of viral binding.

Tissue self-assembly. We are exploring the factors that influence the assembly of cells into functional tissues. We are guided by the Differential Adhesion Hypothesis, which claims that differences in adhesion drive tissue assembly. Using angiogenesis and breast epitheilial cells assembly as models, we are exploring the role of differential adhesion in controlling the self-assembly cellular architectures. We are using imaging to observe endothelial cell decisions during two-dimensional angiogenesis, and cell-cell assembly can be controlled by substratum adhesive strength, matrix elasticity, and matrix micropatterning. Also, in collaboration with Valerie Weaver (UCSF) we are using similar techniques for assembling breast epithelial cells in culture, to understand how matrix architecture and material properties are related to breast oncogenesis. We have found that durotaxis – the interaction of cells through substrate deformation – is a critical determinant of cell assembly, and that cells can sense and respond to their neighbors through substrate mechanics.