It’s well known that, when cells are subject to stress, starvation or viral infection, they sometimes adopt a cubic architecture. Unlike the simple spherical structure of membranes in healthy cells, these cubic membranes, or cubosomes, are very complex, forming an interconnected network of water channels resembling a “plumber’s nightmare.”

Yet scientists still don’t have a clear understanding of how or why this happens.

“The transition from this very simple spherical structure into a complex cubic one is something that happens once in a while,” Virgil Percec, the P. Roy Vagelos Professor of Chemistry in the School of Arts & Sciences at the University of Pennsylvania, said. “But we don’t yet have a clear understanding of the mechanism behind it.”

Now, in a paper published in ACS Central Science, researchers at Penn have completed the first experiment able to model these different biological structures. They used these models to figure out how those structures affect the functionality of certain biological systems. By doing this, they were able to demonstrate that cubic membranes in unhealthy cells might be used as a defense mechanism.

​​​​​​​The study was led by Percec, with Penn postdoc Qi Xiao; recent graduate Sam Sherman; Daniel A. Hammer, the Alfred G. and Meta A. Ennis Professor of Bioengineering in Penn’s School of Engineering and Applied Science; Paul Heiney in the Department of Physics & Astronomy in Penn Arts & Sciences; Hans-Joachim Gabius from Ludwig Maximilian University in Munich; Michael L. Klein from Temple University; and Davis M. Markovitz from University of Michigan. This research was supported by the National Science Foundation.

In cells with a normal vesicular structure, Percec said, everything is contained within the cell. The vesicles are spherical and onion-like; they can contain multiple layers. And on the periphery there are sugars, which are responsible for the interactions between cells and some proteins.

Sick cells, however, form a different, cubic internal structure.

​​​​​​​Sherman explained that this structure is much more complicated than the normal vesicular structure. It forms a network of membranes with water channels connected to form a kind of lattice. This lattice is surrounded by a membrane that follows the contours of this structural network. So, unlike the vesicle, which is smooth, it undulates.

The researchers found that this cubic structure has a different approach to the recognition of proteins.

“If you look at how proteins bind to a cubic structure versus how they bind to our models of a vesicular structure, you can see very clear differences in the behavior of the proteins to the two structures,” Sherman said.

To investigate this, the researchers synthesized molecules that self-assemble into cubic membranes with sugars on the periphery, something that no one else has been able to do. The sugar component was key, as it allowed them to look at how the cubosomes interacted with certain sugar-binding proteins, known as lectins, and compare that to how models of healthy biological membranes interacted with the same kinds of proteins.

According to the results, a transformation from vesicular membranes to cubic membranes might provide a mechanism to defend sick cells against viral or bacterial infection, amplifying the rate, the reactivity and stability with which they bind to proteins.

“For the first time, this provides a potential answer to why some biological membranes from unhealthy people become cubic structures: it’s a potential mechanism for humans and animals to defend themselves,” Percec said. “That could be used to develop artificial defense mechanisms.”

The next step is to get a clearer picture of how these structures behave and how researchers can make them with more complex sugars. The goal is to understand how stable these structures are in the human body.

Percec believes that this work could eventually be used to provide a simple way to develop vaccines that would normally be extremely difficult to make.

“This is a very fundamental project in which we, as a group, have come up with a new way to generate models for biological membranes,” he said. “We have the tools to make almost any kind of structure with different dimensions and functionality. We have models for almost everything; that’s the strength of our lab. It’s very useful for addressing a lot of biological questions.”

Using related methods, the researchers have provided a possible method for transforming harmful E. coli bacteria into hybrid structures that behave in a different, more friendly way.

“That’s a big thing,” Percec said. “One day it could change the way medicine is done.”