This week, Science in Seattle profiles Drs. Adam Lacy-Hulbert (pictured, right) and Caroline Stefani (left). Located at the Benaroya Research Institute, Dr. Lacy-Hulbert is the Director of the Center for Systems Immunology, while Dr. Stefani is a Principal Investigator in the Center for Fundamental Immunology. They expand on the findings in their recent publication in Science Immunology and how their approaches led to exciting and surprising results, uncovering the mechanisms behind membrane repair machinery.
This interview has been edited for brevity and clarity.
Can you provide a brief overview of your lab’s current research focus?
Stefani: I joined Adam’s lab as a postdoc and now I’m in my own, independent lab today. My main focus is what this paper is about—which is understanding how the cell responds to damage or stress. How does the cell sense that something is happening and how will it turn on those mechanisms to start repairs? Can I modify the cells to boost the immune response? Can I make the cells better?
Lacy-Hulbert: What I’m interested in is how the body stops the immune system from attacking itself, but continues to allow the immune system to attack bad things. We look at different mechanisms by which the body can educate the immune system.
This can work on many different levels. For example, we do a lot of work on what’s called “tolerance,” which is teaching the immune system the difference between good things and bad things in self and non-self. A part of this is looking at the ability of every individual cell to sense its environment and decide whether it should be making an inflammatory response and calling in the troops or whether it should be dealing with the attack by itself. After an attack, the cell has two decisions: it can try to repair that damage or it can just give up and die. We’re interested in that decision-making process.
What is the significance of the findings in this publication?
Stefani: We discovered this new gene called LITAF. When it’s turned on it orchestrates the repair machinery by binding to other proteins and relocalizing the damage inside the cell. So it’s a new process of repair that hasn’t been shown before. It is significant because LITAF can be turned on in response to different types of pores. Membrane pores can be formed by bacterial pore-forming toxins or, in the case of autoimmune disease, your own immune cells.
What we found in our research is that if we turn on LITAF, it makes the cell more resilient. This leads us to two questions: can we boost the repair mechanism of those healthy cells in a person with autoimmune disease to make them more resilient, and can we, for cases like cancer, turn down the gene to make the tumor sensitive? We’re trying to find that balance between boosting or limiting the resilience of certain cells.
Lacy-Hulbert: Initially, we were studying LITAF in the context of how a cell might respond to a bacterial infection and how a cell defends against infection. Having found this gene, our findings have much wider implications in regards to cancer and autoimmune diseases. For example, in pancreatic cells that are normally killed during diabetes, there seems to be very little LITAF activity and a very poor ability to repair holes in their membrane.
Did anything in your results surprise you? Did you already have LITAF in mind at the start of your research or before the genetic screen?
Stefani: We would have never looked at it before. The idea of the screen is to be completely agnostic. Regardless of whether it’s coding or non-coding, you just target everything and see what comes out.
Lacy-Hulbert: I think it’s a little more emotional than being agnostic; we want to be surprised by things that we would never assume in the first place. We didn’t even know about this gene, right?
Stefani: No, when LITAF came out the first time we were like, “what is that”? I had to look at it on PubMed because I had no idea what it was. The gene was so strongly represented in our data that we thought we definitely have to follow up on this one. Once we started reading about it, it started making sense.
From the literature, it seems to be interacting with a series of other proteins called escorts, and those have been shown to mediate repair at the membrane. So then we did imaging to look at it at the membrane and we were surprised again to find it wasn’t at the membrane, but completely inside the cell. So it’s a new gene, but it’s also a completely new pathway.
Lacy-Hulbert: With this new pathway, it’s like if you had a flat tire on your car. You could change the tire right on the street or you could bring the car into your garage and fix it there. LITAF is bringing the damage into the cell and then fixing it, which is not how most people think this repair process works.
What are the next steps for this research?
Stefani: We’ve already started the next step, which is looking at LITAF during disease. In the case of diabetes, we are trying to see if we can limit the killing of pancreatic beta cells by turning on LITAF. Can we make the cells more resilient? For neurodegenerative diseases like Parkinson’s disease or Alzheimer’s disease, can we protect the neurons from dying?
Lacy-Hulbert: I’m looking into the role of LITAF in Charcot-Marie-Tooth disease, which is a genetic, neurodegenerative disease. It’s not clear yet why mutations in LITAF cause that disease. What is known, is that LITAF is expressed at very high levels in Schwann cells, the cells that surround neurons and make the myelin sheath to insulate the nerve.
The loss of the myelin sheath means that the nerves become exposed to damage and die, which is one mechanism of this disease. However, it’s not known why mutations in LITAF might cause those myelin sheath and Schwann cells to break down. We already have a few hypotheses we’d love to test.
Is the application of your research a primary motivator for you? If not, would you share what is?
Stefani: Personally, I want to help people, but I’m also a pure cell biologist and I like the fundamental side. I like trying to find new genes, new targets, understanding the cell biology, understanding how the immune system functions first, and then finding an application for it.
Lacy-Hulbert: Yeah, I’m at a similar place to Caroline where I’m not motivated by a single disease. I’m motivated by finding out more about how the immune system works and then trying to apply whatever I find to a disease I think it might be relevant to.
This research is funded by National Institutes of Health.
