Biological research has always had one unavoidable flaw. Dynamic, living processes that move and change over time need to be studied in snapshots.
It has always been the nature of studying living tissues. Samples must be extracted. Microscope slides must be prepared. Tissue must be frozen. Whether watching how proteins unfold or how diseases progress, scientists must study single moments in time and extrapolate what happened in between.
“Spatiotemporal omics – the ability to sample biomolecules at different locations and times – has taken off over the last few years, but has remained incompatible with live tissue,” says Shana Kelley, president of Bioengineering and head of Biohub Chicago. “Existing technologies allow us to look at snapshots, but never the full process.”
A new grant program from the nonprofit research organization Biohub hopes to change that. Four University of Chicago Pritzker School of Molecular Engineering (UChicago PME) faculty members – Prof. Cathryn Nagler, Prof. Savas Tay, Assoc. Prof. Sihong Wang and Asst. Prof. Josh Weinstein – will receive funding for the work.
"Spatiotemporal omics sits at a crossroads of molecular measurement, engineering, and computation that doesn't fit neatly into any single funding bucket,” Weinstein said. “A program like Biohub's recognizes that the measurement tools themselves are often the bottleneck, and investing in them early can open the door to discoveries across many fields – from immunology to drug development – that wouldn't be possible with today's methods."
In total, Biohub will fund 15 projects from American and European universities and hospitals seeking to fill this research gap. From this global search, an impressive three of the projects were birthed at UChicago PME.
HydroSense: A Hydrogel-Based Bioelectronic Platform for In Vivo Spatiotemporal Omics of Inflammatory Diseases
Principal Investigator: Assoc. Prof. Sihong Wang; Co-Principal Investigator: Prof. Cathryn Nagler
For this proposal, Wang, who works on soft, biocompatible, stretchable materials, partnered with Nagler, a leading expert on allergic responses and inflammation. The work, building on a 2024 paper in ScienceWang co-authored, will develop a functional, high-density array of sensors, each with its own sensing capability and target within the cell.
“When we have an array, for example, with 100 devices, each of those devices could be made to just read out one type of protein or metabolite in a very complicated biofluidic environment,” Wang said.
Designed with immune-compatible hydrogels and polymers, the sensor array is expected to elicit minimal immune reactions at the implantation site, so that the original inflammation process to be monitored will not be altered by the sensor.
“As an immunologist, this is very exciting,” said Nagler, the Bunning Family Professor at UChicago PME, the Biological Sciences Division and The College. “We can implant the sensor and follow the production of inflammatory mediators in real time. We can introduce a therapeutic with the sensor in place and immediately see if it is effective.”
Partnering through the University of Chicago system, Nagler and Wang are working to ensure the technology will have immediate impact. Once developed, HydroSense will be put to work helping patients at UChicago Medicine, said Joseph B. Kirsner Professor of Medicine David T. Rubin, Chief of the Section of Gastroenterology, Hepatology & Nutrition.
“There is great enthusiasm and obvious synergy in the work that we are doing on the clinical and translational side that I believe will be of immense value,” said Rubin, who is also Director of the Inflammatory Bowel Disease Center. “This important work brings together the best of bioengineering and immunology combined with an available and highly organized patient population at the University of Chicago and collaboration across disciplines to advance the science of medicine.”
SPATIAL: SPatio-temporal Acquisition of Proteomics in Live tissue
Principal Investigator: Prof. Savas Tay
Tay, who is also the director of UChicago PME’s Institute for Bio and Immuno Engineering, will use the Biohub funding to help develop technologies to study proteins and protein interactions over time. Studying how these proteins react during infection, immune response or drug treatment can help scientists better treat patients.
“You give drugs to cells, these protein complexes rapidly reconfigure themselves as they relate to function,” Tay said. “Being able to measure them opens a new window into understanding basic functions in immunology, in infection, in cancer, in drug response and more.”
Using temporally barcoded proximity ligation assays, SPATIAL (SPatio-temporal Acquisition of Proteomics in Live tissue) will measure 130 individual proteins and over 6,000 protein dimers simultaneously at half-hour intervals over several days, in high resolution.
Tay said the ability to measure single-cell protein complexes will open new vistas for science, the same way the first microscopes opened up biology and the first telescope opened up celestial physics.
“One measurement modality, one technology, can change an entire field,” he said.
DNA-based approaches for molecular mapping in live tissue
Principal Investigator: Asst. Prof. Josh Weinstein
Weinstein, who has a joint appointment with UChicago PME and the Department of Medicine, Section of Genetic Medicine, will explore how DNA can be used as an information-bearing medium to study molecular activity in living tissue.
His work explores DNA-based, optics-free approaches for mapping molecular activity in living tissue over space and time, building on the idea that DNA can serve as a medium for recording biological information, much as light carries information in conventional imaging.
“In traditional imaging, light carries information back from a sample,” Weinstein said. “We’re exploring how DNA can play an analogous role inside living systems – recording molecular patterns as they change over time – so that instead of a frozen snapshot, researchers can start to build something closer to a molecular movie of living biology. That kind of capability could eventually help researchers study disease progression and treatment response.”