Researchers at the University of California, Santa Barbara have developed a new protein-based sensor that could allow MRI machines to detect molecular-level activity inside cells. This innovation is detailed in a recent article published in Science Advances.
MRI technology, which has been widely used since the 1970s, creates images of the body’s internal structures without exposing patients to ionizing radiation. However, traditional MRIs are limited to capturing anatomical changes and cannot observe molecular events that may signal disease before structural changes occur.
Arnab Mukherjee, associate professor of chemical engineering at UC Santa Barbara’s Robert Mehrabian College of Engineering, explained the significance: “You can see the structures of your tissues — whether it’s the brain, the heart, the kidneys or the stomach — but you don’t get molecular information. So, the only time you can know that something is going wrong or something has changed is if you take another MRI, and the structure and morphology of the tissue changes.” He added that for many diseases, by the time structural changes are visible, progression may be advanced.
Mukherjee has focused on enhancing MRI capabilities since his postdoctoral work at Caltech. “If we can see these molecular-level changes happening in real time, then we can ask questions like, ‘How do tumor cells metastasize?’ or ‘How does neurodegeneration progress at the molecular level as an animal ages?’ There’s currently no way to do that,” he said.
The team applied synthetic biology concepts to develop a modular sensor that can be genetically engineered into cells. This sensor allows MRIs to visualize molecular processes such as those involved in neurodegenerative diseases and cancer development. The system is modular—researchers can swap specific proteins to target different cellular processes.
To create this tool, Mukherjee’s team sought a protein that would produce a detectable signal within an MRI scan. They turned to aquaporin—a protein forming channels in cell membranes for water movement—because water molecules respond strongly in MRI’s magnetic fields. “Our water molecules are tiny, tiny magnets,” Mukherjee noted. “If you can control or affect the rate at which water molecules move back and forth across the cell, you can make that magnetic signal specific to certain types of cells or biological processes, which would allow the MRI to report on this process at the molecular level, thus providing much more detailed information than are currently possible.”
Upon joining UCSB in 2017, Mukherjee began adapting aquaporin with other proteins to form genetic circuits tailored for different research needs. Asish Ninan Chacko (Ph.D. ’26), who worked in Mukherjee’s lab as a graduate student, contributed to refining this system. “This protein can be regulated using a lot of chemical signals,” Chacko said. “We can even replace this particular protease with another type of protease and use it to detect many different processes.”
The result is MAPPER (modular aquaporin-based protease-activatable probes for enhanced reporting), an interchangeable system enabling researchers to monitor various chemical activities inside cells during laboratory studies. Chacko explained: “That’s a first in this paper because so far in the scientific literature, you’ve seen only four or five genetic sensors each used to detect a unique analyte… In this paper we describe close to ten systems we can detect with this one setup.”
The researchers believe their approach will improve disease progression studies while reducing reliance on laboratory animals by allowing continuous imaging over time rather than single-time-point assessments requiring animal sacrifice. Chacko stated: “Right now if you need to access an animal’s internal organs as part of a study there is no way to do it without sacrificing the animal… Our approach allows continuous imaging of the same animal over the course of a study giving a far more accurate picture of disease and biology.”
Because MAPPER uses building-block components that can be easily customized for new targets without designing sensors from scratch each time, Mukherjee hopes it will accelerate research development cycles and training opportunities for students.
“We want to take these sensors and put them in the hands of people who will actually use them,” said Mukherjee. “Whether that’s neuroscientists who would be able to use MAPPER to look at calcium changes in the brain or developmental biologists who could use the tools to track mouse development from embryo to adult.”
