by Saksham Vashistha
Affecting nearly 80% of Americans, stress has become an integral part of our communities. However, while stress can affect our mental health, cells, too, experience physical stresses. However, while stress can affect our mood, physical stresses affect our bodies at the cellular level. Getting to the bottom of how cells respond to stresses is a useful tool in a wide variety of fields. Dr. Mike Gustin, a professor of biological sciences at Rice University, aims to understand stress responses in cells and their role in the treatment of cancer.
Dr. Michael Gustin’s passion for cellular biology developed during his time as a graduate student. While working in the Ching Kung lab at the University of Wisconsin-Madison, then-physiologist Dr. Gustin and his team were the first to discover that ion channels, special proteins that span the cellular membrane and help transport charged particles into and out of the cell, exist in yeast and bacteria. Now at Rice University, Dr. Gustin has made the transition to genetics, focusing on the impact of stress on cellular behaviors. His most recent works include collaborations with researchers across the Houston area, namely Dr. Erik Cressman, a chemist at MD Anderson.
Dr. Gustin and Dr. Cressman worked together on an NIH funded project that investigates ways to treat liver cancer. Unfortunately, as Dr. Gustin points out, “for liver cancer, there is no good chemotherapy.” Oftentimes, cancerous tumors in the liver are inoperable and alternative treatments are required. However, Gustin and his team have found that “chemistry-driven exothermic reactions (heat-generating reactions) can ablate (remove) tissues in an increasingly controlled way.” There are a variety of different reactions that can be used to ablate cells. Dr. Gustin’s group decided to use a reaction between an acid and a base. By mixing the two solutions on the cell’s surface and allowing them to react, heat and a high solute concentration (osmolarity) are produced. This extreme heat combined with the high osmolarity is toxic to the cell and kills it.
As Dr. Gustin explains, “there is an ablation zone [on the cell’s surface] where the temperature is high enough to kill cells and there is a combination of not just heat, but also high osmolarity because of the salt that accumulates there.” Gustin’s group is interested in the peri-ablation zone, the area just around the region of high osmolarity. It was hypothesized that the applied cellular stresses are followed by some types of cellular defense mechanisms or signaling pathways. These signaling pathways serve to protect the cell from physiological stresses, helping it survive the harsh ablation conditions. Understanding how these pathways work is key for ablation treatment in cancer patients. The goal is, as Dr. Gustin says, “to inhibit those pathways in a controlled way [to] control how much ablation actually happens.” Thus, by inhibiting certain cellular defense mechanisms, ablation in cancer cells can be modulated and used precisely during cancer treatment.
One of the interesting finds during their investigation was that sometimes the stress applied to the cells prevented the cells from even responding. Upon further investigation, it was found that some of the genes that are activated for the stress response actually inhibited other stress responses. Dr. Gustin’s team attempted to understand these stress responses at the molecular level. By using computer modeling of known proteins that were involved in the stress response pathways, they were able to identify how the structures of the proteins were changed by the cellular stresses. Gustin’s team wanted to understand “what happens to the fluid around a protein and what happens when stresses combine around that protein.” Understanding what happens to the fluid around the protein can indicate what environmental changes the protein is experiencing. The alteration of the fluid condition can lead to altered protein structures. Changes in the molecular structure of proteins affects the cell’s ability to react properly to stress. This is because the structure of the protein is what determines its function. If the structure is altered in any way, the protein wouldn’t be able to carry out its function correctly. This molecular modeling approach can help scientists understand not only at the cellular but also the tissue and organ level of how stress responses operate in a mammalian body. Furthermore, ablation in tumor cells can be controlled via inhibition of the genes and subsequent proteins involved in the cellular stress response. This control over the cell’s genes can help make ablation more effective for liver cancer patients with inoperable tumors.
Dr. Gustin’s investigation into harnessing the power of cellular stresses has the potential to change how physicians approach the treatment of cancer. By identifying mechanisms by which cancer cells resist ablation, Gustin’s work provides new insight into how physicians can directly alter cellular defense mechanisms to make them more vulnerable to treatment. While understanding the influences of stress on cells has made significant contributions in medicine, Gustin’s work can also have applications in other fields. Dr. Gustin has his eyes set on something greater. “I am really curious about … what happens during coral reef bleaching”, Dr. Gustin says with a glint in his eyes. Coral reef bleaching is a direct result of stresses (changing water temperatures) on the cells of the organism, causing them to lose the algae living in them. The algae are responsible for providing the majority of the coral’s energy, without them the coral starve and die. Gustin hopes to use his knowledge of cellular stresses to “genetically engineer algae that stay in the coral” reagrdless of the water temperature in an effort to save an inumerable amount of coral around the world. Such an effort would help lead the effort to rebuild important coral reef ecosystems globally.
[1] Saad, L. Eight in 10 Americans Afflicted by Stress. https://news.gallup.com/poll/224336/eight-americans-afflicted-stress.aspx
[2] Fuentes, D.; Muñoz, N. M.; Guo, C.; Polak, U.; Minhaj, A. A.; Allen, W. J.; Gustin, M. C.; Cressman, E. N. K. A Molecular Dynamics Approach towards Evaluating Osmotic and Thermal Stress in the Extracellular Environment. International Journal of Hyperthermia2018, 35 (1), 559–567.