We want to see the immune system in action...
...right down it its chemistry.
We ask questions such as:
How do cells of the immune system respond to chemical stimulation? How do the location and the timing of stimulation affect the response?
How do local inflammatory chemical signals drive the chronic inflammation seen in autoimmune disease?
With these questions in mind, we build the microfluidic devices, chemical assays, and computational models that are needed to answer them. Ultimately, our work will create new tools to understand how the immune system is organized. We and others will use these tools to make progress towards therapies for diseases such as multiple sclerosis, Alzheimer's disease, and solid tumors.
We build two types of tools:
At their simplest, microfluidic devices are miniature plumbing systems built from channels that are tens to hundreds of micrometers (microns) wide. Because most cells from humans and other mammals are approximately 5 - 20 microns in diameter, microfluidic channels are ideally sized to manipulate and stimulate samples of cells and tissues.
We build microfluidic devices from glass, soft or hard polymers (plastics), or biomaterials such as agarose and gelatin. In all cases, the chemistry on the surface of the device can be modified as needed. For example, surfaces can be made hydrophilic or hydrophobic, cell-adhesive, or protein-repellent. The device can also be used to deliver controlled gradients of signalling molecules.
2. Bioanalytical chemistry
Cells in tissues communicate with one another by releasing proteins and small molecules that travel to their neighbor (or farther!) to carry a message. If we as scientists want to "listen in," most chemical approaches measure the molecules after they have been collected in a fluid -- cell culture media, serum, urine, etc. This approach relinquishes all information about where each molecule came from. In our lab, we specialize in detecting proteins and other biological signals at their source, in living tissue.
We have several lines of ongoing research:
1. Develop and utilize microfluidic platforms for ex vivo analyses of live tissue. For example, we developed the first microfluidic device capable of mimicking the localized stimulation that occurs in lymph nodes in vivo, by delivering localized chemical stimuli through a port beneath a sample of living lymph node tissue (see Publications). We have used this device to measure diffusion of active proteins through live lymph node tissue for the first time (featured in C&E News). We are now creating other innovative device designs to further control the environment around live tissue slices.
2. Design new biochemical assays to visualize the chemistry in living tissue. We are happy to share our method for “live immunostaining” of cells and structures in live tissue explants. We have assays in the works to detect secreted proteins, oxygen consumption, and glucose consumption in living tissue.
3. To enable projects 1 and 2, we first had to verify that live slices of lymph node tissue were useful as a model of immunity. We have spent several years gathering data on the viability and functionality of this unique tissue culture model. We hope to spread this useful system to other laboratories -- ask us for more information.
Applications: Chronic Inflammatory Disease and Tumor Immunology
Currently, attention in the lab is focused on developing tools to understand the mechanisms of chronic inflammation in the context of autoimmune disease and cancer immunology. Chronic inflammation arises when the immune system gets caught in an ongoing state of activation towards a target that cannot be cleared -- for example, against proteins in the joints (rheumatoid arthritis), in the gut (inflammatory bowel disorder), in the myelin that protects neurons in the brain (multiple sclerosis), or in a solid tumor. This state is poorly understood, in part because it is difficult to reproduce it in vitro, and in part because it is driven by a complex set of chemical signals -- cytokines and chemokines -- that have been difficult to quantify over time and with sufficient spatial resolution.