Drew’s research group became the tenth from the same department at Stockholm University to move to SciLifeLab in Solna, which accommodates groups from four universities that together benefit from a world-leading research infrastructure.

“SciLifeLab welcomes research groups that not only use the technical infrastructure but also contribute to developing new research platforms,” ​​says Drew, a professor at Stockholm University.

Two areas

Drew’s research focuses on proteins called SLC transporters – the largest group of transporters in the human cell that ensures each cell receives the nutrients needed to thrive. The goal is to understand how the transporters work at a molecular level. To date, the research has identified 13 different SLC transporters called NHEs, which control intracellular pH, cell volume and salinity.

“Our cells depend on precise pH and sodium levels to function. NHE transport proteins act as reversible doors that exchange sodium for proton ions across cell membranes. This process is crucial for everything from cell cycle division to cell migration to the physiology of major organs, such as kidney, heart and brain,” Drew explains.

In evolutionary terms, these NHE transport proteins date back to the time when the very first life forms emerged on Earth at deep-sea vents from natural geothermal proton gradients. These transporters exchanged the natural protons gradients with sodium ions, converting the cell into a self-sustaining battery that could energize processes required for cell and life survival, by creating an internal environment different from the external surroundings. Today, NHE transport proteins are found in all living organisms where they, among other things, control our pH level.

“Intracellular pH level is critical for cell function. The body needs a pH value of exactly 7.2 – a variation of just two tenths can cause some cells cycle to become arrested in the cell cycle.”

Disruption in the function of NHE transport proteins affects a number of different conditions, ranging from cancer and diabetes to high blood pressure. There are also examples of how mutations in these proteins cause severe neurodevelopmental disorders.

Complex environment

Drew’s research group has determined the atomic structures of a number of transport proteins, including the NHE proteins, which control the uptake of salt, cell volume and pH value. However, it is still not known how the activity of NHE transport proteins is regulated as they have, so far, only been studied in their isolation. The answer lies in the complex interaction with other molecules in the cell.

“Rather than a simple on or off switch, we know from measurements in cells that the activity of NHE transport proteins is influenced by a large variety of other proteins, that are thought to bind transiently. Indeed, intracellular pH is carefully regulated. In addition, there are specific lipids, which can also regulate the activity.”

Therefore, a new approach is required to determine the details for understanding how NHE transport protein activity is regulated.

Traditionally, membrane proteins are purified with detergents, however, these soap-like conditions break apart weak interactions between proteins preventing studies together with these regulatory proteins. Drew now is developing methods to isolate these NHE transport proteins in a way that excludes detergent and maintains the native interactions with their immediate surroundings.

Although transport proteins play a crucial role in cell function, we know very little about how they are regulated. Better knowledge about these processes will lead to more effective drug treatments.

In simple terms, the researchers will use antibodies to capture NHE transporters directly from their natural environment and image these using advanced Cryo-electron microscopy.

Drew likens it to building soft Lego models with the NHE transport protein at the center. While these more diverse and complex samples make it more challenging to build details the help of computer calculations and AI tools such as Alphafold, will help to piece together an understanding of these larger systems.

New drugs

Greater understanding of the regulation of NHE transport protein activity may be vital to the development of new drug treatments, explains Drew, and not only in terms of widespread diseases such as cancer, hypertension and diabetes.

"We’ve determined the structure of an NHE transport protein that is crucial for sperm mobility. Pharma companies are interested in developing a drug that targets this protein, as a potential non-hormonal contraceptive that could be used by men.”

Already as a student back home in New Zealand, Drew fell in love with structural biology. Since then, amongst other advances, he has developed a technique to produce and isolate membrane protein that is now used in laboratories worldwide. Curiosity is a key part of what drives him.

“But it would be difficult to make progress with curiosity alone. A large part of my motivation comes from developing techniques and methods that benefit society,” says Drew. 

Text Magnus Trogen Pahlén
Translation Nick Chipperfield
Photo Magnus Bergström