Even while studying for his medical degree at Semmelweis University of Medicine in Budapest, László Csanády knew his career would involve doing science, not practicing medicine. His fascination with ion channels led to his decision to dedicate himself to learning why these proteins are fundamental to human biology.
Ion channels are gatekeepers that regulate the passage of ions into and out of cells. They are integral to many biological processes, including generation of a heartbeat and communication between neurons. “It’s hard to say why you get attracted by something,” he says. “I was always fascinated by these channels and how they work.”
Although Csanády realized he wanted to work on ion channels, no labs at Semmelweis were doing that research. So after earning his M.D. in 1995, he headed to The Rockefeller University in New York to earn his Ph.D.
As a graduate student in biophysics at Rockefeller, Csanády learned an important lesson. “Once you start studying ion channels, you are trapped,” he says. “They just don’t let you go.” He and his mentor, physiologist David Gadsby, developed a host of approaches for investigating the structure and function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel that transports chloride and controls the movement of salt and water across cells that line the lungs, gut, and other tissues.
People with cystic fibrosis have a mutated CFTR protein, which means the ion channels are often absent from the cell membrane. The channels that are present often don’t open when, or as quickly as, they should. The result is decreased chloride transport and disruption of the defense system that protects the airways from bacterial infection. Bacteria thrive in the thick mucus that develops, making life-threatening infections all too common.
In his research at Rockefeller, Csanády drew on his biophysics training and his extensive undergraduate work in mathematics and computer programming. He focused on developing techniques to measure the time it takes for an ion channel to open and stay open. That information can provide insights into how the various components of the channel work to open and close the pore, for example. This work nailed down important details of how the CFTR channels function. Csanády says that such research may one day be used in developing compounds that increase the fraction of time the pore is open. “That would be beneficial to CF patients by increasing the chloride transport rate,” he adds.
In 2006, when Csanády became an assistant professor at Semmelweis, he started investigating a critical question about CFTR: how the channel processes the fuel for its own engine. In addition to being a selective pore that lets ions in, the CFTR channel can also act as an enzyme. The enzymatic part of CFTR helps provide the energy for opening the pore. “We would like to know how the catalytic cycle itself works and how that drives the gating process,” Csanády says. Channel gating is the mechanism by which channels open their gates to let ions through in response to the appropriate stimulus.
In 2007, Csanády’s lab began studying the structure and function of another medically important channel with enzymatic properties, transient receptor potential melastatin 2 (TRPM2), a calcium ion channel found in neurons, immune cells, and the insulin-secreting cells of the pancreas. Researchers are looking at TRPM2 as a drug target for a diverse set of conditions ranging from stroke and Alzheimer’s to chronic inflammation and diabetes. Csanády says little is known about how the enzymatic role of TRPM2 is related to channel gating or whether it is coupled to gating at all. “We would like to clarify this issue,” he says.
With support from HHMI, Csanády plans to explore the basic structure and function of the TRPM2 channel, which could lead to the design of new drugs. Because channels closely related to TRPM2 are found throughout the body, drugs that target TRPM2 will have to be precise. This makes the detailed work on TRPM2 particularly important, he says.
Csanády will continue to build tools to measure and analyze the timescale on which ion channels open and close. A software suite he developed to analyze these measurements is now used by labs around the world. He is excited by the prospect of using his HHMI support to further contribute to the basic understanding of ion channels and creating tools for others to do the same.
“HHMI support will allow me to focus on my research for the next five years,” Csanády says. “I will be able to buy new equipment and hire the highly qualified postdocs I need for this kind of work. I will also be able to support graduate students. I’m looking forward to getting started.”