Revolutionizing disease treatment with biotechnology and functional molecules

Bryan Dickinson (right) discussing research with graduate students Kaitlin Kentala (left) and Simone Rauch (middle).
Bryan Dickinson (right) discussing research with graduate students Kaitlin Kentala (left) and Simone Rauch (middle). Rauch is the principle author for the CIRTS paper that appeared in the June issue of Cell.

A collaborative atmosphere among world-class researchers is one of University of Chicago’s biggest strengths. Such an environment has allowed Bryan Dickinson, PhD, an associate professor of chemistry, to flourish in biological research and tackle looming challenges such as developing treatments for various diseases using the tools of his trade.

But what is a chemist doing in the world of biology?

The Dickinson lab specializes in creating functional molecules big and small to solve biological problems. Their molecular repertoire ranges from small probes to observe how fat molecules modify proteins, to virus-manufactured biosensors that peer into the inner workings of a living cell. It is precisely Dickinson’s background in synthetic chemistry and protein engineering that gives his group an advantage—they have the ability to design and produce specialized molecules as needed, depending on the research problem at hand. Dickinson brings to the table expertise in molecular technology development to enrich the vibrant medical research at UChicago.

RNA: Ready, “n”, action!

RNA molecules are bite-sized, portable copies of activated genes from the DNA. A common description of the RNA from a typical biology textbook is that RNA is the messenger between the DNA and the protein production line. RNA molecules feature heavily in Dickinson’s research.

With world-renowned RNA sequencing expert Chuan He, PhD, professor of chemistry, literally next door, it is no surprise that Dickinson has also gravitated towards engineering RNA systems. His group has developed a biosensor that can record various protein binding events in a measurable RNA output. The name of the biosensor—split RNA polymerase—is telling: The biosensor is physically split into two fragments and attached to different proteins that bind to each other. When the proteins eventually come together, by proximity, so do the biosensor fragments. Subsequently, the biosensor produces an RNA molecule to broadcast the successful binding of the proteins.

These RNA-producing biosensors are programmable to be sensitive to any arbitrary protein-protein interactions. Specific and precise, they are the perfect tool to study the interaction between a broad range of targeted biomolecules.

Dickinson brings to the table expertise in molecular technology development to enrich the vibrant medical research at UChicago.

“With these biosensors, we can better understand the functions of various biomolecular interactions, and they provide an inroad to think about how to disrupt these interactions,” Dickinson said. “Protein-protein interfaces—the physical site where proteins touch when they bind together—are especially important as drug targets. Currently, the field does not have robust methods to study specificity within interactions sites using high-throughput evolutionary methods. We are trying to change that.”

This research on reading out the RNA to study protein-protein interactions has led to Dickinson’s work on inversely exploiting the RNA to manipulate protein production amid the DNA-RNA-protein communication pathway at the end of that textbook scenario.

Just like a code breaker at a wartime listening post, Dickinson’s group can intercept the RNA messenger molecules with a protein that can alter the RNA down to the single-base level, thereby modifying the original message. The modified RNAs can then manipulate protein production in the same way transmitting false messages on radio airwaves fools unsuspecting enemies. As the decision for which protein is produced is controlled by the DNA, manipulating protein production via engineering the RNA is effectively controlling the DNA itself, despite taking place further downstream in the process.

“Our CIRTS protein is essentially the RNA version of the CRISPR/Cas technology,” Dickinson said, referring to the groundbreaking tools that allow scientists to precisely edit snippets of DNA. Instead of making programmed changes to the DNA by the Cas9 protein, CIRTS modifies the RNA to achieve basically the same effect on protein production.

But even better than Cas9, he added, “CIRTS is more suited for making changes to whole suite of different RNA genes to tackle multigenic diseases. It is harder to program multiple changes in the DNA as they would be irreversible and not independent of one another.”

As RNA is merely a genetic copy and not the source code, changes made to the RNA are not permanent, making future CIRTS therapeutics a much safer option. But Dickinson’s RNA-modifying protein is not one of the many Cas family proteins outsourced from bacteria like the CRISPR/Cas9 protein. The human body is constantly infected with Cas-bearing bacteria, and our immune system recognizes these proteins as a sign of bacterial invasion. To avoid triggering an immune response in patients injected with the drug, Dickinson's group has leveraged their expertise in protein engineering to assemble CIRTS purely from human protein ingredients. Yet, CIRTS is still able to perform all the RNA modifications as expected of a bacterial RNA Cas protein.

Having the medical school with the chemistry department all on one campus is pretty unique.

Equipped with such a versatile weapon in the arsenal, one would expect that Dickinson is ready to take on a variety of global health problems. Dickinson personally would like to apply his technology to heart disease, stroke, and neurodegenerative disorders, simply because these intransigent diseases affect the greatest number of people. Nevertheless, the group’s research is driven by molecule-based technological development instead of select diseases. The group relies on exchanges with disease specialists and geneticists to decide where the most fruitful applications lie.

This is where the collaborative atmosphere at UChicago is especially valuable to address the most pressing problems in medicine. UChicago is and will continue to be the crossroad where basic science researchers, bioengineers, pathologists, medical experts, and doctors meet and work together, allowing the research of the likes of Dickinson to reach its full potential and maximum impact in therapeutics development.

Medical collaborations

Using their protein biosensor technology, the Dickinson lab is currently working with hematologist James LaBelle, MD, PhD, to study the interactions between cancer cells and pinpoint a drug target for cancer. The group is also collaborating with gastroenterologist David T. Rubin, MD, on potential treatments for digestive diseases.

Dickinson’s latest research on RNA genetic engineering using CIRTS, published in the June issue of Cell, is currently seeking new health challenges to take on. Dickinson and Chuan He have had a field day coming up with possibilities for therapeutics development as each team deepens their understanding of RNA regulation.

Collaborating with all these different experts at UChicago has allowed Dickinson’s research to extend its reach to multiple biomedical problems wherever his technology is applicable. He acknowledges that having such a diverse cadre of researchers at UChicago has also significantly benefitted his lab, propelling his work to the heights it has attained today.

“Having the medical school with the chemistry department all on one campus is pretty unique,” Dickinson said. “We are able to obtain clinical samples, perform mouse work, and leverage the hospital’s collective expertise to push the biology as far as we want. As our specialty is technology development, we often look for collaborators to extend our technology to real-world medical applications. But in other cases, we’ve also had clinicians come to us with a particular clinical problem. If it fits in with our turf of technology development, we work together to solve that problem. It goes both ways.”