Prof. David J. Mooney
Harvard University, US
Cell and Tissue Engineering
Biomaterials for Immunotheraphy
Cancer immunotherapy (e.g., checkpoint blockade therapy, CAR-T cells) is revolutionizing cancer treatment, but many patients do not benefit from the current therapies. We propose to utilize biomaterials to better program immune cells and enhance therapeutic outcomes. The materials promote spatial concentration of target immune cell populations, and manipulate the assembled cells via temporal control over immunomodulatory agents presented from the material. This approach has shown significant promise in the development of robust anti-cancer T cell responses in the context of a wide range of cancers. The resultant biomaterial systems allow for significant control over antigen presentation and antigen presenting cell activation, leading us to explore their utility as a platform for vaccination against infectious agents, including SARS-CoV-2. Further, these systems can also serve as synthetic analogs of antigen presenting cells, allowing for rapid expansion and tuning of T cell products to enhance adoptive therapy. Biomaterial-based systems are a promising approach to program immune responses in vitro and in vivo and improve the outcome of current immunotherapies.
1. Ali OA, Huebsch N, Cao L, Dranoff G, Mooney DJ. Infection-mimicking materials to program dendritic cells in situ. Nat Mater. 2009 Feb;8(2):151-8.
2. Kim J, Li WA, Choi Y, Lewin SA, Verbeke CS, Dranoff G, Mooney DJ. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat Biotech. 2015 Jan;33(1):64-72.
3. Li AW, Sobral MC, Badrinath S, Choi Y, Graveline A, Stafford AG, Weaver JC, Dellacherie MO, Shih TY, Ali OA, Kim J, Wucherpfennig KW, Mooney DJ., A facile approach to enhance antigen response for personalized cancer vaccination, Nat Mater. 2018 Mar 5. doi: 10.1038/s41563-018-0028-2.
4. Wang H, Sobral MC, Zhang DKY, et al. Metabolic labeling and targeted modulation of dendritic cells. Nat Mater. 2020;10.1038/s41563-020-0680-1. doi:10.1038/s41563-020-0680-1
5. Shah NJ, Najibi AJ, Shih TY, et al. A biomaterial-based vaccine eliciting durable tumour-specific responses against acute myeloid leukaemia. Nat Biomed Eng. 2020;4(1):40-51.
6. Cheung AS, Zhang DKY, Koshy ST, Mooney DJ. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat Biotech. 2018 Jan 15. doi: 10.1038/nbt.4047. PMCID: PMC5801009
7. Wang H, Mooney DJ. (2018) Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nat Mater. Sep;17(9):761-772.
Cancer, CAR-T, vaccine
Prof. Paul S. Weiss
Surface Chemistry and Physics
Molecular Device and Nanolithography
Enabling Cellular Therapies & Other Adventures in Biology and Medicine
By controlling the exposed chemical functionality of materials from the submolecular through the centimeter scale, we have enabled new capabilities in biology, medicine, and other areas. I will discuss current and upcoming advances and will pose the challenges that lie ahead in creating, developing, and applying new tools using this capability. These advances include using biomolecular recognition in sensor arrays to probe dynamic chemistry in the brain and microbiome systems. In other areas, we introduce biomolecular payloads into cells for gene editing at high throughput for off-the-shelf solutions targeting hemoglobinopathies, immune diseases, and cancers. We circumvent the need for viral transfection and electroporation, both of which have significant disadvantages in safety, throughput, cell viability, and cost. Mechanical deformation can make cell membranes transiently porous and enable gene-editing payloads to enter cells. These methods use specific chemical functionalization and control of surface contact and adhesion in microfluidic channels.
1. A. Paul Alivisatos et al., Nanotools for Neuroscience and Brain Activity Mapping (2013), ACS Nano 7(3), 1850-1866
2. Julie S. Biteen et al., Tools for the Microbiome: Nano and Beyond (2016), ACS Nano 10(1), 6-37
3. Jason N. Belling et al., Acoustofluidic Sonoporation for Gene Delivery to Human Hematopoietic Stem and Progenitor Cells (2020), Proceedings of the National Academy of Sciences 117(20), 10976-10982
4. Jiantong Dong et al., Covalent Chemistry on Nanostructured Substrates Enables Noninvasive Quantification of Gene Rearrangements in Circulating Tumor Cells (2019), Science Advances 5(7), eaav9186
5. Jiantong Dong et al., Bio-Inspired NanoVilli Chips for Enhanced Capture of Tumor-Derived Extracellular Vesicles: Toward Non-Invasive Detection of Gene Alterations in Non-Small Cell Lung Cancer (2019), ACS Applied Materials & Interfaces 11(15), 13973-13983
Nanoscience, nanotechnology, biotechnology, gene editing, genetic disease, cancer immunotherapy, liquid biopsy
Prof. Ralph Weissleder
Harvard Medical School / Massachusetts General Hospital, US
Bioimaging and Biosensing
Chemical Biology for Therapeutics
Methods for extracellular vesicle (EV including exosomes) analysis have significantly advanced over the last several years but challenges remain to reproducibly analyze samples in a clinical setting. If more sensitive and reproducible methods could be established, they would have far-reaching applications in early cancer detection, measuring patient response to drugs, understanding tumor heterogeneity and discriminating different diseases. One challenge is the differentiation of tumor cell-derived EV (TEV) from host cell-derived EV (HEV) based on biomarker abundance. An engineering challenge is to develop more sensitive analytical approaches. Most existing technologies rely on bulk EV measurements which are inherently less sensitive since markers of interest are diluted. To increase the diagnostic accuracy of EV profiling methods, there is thus a need for reliable single vesicle analytical methods. In this presentation, I will review the different single EV methods developed in our labs, summarize lessons learned and outline remaining hurdles. It is clear that single vesicle methods have the potential to transform cancer research and clinical practice but this will require more work and close collaboration between engineering, biology and medical fields. If successful, the new single EV approaches will allow us to discover the make-up of EV in clinical specimen with far-reaching diagnostic applications.
Prof. David Sherman University of Michigan, US
Synthetic Biology for Natural Products
Emerging Insights into Function, Structure and Metabolite Diversification from Modular Polyketide Synthases
Bacterial modular polyketide synthases are multi-functional enzymes that mediate the assembly of a wide variety of complex natural products. Many of these metabolites have been developed into clinically approved antibiotics, anti-parasitic agents and cancer therapeutics. For the past three decades numerous groups have worked to understand the function and structural parameters involved in expanding the metabolic diversity of modular PKSs through in vivo and in vitro approaches. Although some successes have been reported, there continues to be a need to expand our knowledge about the role of individual catalytic domains, protein-protein interactions and substrate selectivity parameters in order to engineer these systems. We have focused on studies of PKSs that generate 12-, 14- and 16-membered macrolactones in order to understand the primary bottlenecks in production of new metabolites using natural and unnatural chain elongation intermediates. A particular focus in these studies has been the PKS terminal thioesterase domain and the determinants that contribute to selectivity and macrolactonization. Recent studies have revealed the ability to maximize efficiency of macrolactone formation by appropriate pairing of a TE domain in an engineered PKS involved in processing of unnatural substrates. We have also significantly expanded our pool of unnatural substrates to assess flexibility of PKSs toward proximal/distal functional group alterations, heteroatom replacements, and odd-numbered chain elongation intermediates. In numerous examples, new 12-, 14- and 16-membered ring macrocycles are generated, and can be further transformed into novel macrolides by glycosylation and late-stage oxidation with heterologous CYP450s. This biocatalytic cascade approach is enabling scalable methods for understanding PKS function, engineering biosynthetic enzymes and obtaining new bioactive molecules for analysis against a range of disease targets.
We are also making progress in the realm of structural studies on complete modular PKSs using cryo-electron microscopy. Following our work on the pikromycin PikAIII (module 5) structure determined several years ago, we are gaining new insights from a terminal PKS module that includes KS-AT-KR-ACP-TE domains. These new studies are revealing a more complete understand of the dynamic forms of the mega-synthase, which is being probed by orthogonal analytical approaches to deepen the insights into these amazing molecular machines.