The donor-driven liaison enables Wyss project to overcome central bottlenecks in accurately modeling the infectious disease and developing much needed therapeutics
By Benjamin Boettner
(BOSTON) — A year of generous funding by the Bay Area Lyme Foundation enabled a Wyss Institute project that aims to identify novel therapeutic strategies for acute and chronic Lyme disease (Lyme) to proceed into new and potentially therapeutic territory. Girija Goyal, Ph.D., Director of Bioinspired Therapeutics at the Wyss Institute and her team were honored at the recent Foundation’s annual gala event with a presentation of their breakthroughs. Following a first funded research period, the Wyss team’s achievements convinced the Foundation to extend its support for the project for an additional period. “The support that the Bay Area Lyme Foundation provided has helped us move the needle on the project and, working together, we can hopefully get to new solutions for patients in need,” said Goyal.
The Bay Area Lyme Disease Foundation’s mission, “to make Lyme easy to diagnose and simple to cure by partnering with leading scientists and institutions to accelerate breakthroughs in diagnostics and treatments,” addresses critical unmet clinical needs. Despite being one of the most common vector-borne diseases – about 620,000 new cases reported annually in the U.S. and many more in 65 other countries – Lyme research remains significantly underfunded.
The support that the Bay Area Lyme Foundation provided has helped us move the needle on the project and, working together, we can hopefully get to new solutions for patients in need.
The Wyss Institute project, which was originally developed by Goyal and Wyss Founding Director Donald Ingber, M.D., Ph.D. and funded by Northpond Ventures, is taking an entirely new approach to advancing Lyme disease (Lyme) research and therapeutics by leveraging human Organ Chip technology. Ingber’s team broadly developed Organ Chip technology to capture human biology, disease pathologies, and drug responses better than traditional models can, and they are enabling medical progress in many areas. By modeling actual human lymph node tissue in a microfluidic Organ Chip device the size of a USB memory stick, Goyal and her team can recapitulate how the Lyme-causing pathogen, the infamous Borrelia burgdorferi bacteria transmitted by ticks, interacts with the human immune system at a critical crossroads and to identify how the pathogen manages to evade immune surveillance.
“By specifically engineering the immune environment that the Lyme pathogen is encountering, using human immune cells that we obtain from donors’ blood as a starting material, our approach has unique potential to identify the critical molecular pathways that are disrupted by it, provide insight into why some patients develop chronic symptoms and others do not, and be used as a testbed for therapeutic developments harnessing these insights,” said Goyal, who is leading the Lyme disease project now. “Our project is making significant headway toward validating a potential therapeutic target which, when disabled, improves Lyme-specific immune responses.”
Our project is making significant headway toward validating a potential therapeutic target which, when disabled, improves Lyme-specific immune responses.
The Wyss’ Lyme project overcomes major shortcomings of animal models of Lyme, which cannot capture human biology well enough to explain how chronic Lyme symptoms manifest themselves in patients. Importantly, they cannot recapitulate how the human immune system responds to Borrelia at the cellular and molecular level. Interestingly, in infected people, the antibody response to Borrelia is significantly weaker than in mice, and they get sicker, with 5-20% of them developing chronic Lyme. Also, more short-lived traditional human cell culture models that are often used to study Lyme are unable to effectively read out human immune responses to the Lyme pathogen.
The Lyme pathogen drains from the blood circulation to lymph nodes, which are important centers of immune coordination scattered throughout the body. By simulating important aspects of the three-dimensional structure and function of human lymph nodes, the Wyss’ human Lymphoid Organ Chip enables different immune cells to sense the pathogen, signal to each other very similarly to immune cells in actual lymph nodes, and orchestrate protective B- and T cell-mediated immune responses against pathogens, such as Borrelia.
Our ultimate goal is to leverage these Organ Chip-borne insights to develop therapeutics that protect patients from developing chronic Lyme or even reverse this terrible condition.
“We essentially study in real time how the immune system reacts to the Lyme pathogen and how its broader response is shaping up,” said Ingber, adding that “by comparing personalized Lymphoid Organ Chips that are made from blood cells derived from different Lyme patient donors, and utilizing a range of analytical tools, we can pinpoint weaknesses and parts of the immune response that can be therapeutically strengthened. Our ultimate goal is to leverage these Organ Chip-borne insights to develop therapeutics that protect patients from developing chronic LD or even reverse this terrible condition.” Ingber also is the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard John A. Paulson School of Engineering and Applied Sciences.
Past and present team members of the Wyss Institute’s Lyme disease project include Ernest Aguinam, Sruthy Pallikonda, Mizanur Rahman, Anastasia Ershova, Wyss faculty collaborator William Shih, Aakanksha Gulati, Marina Feigenson, Min Wen Ku, Kavya Menon, Demi Laforest, Jessica Feitor, Bogdan Budnik, Nandhinee Shanmugam, and Rohini Singh.