The Sugar Code

The skin-like membrane of every cell is not a static wall, but a canvas of protein molecules. These proteins allow the cell to detect what’s occurring around it and respond to cues from its neighboring cells and environment. The cells in the body are at this moment sending and receiving millions of messages through chemical signaling molecules, dictating cell behavior.

Each complex protein has a specific job controlling different aspects of the cell, from a cancer cell breaking away from a tumor to an immune cell recognizing a virus to a cell receiving insulin. Cells communicate through the proteins that decorate the cell membrane. 

But there is something missing from the current picture of cell communication: the sugar code, a relatively new concept in biology and biochemistry. Cell function is not only determined by messages sent through proteins, but through sugars attached to proteins or to the cell membrane forming molecule clusters that cover the cell.  

Crystal Vander Zanden, Ph.D. and assistant professor of chemistry and biochemistry, is filling in the missing picture by researching the proteins that read the sugar code.   

Vander Zanden (left) and students at the Advanced Photon Source

The family of proteins that read sugars are called galectins; Vander Zanden is specifically studying galectin-3. 

“This pattern of sugars decorating the cell surface tells a story about the cell,” said Vander Zanden. “These sugar patterns change based on the type of cell and what it’s doing, and cells use galectin proteins to read the sugars. This concept is important for so many cell types; it’s such a fundamental part of cell signaling that we don’t really understand.” 

Other research being performed into galectin-3 has connected it to tumor metastasis. Galectin-3 is found in concentrations 30 times higher in metastasizing cancer cells, and one specific sugar pattern read by galectin-3 appears in 75% of human tumors — suggesting a role in cell adhesion. But despite these well-linked connections and research targeting specific applications of galectin-3, the sugar code is not well understood.  

“I’m trying to understand the fundamental idea of how does this reader protein, galectin-3, read the sugar code and reorganize cell signaling molecules,” Vander Zanden continued. “Because if you can understand this and control it, you can control cell behavior.” 

Being able to control cell behavior has immense potential in medicine, from preventing cancer cells from metastasizing to controlling the immune system, with implication for much more.  

Vander Zanden uses a model of the cell membrane to study galectin-3. Cell membranes are formed from lipids, fat-based molecules. The simplified model system contains only sugar-decorated lipids and galectin proteins resting on a water surface. With a model system, every component of the experiment is precisely controlled, allowing systematic modifications that isolate the role of galectin-3. X-rays are then reflected from the water’s surface. Measuring the strength of the x-rays coming off the cell membrane model allows Vander Zanden to determine a nanoscale picture of the cell surface and the structure of galectin-3.   

The Advanced Photon Source at Argonne National Labs

To do this, Vander Zanden travels with her undergraduate and graduate research students to use synchrotron x-ray scattering at Argonne National Laboratory outside of Chicago and Brookhaven National Laboratory in New York, international facilities where scientists come from all over the world to do research. 

The Advanced Photon Source at Argonne National Labs is a synchrotron light source that uses particle acceleration to produce x-ray beams approximately one billion times brighter than a typical x-ray machine. The ultra-bright x-ray beams are used to visualize the behavior of atoms in molecules. Vander Zanden uses biophysics to model the strength of the reflected x-rays and interprets the data to understand how the membrane is behaving. Combining experimental data with computer simulations forms a picture of galectin proteins bound to cell membrane models.  

This research will be foundational for other clinical scientists studying how to prevent cancer cells from metastasizing to many other applications including COVID treatment and overcoming insulin resistance. Several clinical trials targeting galectin-3 are already in progress.  

“We get these little curves in the profile that change based on the membrane structure,” said Vander Zanden. “We model it, and then we align this with our simulation data. And that’s how we get a whole picture of what’s happening.” 

“It’s such a fundamental mechanism of cell signaling,” said Vander Zanden. “If you can control this, you can control what the cell does.” 

By studying the biomolecular structure of the proteins that read the sugar code, Vander Zanden is uncovering a pivotal way that cells communicate. And she is not doing it alone. Vander Zanden is passionate about involving students in her research.  

“That’s my favorite part of the job,” said Vander Zanden. “I love working with students because it’s where I get to really make a difference.”  

“The impact I have in the classroom is multiplied by what my students will do in their future careers. For example, Alzheimer’s disease is the only of the top ten leading causes of death in the US that we don’t have a good way to prevent, treat or cure. By teaching a class about neurodegenerative diseases and inspiring future biochemists, they’re motivated to go on and do research on this topic. The collective achievements of my former students are much more impactful than anything I could ever do on my own.”

Research in the UCCS chemistry and biochemistry department is thriving, having acquired approximately $2 million in research grants through a combination of funding from the National Institute of Health, National Science Foundation, and internal UCCS awards over the past five years. “These research dollars have tangible benefits to undergraduate-level students,” said Vander Zanden. “At a place like CU Boulder or CSU, there’s lots of research money flowing through there, but it’s mostly being used to pay PhD students and postdoctoral researchers. Whereas the grant to do this sugar code research is specifically intended to pay undergraduate researchers. That’s the advantage of completing an undergrad degree at UCCS — the ability to be an integral part of a small team doing cutting-edge research.”  

This research was recently funded by a $430,000 National Institutes of Health grant to UCCS titled “Galectin-3 and Engineered Variants for Clustering Glycolipids and Gycoproteins on Membrane Surfaces.”  

About the UCCS College of Letters, Arts & Sciences

The College of Letters, Arts & Sciences at UCCS is the university’s largest college, enrolling nearly 6,000 students across 21 departments and programs. The college offers 19 majors and 53 minors in the arts, humanities, social sciences and natural sciences. Students can also choose from five accelerated bachelor’s and master’s degrees, nine full master’s degrees and three Ph.D. degrees, as well as pre-medical and pre-law programs. The mission of the college is to position graduates for success in their personal and professional lives, with a focus on thinking, creating and communicating — skills vital to employers and graduate and professional schools. Learn more about the College of Letters, Arts & Sciences at UCCS.