Thesis Watch: Alex Cornwell, Biology
By Zeke Shomler
On Monday, March 20th, 2023, biologist Alex Cornwell successfully defended his M.S. thesis entitled “The role of cystathionine γ-lyase and hydrogen sulfide in glucose transporter GLUT1 expression in macrophages.” His project takes an in-depth look at cellular mechanisms to better understand the role of hydrogen sulfide in immune processes.
Hydrogen sulfide (H2S) is a poisonous gas; it’s considered an environmental toxin, and is usually associated with sites of geothermal activity like volcanoes and hot springs. Cell biologists have found, however, that not only is it likely one of the keys to the origins of life on Earth, hydrogen sulfide also has essential roles in a number of different bodily processes. Our own cells actually produce H2S, which regulates cellular metabolism, works as a vasodilator, and even functions as an antioxidant in some situations. It’s also an important molecule in inflammation and immune responses, which is what Alex took a look at with this particular research.
Macrophages are the immune system’s main line of defense. They cruise around the body looking for invaders like viruses and foreign bacteria, and then mobilize defenses to attack. Previous researchers have found that when macrophages are activated, we also see an increase in an enzyme called cystathionine gamma-lyase (or CSE). CSE is one of enzymes involved in the body’s production of hydrogen sulfide. It’s been found that knocking out CSE prevents macrophages from doing their job—but it hasn’t been fully understood how the two are linked.
Another molecule that’s important during immune responses is called GLUT1. Attacking other cells, like microphages do, takes a lot of energy, and that energy comes from breaking down glucose (sugar) molecules. GLUT1 is the enzyme in macrophages that lets glucose in to be used as energy during immune responses. In 2015, researchers found a link between hydrogen sulfide and GLUT1. When Alex Cornwell came on the scene, the exact link between GLUT1 and the hydrogen sulfide/CSE system was still not understood.
To figure out the relationship between these important molecules, Alex looked at lab-grown cells derived from mice, which have been found to be a great model for showing how macrophages work. He treated the cells with lipopolysaccharide (a molecule that lives on the surface of bacteria) to trigger immune responses. Some of these cells were treated with small interfering RNA strands to knock out CSE gene expression and hydrogen sulfide production. Then he performed a number of sensitive tests to measure the levels of particular proteins and mRNA in the cells, using complicated equipment like a spectrophotometer, a microplate reader, and a thermal cycler. He also took a look at several other mediating molecules that are involved in this system of immune response.
One thing Alex’s research found is that there is a direct link between hydrogen sulfide and GLUT1 during immune responses. Preventing macrophages from having the CSE required to make H2S meant that they couldn’t make GLUT1, and therefore couldn’t get the energy they needed to perform their inflammatory immune reactions.
He also confirmed that it is definitely possible to have too much of a good thing: immune signaling by hydrogen sulfide operates within a narrow window of concentrations. When cells were given extra hydrogen sulfide, instead of making even more GLUT1, they actually turned off production of the glucose-transporting molecule. That means that even though not getting enough H2S means the macrophages can’t do their job, too much and it ends up doing the same thing—hydrogen sulfide is what’s called biphasic.
As far as our understanding of H2S in the human immune system, Alex’s work comes right at the beginning of what looks to be an exciting area of exploration within biology and medicine. This research shows a lot of potential in helping us understand macrophages and immune responses, and could be really important in treating diseases like sepsis. Future work might start exploring hydrogen sulfide in living organisms, since this work with petri-dish cell lines was so promising. Alex noted that hydrogen sulfide is also being studied at UAF in relation to hibernation in arctic ground squirrels—it was initially for separate reasons, but looks to be interrelated with Alex’s work with mouse cells in really interesting ways.
Before coming to UAF for his master’s degree, Alex got his BA in biology with a minor in physics from Capital University in Ohio. Then, he worked for six years at the Ohio State Comprehensive Cancer Center working as a lab assistant for the flow cytometry core facility, which involves firing lasers at cells grown on petri dishes to understand which receptors are present on them. His ability to perform precise work with sensitive lab equipment made him the perfect candidate for working on this hydrogen sulfide project at UAF.
During his two years here, Alex has spent a lot of time in the lab, working on a number of other projects and publishing a scientific paper in addition to completing his M.S. thesis. He hopes to continue working in biology labs in the future, and might go on to get a PhD. No matter what the future holds, Alex’s work with macrophages will undoubtedly lead to even more interesting insights into the processes that regulate essential aspects of life.