Our body temperature is kept in check by an elegant biological thermostat.
But, despite its critical role in keeping us healthy and protecting us from temperature-related injury, little is known about how exactly this system works.
Van Andel Research Institute’s Dr. Juan Du hopes to solve this problem by determining the structure and functions of its components, namely communication hubs called ion channels that allow chemical messengers to pass into and out of cells. Her groundbreaking work, which has implications for treating fever, pain and neurogenerative disorders among others, recently earned her a 2019 McKnight Foundation Scholar Award (more on that here).
We caught up with Dr. Du to discuss her research, what we know and don’t know about temperature regulation, and how a better understanding could improve health.
Q: Why study temperature? Why is it important?
JD: Our tissues, especially our brains, are extremely vulnerable to temperature. For example, a bad fever may cause seizures or damage the brain. If you stick your finger into fire or liquid nitrogen for more than a few seconds, it will badly damage your skin, muscles and nerves.
Thankfully, our bodies have an amazing temperature sensation and regulation system to protect us from doing these dangerous actions and maintain body temperature within a narrow range. Temperature homeostasis is thus one of the most critical functions of the nervous system.
Temperature is measured by activating a number of temperature-sensitive ion channels in specialized cells called sensory neurons. This sets off a series of reactions that ends with the neuron sending information about temperature to the brain. My goal for this research is to solve the mystery of how temperature activates ion channels using structural biology, or looking at molecular shape, and functional studies, which link structure to molecules’ roles in the body.
Q: What are some of the gaps in knowledge that you hope to figure out?
JD: In the past several decades, we have learned a great deal about how ion channels work because there are plenty of biochemical and biophysical tools to do this. You may think that this means we should have a good understanding about how temperature-sensitive channels work because temperature sensation is such a fundamental physiological function of all livings. But, in fact, we don’t.
Our understanding of how temperature is perceived by ion channels is still very limited. X-ray crystallography used to be the dominant method in structural biology to solve protein structures at high resolution; however, it is extremely challenging and even impossible at times to use this method to determine protein structures at different temperatures. As a result, we still have no idea what temperature sensors should look like, where they should be located or how temperature relates to channel activation. We also don’t know why different ion channels can be activated at different temperatures.
Q: What are the big questions you would like to answer?
JD: Our research will use a relatively new technique called cryo-EM to solve the fundamental questions in the field about how thermosensitive ion channels work, and will lay a solid foundation for understanding the mechanisms underlying temperature sensation and regulation. Cryo-EM allows us to look at molecules at the near-atomic or atomic level in their natural state, which gives us tremendous insight into their function and how they may interact with new medications. The molecular structures we determine also will provide a basis for development of new pharmacological compounds that could be potentially used for manipulating thermosensitive ion channels and, therefore, treating temperature-related pathological conditions, such as fever.
Learn more about Dr. Du and her work here.