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Photo of several "copies" of William Balke in brand new labIn his lab space in UK's new $74.4 million Biomedical Biological Sciences Research Building, William Balke is beside himself with anticipation as his team sets up shop to continue several projects that were well under way at the University of Maryland. "It is amazing that so many people, mostly in early- to mid-career, have decided to come. It's really a testament to what's been built here and how those opportunities have been made obvious to potential faculty and staff who visit the College of Medicine."

Room To Move
Top team of heart researchers comes to UK

by Jeff Worley

One of the reasons Jay Perman came to UK last year to become dean of the College of Medicine was UK's growing reputation as a top-notch research institution. But he wasn't so sold on the university's efforts to "grow," as he puts it, physician scientists.

"I saw a need for us to develop our clinical disciplines here so that more physicians could contribute to the national research agenda as physician-scientists. So I started thinking early on how we could improve our efforts in the clinical area," says Perman, who also serves as the university's vice president for clinical affairs. He adds that this relative lack of growth in the clinical area isn't specific to UK; it's a shortcoming at other universities, too.

"There are plenty of reasons for the lack of physician-scientists. You need years of additional training for one thing. And there's the very understandable impulse among freshly minted physicians, after years of preparation, to get out there and serve humanity." He mentions, too, the simple lack of time physicians have to also train as scientists.

So Perman went looking for someone who could organize a wide-based clinical research effort here, and serendipity intervened.

"Last June I was part of an NIH group focused on preparing physicians to be scientists. Lo and behold, my recent University of Maryland colleague Bill Balke chaired this section." At Maryland, Balke had been chief of cardiology in the department of internal medicine and Perman chair of pediatrics.

"I knew Bill was a national leader in developing programs for physicians who wanted to do research, and after a long day, we got together for old times' sake over a glass of wine. I told him I was looking for someone to head up clinical research at UK, and I encouraged him to apply when the position was announced."

Balke applied for the job, and after a lengthy search process the UK committee made him their top choice; so last fall Balke was offered the job and eagerly accepted.

Perman also knew that Balke's primary research focus, cardiovascular disease, couldn't have been more pertinent to Kentucky. "Along with his skills in developing clinical research programs, Bill brings an impressive background in heart research." Heart disease is the leading cause of death for Kentuckians. In 2001, Kentucky was ranked third in the nation for heart disease risk by the United Health Foundation. "Getting Bill here is a big plus for us in Kentucky."

The Maryland migration

This good news for the College of Medicine and for UK got even better in the weeks that followed. Balke was also bringing with him nearly his entire lab from the University of Maryland—faculty, postdocs and staff. When all the bags are unpacked and the dust from this influx of research talent has settled, as many as 20 new hires will set up shop in UK's new $74.4 million Biomedical Biological Sciences Research Building.

Balke realizes that such a migration is unusual, but he emphasizes that he and his group weren't chomping at the bit to leave the University of Maryland. It was almost totally a "pull factor," says Balke, who manages to be soft-spoken and intense at the same time.

"It is amazing that so many people, mostly in early- to mid-career, have decided to come. It's really a testament to UK, to what’s been built here and how those opportunities have been made obvious to potential faculty and staff who visit the College of Medicine."

Balke, sitting at a small round table in his office, one wall hidden by a fortress of unpacked boxes, says the primary reason he came was that he saw a career opportunity that would allow him to make a difference in how his work is translated into health benefits for people.

"What I see here is the possibility of coordinating various research projects in the colleges of Medicine, Pharmacy, Nursing, Dentistry, Public Health, and other academic groups. This mutual reinforcement can really make a difference to the health and well-being of the population the university serves," says Balke, loosening his tie after a long day of introductory meetings.

What keeps calcium on the move?

Balke’s lab will be running at full-speed by mid June, continuing half a dozen federally funded projects, to the tune of $3 million to $4 million, that focus on the underlying mechanics of the heart. This work builds on several successes the group has enjoyed recently.

The first project, focused on calcium release in cardiac cells, has gotten scientists a few steps closer to solving a longtime mystery.

"One of the important features of cardiac cells is their ability to take an electrical signal and turn it into mechanical movement so that a heartbeat initiates muscle contraction," Balke explains. "That's absolutely essential for blood to move through the body and nourish all the organs that it does. But exactly how the electrical impulse of the heartbeat causes the heart muscle to contract has been a mystery."

From previous work scientists knew that when the heart is stimulated with a heartbeat, the electricity excites changes in each heart cell, and that calcium goes inside the cell and becomes a trigger. What's triggered is the release of a much larger amount of calcium from inside the cell. That calcium activation causes the whole cell to shorten so that the heart muscle contracts and blood that's in the heart moves forward.

"Based on our own work and in partnerships with other scientists, we were able to use new technology, a laser scanning con-focal microscope, to visualize—in real time—calcium movements in a cell at a level that had never literally been seen before."

Using heart cells from rats, Balke's group added special indicators that glow when they bind to calcium, and because of the extremely high resolution of this microscope, the researchers could see the fluorescence. "With this tagging, we were able to describe in much greater detail the relationship between the calcium that enters the cell from the outside and the calcium that's released from the internal deposits in the cell."

Balke's team was able to determine the relationships of dozens of molecules that serve as what he calls "micro-architecture" to move calcium from one place to another. The group then defined the key molecules involved in calcium triggering in a heart cell and the roles of these molecules. This description involved some very complicated math when the lab's results were published in Science magazine, but Balke says what they discovered can also be understood as a football analogy.

"We not only identified all the major players on the team, but we now know the roles expected of them. The moves of the quarterback, the fullback, the receivers—and how they handle their different positions."

Balke says the discovery is exciting in at least two ways. "It answers the most basic question of basic science—Why? And there are important potential applications for this discovery.

"Our work can help the medical community understand, at least partially, why the hearts of people with heart disease don't contract normally. Understanding the players in calcium metabolism and how they interact with one another also clues us in to potential mechanisms that could go wrong to cause hypertension, heart attacks and heart failure." He adds that his lab is using their discoveries about cell proteins and calcium in normal hearts as the basis for a new research focus: to try to understand and find solutions for hearts that go wrong.

“We hope down the line our work will impact patient care. You’ve heard that overworn expression 'bench to bedside?' I would borrow a page from Lord of the Rings and say that where we want to go is from 'bench to bedside and back again.'"

Doing some (ion) channel surfing

In a second major project, Balke and his team are working to characterize an ion channel they recently found on the surface of cardiac cells. He thinks this channel may play a role in arrhythmia (irregular heartbeats), and if this is true, their work has major implications for patients with this condition.

Think of cells as flashlight batteries. What makes the batteries work is the metal contacts they fit into. Like these metal contacts, ion channels in the cell allow electricity to pour through a cellular membrane so that the cell becomes activated.

"Almost through serendipity we discovered a new channel on the cell surface of most cardiac cells, and, coincidentally, it also happens to exist in most neurons. We don't know the function of this channel but suspect it plays a very important role in getting the cell to accept the electrical impulse of a heartbeat. If this is its role, then it may be a key player in potentially deadly arrhythmias."

His lab has been doing a rigorous study of this channel and what gene controls it, and this work will continue when the team re-groups here in June. Once the channel is understood, the lab plans to work with drug companies to identify pharmacologic agents that make the channel work better.

Balke is clearly excited by the potential of this work. "One outcome could be a pharmacologic alternative to implanting cardiac defibrillators in patients. Another implication might be that because this channel also exists on neurons, it may be a common feature of all cells that are excitable. If we discover that this channel is an important player in devastating neurological diseases, like epilepsy and Alzheimer's, this would be a major, major finding."

Toward better heart treatment

Balke says his group will continue to follow these two major projects where they lead and that several other projects related to cardiovascular disease will be launched at UK. "I hope the work on the ion channel is going to move us forward to understanding what's causing sudden cardiac death in patients and that we'll come up with a more effective way of treating that.

"And I think we're going to find a better environment here to do a systems-biology approach, in other words unite mathematics and molecular biology and physiology, and do multidisciplinary work in a way we couldn't when we were locked into the traditional silos of most academic medical centers," Balke adds.

He emphasizes that it's the unique combination of expertise in his research group that makes the unit so effective—and which allows the imagination of the whole group to blossom.

"We have physicians and we have Ph.D. scientists and technicians who are all equal citizens in the group. Several are experts in studying individual ion channels or molecules on the surface of the cell. Others are skilled in the imaging techniques we use to visualize calcium as it moves in the cell."

Balke singles out the crucial role played by the senior laboratory technician, Stacey McCulle. "She brings invaluable technical expertise to the group and has been absolutely essential in moving our lab forward over the last couple years."

"We're a tight-knit group, and I'm really glad to continue with Dr. Balke," says McCulle, who is planning to move to Lexington in June. "He doesn't micro-manage, and he fosters a good research environment."

Balke is also excited that the team's mathematician, Leighton Izu has come to UK. "Leighton contributes some amazing skills with mathematical modeling, a dimension of this research that few groups have."

"William Balke is a very major recruitment for us," says Perman. "To get somebody of Bill's caliber and national reputation to come—and move his lab here—is a major coup."

UK's newest building, the Biomedical Biological Sciences Research Building, was dedicated on April 11, 2005. The $74.4 million research facility will house 400 faculty, staff and students focusing on neuroscience, proteomics and genomics. In addition to Senior Associate Dean William Balke's Institute for Molecular Medicine, the BBSRB houses the Department of Molecular and Cellular Biochemistry chaired by Louis Hersh, the Spinal Cord and Brain Injury Research Center directed by Edward Hall, and the College of Pharmacy's Drug Abuse Treatment Research Program directed by Linda Dwoskin.

Leighton Izu
Understanding Arrhythmia by the Numbers

One of UK's most recent faculty hires is the first occupant of UK's newest building—the Biomedical Biological Sciences Research Building (BBSRB), west of the Kentucky Clinic across Limestone Street. Leighton Izu, an assistant professor of internal medicine, is one of several members of William Balke's cardiovascular research group who have come to UK in the past few months from the University of Maryland.

Back in February, Izu's second-floor office in the BBSRB was so new, it didn't have a number yet. Workers hammered all around him. The staccato bursts of a pneumatic drill rended the air. Two guys with electricians' belts pulled a huge red and black spaghetti of wires from the ceiling just outside his unpainted door.

"Yeah, I guess you could say I was a little eager to get started here," Izu says, gesturing toward the two tandomly linked, flat-screen computers on his desk, both screens pulsing with what appear to be complex mathematical formulas. "I may be the only faculty member at UK right now who has a key to the building," says Izu, holding the key up like a bright trophy.

Izu's research focuses on understanding the system that controls calcium in heart cells and how that system can get off track. Specifically, he has been working to understand the link between the sudden change in behavior of the calcium control system and the onset of cardiac arrhythmias, or irregular heartbeats. Balke's group is studying the calcium control system by combining mathematical modeling and supercomputer simulations with more traditional lab experiments. The researchers work with rat heart cells, which, Izu says, are models for the heart cells of humans.

"Lately I've been working on what are called 'forward' problems: you have a model, in this case the heart cell, you focus on the most important parameters for the model, and then predict what the system is going to do given these parameters."

Photo of Leighton IzuLeighton Izu, an assistant professor of medicine, is a member of William Balke's cardiovascular research group, which has come to UK in the past few months from the University of Maryland. Izu does complex mathematical formulas to determine how heart cells behave.

Izu says to think of parameters in terms of the performance of a car's engine. Just as an engine has many parts, the calcium control system has many components, each characterized by a set of parameters, such as calcium release units, transporters and channels. "A mechanic can tinker with many, many parameters and that will change the performance of your engine," says Izu, "and I'm doing the same thing with the cell's calcium control system."

His work involves fine-tuning the performance of the heart to avoid arrhythmias. Izu explains that of the two types of arrhythmia—atrial and ventricular—atrial arrhythmias are the more common type and the least understood. The atria are the chambers of the heart that receive blood from the veins and force it into the ventricles.

"Lots of work has been done to try to understand ventricular arrhythmias, and that's totally understandable: If you have a ventricular arrhythmia, you have about a minute to live. You can live with an atrial arrhythmia for years. The fact that not much work has been done with atrial arrhythmia is a good scientific reason to study it—and mathematically, it's fascinating."

With his strong background in mathematics (a B.A. in math and a Ph.D. in biophysics), Izu assigns numerical values to the various parameters of the heart cell and then uses complex mathematical formulas to determine how, given these parameters, the cell will behave. He likens the interactions of the components of the calcium control system to the members of a jazz band.

"Each member adjusts his playing to the mood and tempo of the others, resulting in a dynamic and everchanging piece of music. A band of stubbornly independent members would produce nothing but noise. Likewise, if the control system components are uncoordinated, the calcium dynamics can be chaotic and could give rise to arrhythmias."

Izu laughs that with this analogy in mind, the whole concept of conducting research takes on an additional meaning. "The point is, that using this mathematical modeling, I can predict and, I hope, control the outcome of the inner workings of a cell."

He admits that what he does is extremely complicated, which is why he works with experimentalists at UK and a major national laboratory to fine-tune his mathematical equations. He sends these equations describing the calcium control system to Sandia National Laboratories in Albuquerque, New Mexico, a group funded by the Department of Energy whose primary mission is national security research (but they also work with researchers such as Izu on bioscience projects with no national security implications).

In Albuquerque, Izu's colleagues turn these equations into dynamic 3-D representations of the cell’s inner workings that, on his computer screen back in Lexington, pulse and flow. "You can actually see how the calcium release units set each other off, like a string of fireworks. You can see whether the flow of calcium is even or ragged; you can see which parts of the cell interact most strongly with their neighbors, and so forth."

Although Izu comes across as a man who would probably be happy no matter where he lived, he seems downright ebullient about being in Lexington. "I love it here. Being able to get from home to work and back is a whole lot easier and faster than in Baltimore." He's excited that so many of his lab partners at the University of Maryland have decided to come to UK, adding that he does have a "very favorite" lab partner—his wife Ye.

"Ye has very impressive mathematical abilities," Izu says, his tone an applause of sorts. "I'm horrible at doing routine math." He adds that when he was working on his dissertation, he had terrible trouble simplifying some complicated equations. "Ye took a look at the equations and within an hour got the correct answer."

Click here for Ye's narrative on her road to UK and her account of first meeting Leighton.