Whether it’s helping us or harming us, our immune system plays a critical role in our health. It’s our best defender against disease and infection but, in the case of autoimmune disorders like type 1 diabetes or lupus, it’s also the cause of life-limiting or life-threatening symptoms.
Immunology research at BC Children’s got a boost earlier this month with the arrival of Dr. Ramon Klein Geltink. He’s an expert in immunometabolism, an emerging field that examines the relationship between immune cells and the nutrients that fuel them to find new ways to spur our immune system on when it’s working for us and reign it in when it’s working against us.
Dr. Klein Geltink’s pioneering research has shown that the way in which immune cells derive their energy can determine whether they die off shortly after responding to an infection or stick around to “remember” the disease if it comes back. These insights suggest that manipulating these signals could be used as a new therapy for encouraging the best possible immune response for a given disease.
Dr. Klein Geltink is a new investigator at BC Children’s and Assistant Professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia. Prior to moving to Vancouver, he was a postdoctoral research fellow at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany. He holds a PhD in Molecular Biology from Erasmus University Rotterdam, while he did his graduate work at St. Jude’s Children’s Research Hospital in Tennessee.
We talked to Dr. Klein Geltink about his work and how it could help kids with a range of diseases including autoimmune disorders, chronic infections and cancer.
What is immunometabolism and what does it mean for children?
Metabolites are a fancy name for the small molecules or building blocks that fuel the cells in our bodies.
Typically, when researchers grow immune cells in a dish, they provide all the nutrients and metabolites the cells could possibly need. However, for reasons we don’t yet fully understand, cells will pick some metabolites to use, some to store, and some to ignore.
To better understand how cells use specific metabolites, my lab is investigating the signals that tell immune cells what to do with these nutrients and how this changes their ability to engage cancer cells or infections. In the future, clinicians could use this information to reprogram immune cells to use specific molecules and better equip them to help children fight disease.
For example, we know both tumour cells and immune cells need a particular type of metabolite called glucose. Tumour cells need a lot of it to grow and can quickly consume all that’s available. This leaves immune cells without the fuel they need to fight the tumour cells. If we could coach immune cells to thrive with less glucose, or better compete for it near tumours, we’d effectively boost the body’s ability to fight cancer.
The same approach could be used in childhood autoimmune diseases by flipping this equation. Autoimmune diseases occur when a person’s defense system attacks their own body. If we could pinpoint which metabolites are fueling these cells and disrupt that process, we could dial down the immune system’s response and help reduce symptoms of the disease.
So how do you work out which signals or metabolites are important?
We plan to grow immune cells in the lab and then selectively remove metabolites one by one to test how this impacts their ability to mount an immune response.
Learning the role that specific metabolites play will be a bit like untangling a nest of cables behind the TV; we’ll have to carefully follow where each cable leads. It’s not going to be easy but it’s going to tell us a lot.
Understanding these changes is really important because immune cells, by their nature, travel all around the body and are exposed to different environments with varying levels and types of metabolites. Just because immune cells behave one way in a dish, does not mean that they will behave the same way at the site of a tumour or an infection.
We can get a better idea of how these different environments might interact with immune cells thanks to recent technological advances that make it easier to ‘label’ metabolites and track their movements and absorption in the body. Once we understand what might happen to metabolites in the body, we can study the impact this has on the immune system.
One of the reasons I am excited to be doing this work at BC Children’s Hospital is that we can see right away if the effects we see in the lab are relevant for sick kids. If we are seeing children diagnosed with metabolic disorders in the hospital falling ill to certain infections, then it offers a real-world clue as to how that disorder influences the immune system. Then we can get to work in the lab to find new treatments.
What is a common misunderstanding about metabolites and the immune system?
Among researchers, it’s pretty common to assume that if a cell is taking in a metabolite, it’s using that metabolite. But, actually, the cell could simply be storing it for later.
One way to think of it is to compare metabolite uptake to stocking up the fridge. If I were to show you a fridge full of vegetables and one full of chocolate, which one do you think belongs to the person with an unhealthy lifestyle? Now, what if I told you the person with the fridge full of chocolate is on a diet and has eaten their vegetables? In this scenario, we’re seeing chocolate not because they’re eating it but because they’re not eating it.
The lesson is that we have to do more than simply peek into the fridge of an immune cell. We need to know what they are doing with the metabolites they absorb to understand what’s really going on.
What brought you to BC Children’s?
Although my work is based in a lab it’s very important to me to be able to work in close collaboration with clinicians and patients. That way it’s easy to see whether children suffering from immune-related diseases actually benefit from the discoveries we make in the lab.
BC has an incredible program of inborn screening where all children are assessed at birth to see if they have any problems with metabolism. If researchers in the hospital find rare diseases related to metabolism we can study it in the lab to tease out how these diseases affect the immune system.
Outside of work, I love wildlife photography and the idea that we can escape to nature just 30 minutes from the city is absolutely amazing. We’ve already managed to photograph black bears with cubs on a hike after work on a Friday evening. Coming to Vancouver has been a pipedream of mine for a decade and I can’t wait to get started.
