KGI’s Dr. James Sterling Co-Authors New Publication Investigating Biological Compartments

New discoveries in biology have revolutionized our understanding of the cell. Mathematical modeling of microscale biology: Ion pairing, spatially varying permittivity, and Born energy in glycosaminoglycan brushes, a Physical Review E publication from Keck Graduate Institute (KGI) Professor Dr. James Sterling—which he co-authored with Dr. Ali Nadim, Dr. Marina Chugunova, and PhD student William Ceely of Claremont Graduate University (CGU)—sought to better understand these findings by constructing mathematical models of cell structures. Such insights can, in turn, guide the design and development of therapeutics.

The phenomena investigated were ion pairing (the partial association of oppositely charged ions in electrolyte solutions to form distinct pairs), spatially varying permittivity (electric fields and how they vary in space), and Born energy (the response of water to ionic charges).

While molecule sizes are usually measured in nanometers, microscale structures are 1,000 times bigger, which is close to the size of a cell. Thus, by providing models at the microscale level, the study sheds light on cellular structure and formation.

Sterling collaborated with his colleagues at CGU’s Institute of Mathematical Sciences as they are experts in continuum models, which are ideal for studying biological structures at the microscale level.

“These kinds of mathematical models demonstrate how salts play a role in structure formation,” Sterling said. “The models should be applicable to many biophysical environments that contain big, long molecules that are intrinsically disordered, meaning they do not attain a definitive structure.”

Cell surfaces are covered by a microscale sugar-coating called the glycocalyx that looks like a brush of soft, flexible bristles. The study investigated the nature of ion-partitioning into the glycocalyx. The electrostatic environment of the glycocalyx has been found to be controlled not only by the overall charges of the molecules but also by the nature of the water as it becomes constrained by the sugar macromolecules.

Specifically, Sterling and his colleagues demonstrated how a glycocalyx component, hyaluronic acid, and heparan sulfate—sugar molecules that are found naturally in the eyes and skin and are often used in face creams—interact with salt and water to affect the glycocalyx structure. 

In addition to the glycocalyx, other microscale structures have been observed and studied, revolutionizing our understanding of the way biological processes proceed. Researchers have found that many events are controlled by a process of liquid-liquid phase separation (LLPS) inside and outside of our cells. 

Traditionally, the cell has been viewed as containing membrane-bound organelles such as the nucleus, mitochondria, and endoplasmic reticulum. However, new research has reviewed organelles that do not contain a membrane, known as biomolecular condensates.

Condensates display emergent properties, taking on characteristics distinct from those of their individual counterparts and expanding into their separate units, much in the same way that condensation (for instance, morning dew on a plant) forms.

These biomolecular condensates can segregate enzymes or increase concentrations of certain proteins to enhance reactions. Dysfunction of these condensation processes has been associated with cancer and other serious diseases.

“The processes depend upon specific molecules, but the condensation occurs on a scale of cells that is much bigger than the size of the molecules themselves,” Sterling said. 

LLPS is the driving mechanism behind biomolecular condensates. As oil and water separate, LLPS causes a uniform solution to separate, forming distinct regions. 

“Bio condensates carry out specialized functions within the cell,” Sterling said. “But new research has revealed that we’re finding these on the outside of cells as well.”

“The mathematical models we’ve developed with our CGU collaborators are currently being applied to understand how salt ions partition and affect bio condensate structure and function.”

“This work is being performed with a group of experimental collaborators at the University of New South Wales in Sydney, Australia,” Sterling said.

Condensates compartmentalize and concentrate molecules, contributing to a range of biochemical processes, including RNA metabolism, ribosome biogenesis, DNA damage response, and signal transduction. Aberrations in a condensate’s composition or behavior—for example, when a condensate is either inappropriately formed or fails to form—have been associated with disease.

Thus, by better understanding condensate structure and how condensates form, scientists can develop drugs to target condensates. One company undertaking this work is Dewpoint Therapeutics, co-founded by Dr. Anthony Hyman and Dr. Richard Young —pioneers in the study of condensates.

“Dysregulation of biomolecular condensates has been found to explain the root cause of an increasing number of complex diseases and could pave the way to novel therapies,” Sterling said.