This year, three teams of Chemistry of Life Processes Institute investigators received $90,000, collectively, in CLP-Cornew Innovation Awards to pursue potentially transformative proof-of-concept studies to better detect, diagnose and treat disease. The awardees included Neha Kamat (biomedical engineering) and Julius Lucks (chemical & biological engineering) for development of a next generation biosensor; Tom Meade (chemistry) and Keith Tyo (chemical & biological engineering) to develop a more accurate, portable diagnostic kit; and Nathan Gianneschi (chemistry) and Bin Zhang (Medicine) for a proof-of-concept study for a new immunotherapy.
A next generation biosensor
From detecting pathogens in water to attacking toxins in the blood stream, an enormous need exists for biosensors in a variety of health and environmental fields. Clinicians currently must draw blood to detect the presence of molecules that signal trouble in humans, but this method can miss critical information. For instance, a molecule located near the site of a cancerous tumor can become diluted by the time it reaches the side of extraction rendering it undetectable.
Collaborators Neha Kamat and Julius Lucks want to build a radically different biosensor— one that acts as a “molecular taste bud” that can travel through the body in a carefully designed container, detect its target, record what it sees and even act as a kind of therapeutic.
One of the biggest challenges is designing a compartment that will allow the sensor to move through the body.
“What is needed is a sensor that moves through those environments, see something it’s been designed to see, and then records that event,” says Kamat. “It basically generates a memory that it saw a toxin or a low ph, or a molecule, so that when we do collect it, the sensor tells us what it saw.”
Taking a cue from the basic structure of a cell, the collaborators will use an RNA-based sensor that takes the sensing capability outside of the cell. This genetic polymer has the unique ability to detect very specific biological analytes of interest and report detection of a molecule.
“This little RNA switch is thought to be one of the more ancient ways that cells have evolved to sense their environments,” says Lucks.
The tool promises a wide range of potential diagnostic and therapeutic applications. In countries, such as India and Bangladesh, it could be a game changer. The overabundance of fluoride in the ground water in certain areas has led to a widespread health condition known as skeletal fluorosis, a painful and deforming bone disease.
Ultimately, the team hopes to build a modular tool that can diagnose a wide range of conditions, but for this project, they will focus on fluoride.
“You could make a therapeutic product that binds fluoride and pulls it out of circulation. You could make a fluorescent protein just to tell you that it’s there, which opens up the door to a huge range of responses that would expand what the biosensor does,” says Lucks.
A more accurate portable diagnostic test
CLP members Thomas Meade and Keith Tyo are developing a more accurate portable diagnostic tool that will enable patients and doctors to make better on the spot health decisions.
Currently, there are limitations to the accuracy of certain kinds of portable diagnostic tests. The hepatitis C test, for example, can accurately detect antibodies, but it can’t distinguish whether the patient was infected years ago or is experiencing an active infection.
“Typically if an antibody-based test comes back positive, they then will have to do a second round of tests that are based on a PCR and molecular diagnostics— things that are very, very lab heavy, require a lot of infrastructure and require a lot of training and personnel. It’s just not useful for a point-of-care (POC) testing,” says Catherine Majors, a postdoctoral scholar in Tyo’s lab involved in the project.
Another problem with POC diagnostic tests is that a lack of sensitivity can lead to a weak positive or false negative result. In home pregnancy testing, for example, if only a small amount of the analyte for pregnancy is detected, the test will barely register a signal, and the person reading the test may be unable to read the signal.
“What we’re trying to do is make something that’s analogous to the molecular mousetrap. There’s no such thing as a weak positive for a mouse trap,” says Tyo. “There’s no pushing halfway down on the trigger and the trap slowly turning over. It’s either snapped or it’s not fired yet.”
The first order of business is getting the molecular switch to work. Once the switch is working, the researchers will look upstream to see if they can get their test input, a hepatitis C antigen, to flip the switch. In future, they hope to use the new mechanism to detect a variety of conditions. The approach is a plug-and-play system that could easily be adapted for other tests. The team will leverage a proprietary technology developed by Meade to convert the molecular information into an electrical signal that will enable them to develop a new digital tool for reporting and analyzing test results.
“CLP allows for this intersection of interdisciplinary scientists,” says Tyo. “It is extremely enabling to combine my synthetic biology expertise with Meade’s chemistry and surface science expertise. That wouldn’t be possible otherwise. If we’re successful with our proof of concept, CLP has lots of infrastructure to help us move this forward to an actual application in the field. That’s really exciting.”
A more effective cancer immunotherapy
“The common theme is how do I deliver material? How do I deliver your drug to the bloodstream, or in the mouth, or rub it on your skin, and get it where you need it to be to have the desired effect?” says Gianneschi. “We’re trying to solve both.”
The investigators’ approach targets the signals associated with inflammation, which are found in a number of diseases like cancer and heart disease. The goal of the project is to develop a new kind of injectable immunotherapeutic designed to circulate throughout the body and localize in tumor cells while avoiding normal tissue. Over time, the material will accumulate in the tumor in just the right concentration until its signal triggers the immune system to recognize and attack not just the material, but the surrounding tumor tissue as well.
“It’s absolutely necessary that you localize the materials, but you don’t always know exactly where you want to put the drugs,” says Gianneschi. “You need to be able to do a delivery to the whole body where the drug is activated and localized only at the tumor. This is a massive global challenge with many different types of drugs that fall under the general category of targeted therapeutics.”
When Gianneschi first moved to Northwestern, he knew from experience that collaboration was essential for his kind of work. As a member of CLP, he found Zhang, a highly skilled immunology expert, and Irawati (Angki) Kandela, Assistant Director of the Developmental Therapeutics Core, who helped test and evaluate promising therapeutic agents. The researchers also utilized the imaging technology and expertise of the Center for Advanced Molecular Imaging. Both CDT and CAMI are CLP-affiliated cores.
The team hopes the Cornew Award will enable them to generate enough seed data to provide the basis for an NIH grant.
“We’ve done a lot of studies in the run up to this in CLP core facilities. This is such complicated research that involves imaging, animal dosing and the right animal models,” says Gianneschi. “It’s more than just technicians at CLP; these people are fully engaged. We’ve worked in the past with technicians who have said, ‘I did your injection— it didn’t work’ and then you’re stuck. I’d have to have half my group trying to do it. This is a totally different game here.”
The CLP-Cornew Innovation Awards
Currently in its ninth year, the CLP-Cornew Innovation Awards, are made possible by the generosity of Chemistry of Life Processes Institute Executive Advisory Board members, support promising interdisciplinary teams of CLP researchers in early stage development of high-risk, high-reward research projects with the potential to make significant impact.
Since the program’s inception in 2010, the CLP Board has awarded more than $900,00 to faculty collaborators in pilot funding. Cornew Awards have resulted in 39 publications, nine patents, and more than $18 million in new external funding to advance these projects opening up critical areas of transdisciplinary research and resulting in discoveries that impact human health and disease.
by Lisa La Vallee
Featured image: (left to right) CLP-Cornew Awardees Julius Lucks, Neha Kamat, Keith Tyo and Thomas Meade.