Human health has been transformed by our collective capacity to engineer immunity – from the pivotal development of the smallpox vaccine to the curative potential of recent cancer immunotherapies. These examples motivate our research program that is conducted at the interface of Engineering and Immunology, and where we develop biomedical technologies and applications that shape a diverse array of immunological systems.
The questions that are central to our exploration include: How do we begin to study an individual's repertoire of well over one billion immune cells when current technologies only allow us to study a handful of cells at a time? What are the biomarkers of immunological health as the body responds to disease and ageing, and how may these indicators trigger clinical decisions? And how can we genetically rewire immune cells to provide them with entirely new functions to better fight complex diseases such as cancer?
To aid in our studies, we use high-throughput technologies such as next-generation sequencing and quantitative mass spectrometry, and pioneer the development of micro- and nanotechnologies in order to achieve our goals. We focus on clinical problems in cancer, infectious diseases and autoimmunity, and ultimately strive to translate key findings into therapies for patients.
Thematic research programs at LSI. We develop biomedical technologies focused on profiling immune repertoires, sensing cell activities in living systems and augmenting cellular responses.
Profile: DNA nanotechnology
Our immune system is comprised of hundreds of millions of distinct immune cells that protect the body from innumerable micro-organisms, but its complexity makes it incredibly challenging to study. One of the simplest questions to ask in medicine relates to the composition of an individual’s repertoire of immune cells. Why is this important? Because it turns out that an individuals’ repertoire is identical to no one else’s; the genetic mechanisms that evolved to produce and mature immune cells (specifically B and T cells) ensure that this is so. One serendipitous consequence of this diversity is that individuals produce rare immune cells with the ability to recognize and eradicate complex human diseases such as cancer as if it were the common cold. Indeed among the most exciting advances occurring in oncology today is learning how to harness and engineer T cells to treat cancer without the debilitating side effects of chemotherapy or radiation.
We are developing high-throughput methods that leverage advances in DNA nanotechnology to profile and explore the immune repertoire at depths currently challenging to achieve by conventional approaches. As an example, we design synthetic DNA gates that interface with immune cells according to their expression of cell surface markers, allowing us to isolate and perform large-scale analysis of antigen-specific T cells. These technologies may accelerate the development of vaccines and immunotherapies, and provide new ways to monitor immunological health.
Sorting cells using DNA. (a) Schematic of approach. Fluorescent image of pMHC microarray used to sort T cells specific for tumor antigens (green, MART-1; red, Tyrosinase). (b) Single cell capture of viral-specific T cells (arrow, EBV)
“Individually addressable and dynamic DNA gates for multiplexed cell sorting” Proc. Natl. Acad. Sci. USA 115(17) 4357–4362 (2018). [DOI: 10.1073/pnas.1714820115]
“Modular nucleic acid assembled p/MHC microarrays for multiplexed sorting of antigen-specific lymphocytes” J. Am. Chem. Soc. 131(28), 9695-703 (2009). [DOI: 10.1021/ja9006707]
“DNA-encoded antibody libraries: a unified platform for multiplexed cell sorting and detection of genes and proteins” J. Am. Chem. Soc. 129(7), 1959–67 (2007). [DOI: 10.1021/ja065930i]
Sense: Synthetic biomarkers
Many different types of nanoparticles – particles one thousandth the width of a human hair – are now found in experimental medicines ranging from metallic nanoparticles that produce heat and kill cancer cells to iron-based nanoparticles that increase the contrast of medical imaging such as MRI. We recently developed a class of nanoparticles called ‘synthetic biomarkers’ that are designed to detect cancer at its earliest stages when treatments are most effective. Our approach is inspired by the way malignant cells spread; cancer cells produce a class of enzymes called proteases in order to break down the surrounding tissue during growth and colonization. Our nanoparticles are coated with peptides that mimic the connective tissue, allowing cancer-specific proteases to cleave peptides from the surface of nanoparticles and triggering the release of the degradation products into urine for easy analysis. For each infusion, over one trillion individual nanoparticles are administered, allowing single tumor cells to break down many copies, amplifying detection signals into urine and making early detection possible.
We are developing these ideas in nanotechnology and remote sensing in order to construct synthetic biomarkers of immune cell activity. For example in the setting of cancer, tumor cells have the uncanny ability to evade the immune system by inducing an immunosuppressive microenvironment. In one aim, we seek to noninvasively monitor the dynamics of immune modulation in order to assess immunogenicity and predict treatment responses.
Sensing cellular activity in living systems. Fluorescent imaging of disease and control mice following administration of (a) free peptides, (b) nanoparticles or peptide-conjugated nanoparticles (c). Protease activities associated with disease cleave peptides from the nanoparticles, triggering their accumulation into urine as synthetic biomarkers.
"Mathematical framework for activity-based cancer biomarkers" Proc. Natl. Acad. Sci. USA 112(41), 12627–12632 (2015). [DOI: 10.1073/pnas.1506925112]
“Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics" Proc. Natl. Acad. Sci. USA 1119(10), 3671–3676 (2014). [DOI: 10.1073/pnas.131465111]
“Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease” Nature Biotechnology 31, 63–70 (2013). [DOI: 10.1038/nbt.2464]
Augment: Engineered T cells
Recent advances in engineered T cell therapies are providing physicians with a rapidly expanding repertoire of cell-based treatments to fight cancers that are otherwise refractory to conventional treatments. For example, strategies harnessing T cells engineered with tumor-targeting receptors have resulted in the dramatic regression of tumors and in some patients, complete remission of metastatic disease. Yet despite such striking progress and the enormous potential of engineered T cells, our ability to precisely control T cell-killing activity remains limited. This is a significant clinical challenge as cancer cells have the uncanny ability to evade the immune system by creating an immunosuppressive microenvironment, and adjuvant drugs designed to hyperactivate T cells do not discern between beneficial and deleterious T cells, leading to systemic toxicities including off-target cell killing. The ideal engineered T cell would provide physicians the ability to control when and where they are activated in the body, tune their tumor cell-killing potency, and noninvasively monitor their treatment efficacy. Achieving this degree of precision would be a major advance and make engineered T cells a safe and potent therapy for cancer.
"Remote control of mammalian cells with heat-triggered gene switches and photothermal pulse trains" ACS Synth. Biol. 7(4) 1167–1173 (2018). [DOI: 10.1021/acssynbio.7b00455]