Bioengineers Develop a Non-Invasive Method for Cell Control Using Temperature

Researchers from the University of Pennsylvania have developed an innovative method for controlling cells using temperature. This approach could serve as the foundation for new types of cell therapy, where modified cells will respond to natural physiological changes, such as an increase in body temperature. The work of Lukas Bugay's team opens up prospects for more precise and safer treatments for various diseases, including oncology.

"Inside complex biological systems, numerous processes are constantly occurring. When we introduce modified cells into the body to perform specific functions, such as seeking and destroying pathogens or tumour cells, it would be ideal to have the ability to control them, directing them to the right place at the right time and controlling their behavior," explains Lukas Bugay, a bioengineer from the University of Pennsylvania.

In their new work, Lukas Bugay's laboratory presented an innovative tool that allows for remote and non-invasive interaction with cells, controlling their activity after they enter the body. The study, published in Nature Methods, describes a new protein called Melt, which can be activated by temperature.

From Optogenetics to Thermogenetics: The Evolution of Melt

Biology has long used methods to control cellular processes using light — this field is called optogenetics. It has revolutionized science by providing the ability to turn specific cellular pathways on and off with high precision. However, this technology has a significant drawback: light penetrates poorly through tissues, making it ineffective for many medical applications.

"We needed a more universal tool capable of affecting cells deep within tissues," explains Bugay. "That's why we turned to temperature. Heat penetrates much deeper than visible light and can be used to control cellular processes in a wide variety of conditions."

A breakthrough discovery occurred unexpectedly — during the study of the fungus Botrytis cinerea, known for its ability to cause rotting in berries and grapes. Scientists found that this fungus produces a protein BcLOV4, which was initially studied for its sensitivity to light. However, when Bugay's lab introduced this protein into human cell lines, something unexpected happened.

"We noticed that the protein responds not only to light but also to temperature," says the first author of the study, former Bugay lab graduate student Will Benman. "This discovery amazed us because there are many proteins that respond to light, but very few that respond to temperature changes."

This prompted the team to consider: is it possible to create a protein that responds exclusively to heat? And if so, can it be used to control cell behavior without the need for invasive intervention?

After numerous experiments, they modified BcLOV4 and created a new protein that became exclusively thermosensitive. It was named Melt — short for Membrane Localization by Temperature.

"We disabled its light sensitivity and tuned its temperature sensitivity to work at human body temperature," adds Pavan Iyengar, a former research associate in Bugay's lab. "Now it acts like a dimmer: an increase in temperature activates the protein, while a decrease deactivates it."

Melt in Action: From Regulating Cellular Pathways to Fighting Cancer

By combining Melt with various biological mechanisms, the team was able to control processes such as cell signaling, peptide cleavage, and even induced cell death. In one of the most impressive experiments, scientists demonstrated that simple local cooling (essentially, an 'advanced ice pack') can activate the mechanism for killing tumour cells without the systemic toxic effects characteristic of chemotherapy.

But the potential of Melt is not limited to therapeutic applications. Researchers view it as a powerful tool for fundamental science that can help study complex cellular processes in real-time.

"This is one of those rare cases where a protein can perform multiple functions at once," explains Bugay lab graduate student and co-author of the study Zikan (Dennis) Huang. "It can respond to light, sense temperature, move to the membrane, and participate in other molecular processes. In most cases, natural proteins perform only one function, but here we have a unique multifunctional tool. Once we fully understand its mechanism of action, we will have the opportunity to create new proteins with similar integrated functions."

Prospects: Melt and the Future of Cell Therapy

In the short term, Melt could play a key role in developing more effective and less toxic cancer treatments, as well as in personalized medicine. The ability to control cells using temperature paves the way for innovative therapy strategies, allowing the activation of necessary processes only in specific areas of the body.

"This work was made possible by funding from the federal government, as well as support from the Precision Engineering Center for Healthcare in Pennsylvania," emphasizes Bugay. "Based on our early results, we recently received a large NIH grant for further development of the technology and testing its effectiveness in cancer models."

In the future, Melt and similar tools could lead to the creation of fundamentally new types of cell therapy, where cells respond not only to artificial signals but also to natural physiological changes, such as an increase in body temperature during fever or inflammatory processes. This will open new horizons in medicine, allowing for the implementation of even more precise, adaptive, and safe treatment methods for various diseases.