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National Institutes of Health

Danny Bluestein and Wei-Che Chiu, a Stony Brook biomedical engineering doctoral student, with ventricular assist devices. Photo from SBU

By Daniel Dunaief

Some day, a doctor may save your life, repairing a calcified heart valve that jeopardizes your health. But then, the doctor may owe his or her latest lifesaving procedure to the work of people like Danny Bluestein, a professor in biomedical engineering and the director of the Biofluids Laboratory at Stony Brook University, and an international team of colleagues.

The group is working on restoring blood flow from the heart to the body using approaches for patients for whom open heart surgery is not an option.

Recently, the National Institutes of Health awarded the research crew a five-year $3.8 million grant to work on a broad project to understand ways to improve transcatheter aortic valve replacements, or TAVR, while reducing or minimizing complications from the procedure.

Danny Bluestein with his wife, Rita Goldstein. Photo from D. Bluestein

The grant is “not just about developing a new device, which we’ve been developing already for several years, but it’s also developing it in such a way that it answers challenges with disease and what clinical problems current technology offers solutions for,” Bluestein said.

TAVR provides a prosthetic valve for high-risk surgery patients. Like stents, TAVR is inserted through an artery, typically near the groin, and is delivered to the heart, where it improves the efficiency of an organ compromised by calcification on a valve and on the aorta itself.

Patients who have been candidates for TAVR are usually over 70 and often struggle to walk, as their hearts are enlarged and lose flexibility.

TAVR surgeries are performed in as many as 40 percent of such operations in some parts of Europe and the United States. The numbers have been increasing in the last couple of years as the technology has improved in different iterations of TAVR.

These valves are not only helping high-risk patients, but they are also assisting moderate and lower risk candidates.

Doctors have used TAVR for off-label uses, such as for people who have congenital difficulties with their valves, and for people who have already had open heart surgeries whose replacement valves are failing and who may be at risk for a second major heart operation.

Recovery from TAVR is far easier and less complicated than it is for cardiac surgery, typically requiring fewer days in the hospital.

Indeed, numerous researchers and cardiologists anticipate that this percentage could climb in the next several years, particularly if the risks continue to decline.

The team involved in this research effort is working with a polymer, hoping to reduce complications with TAVR and develop a way to tailor the valve for specific patients.

“If you’re a polymer person like me, you know we can make this work,” said Marvin Slepian, the director of the Arizona Center for Accelerated BioMedical Innovation at the University of Arizona. Slepian is pleased to continue a long collaboration with Bluestein, whose expertise in fluids creates a “unique approach to making something happen.”

The tandem is working with Rami Haj-Ali, the Nathan Cummings Chair in Mechanics in the Faculty of Engineering at Tel-Aviv University in Ramat Aviv, Israel. “To enable this technology, we need to better understand the current” conditions, said Haj-Ali, who uses computer methods to study the calcium deposited on the valve to understand the stages of the disease.

The valve Bluestein is proposing includes “new designs, new simulations, and new materials” that can create “less reactions with patients and overcome” problems TAVR patients sometimes face, Haj-Ali explained.

One of the significant challenges with TAVR is that it typically only lasts about five to six years.

“The idea of the NIH and this project is to extend the built-in efficiency of such a procedure,” Bluestein said. “TAVR is moving very fast to extend its functionality and durability.”

When the valve is inserted into the body, it is folded to allow it to fit through the circulatory system. This folding, however, can damage the valve, making it fail faster than in the surgical procedure.

As a part of this research, Bluestein and his team will explore ways to change the geometry of the TAVR according to the needs of the patient, which will enhance its functionality for longer. Bluestein and others will test these changing shapes through models constructed on high-performance computers, which can test the effect of blood flowing through shapes with specific physical passageways.

“Eventually, the future would involve custom designed valves, which would be optimal for the specific patient and will extend the lifespan of such a device,” Bluestein said.

A current off-label use of the TAVR valve involves assisting people born with an aortic valve that has two leaflets. Most aortic valves have a third leaflet. People with bicuspid aortic valves develop symptoms similar to those with calcification.

Going forward, Bluestein and his team plan to design valves that are specific for these patients.

A small percentage of patients with TAVR also require pacemakers. The device can interact with the electrophysiology of the heart and impair its rhythm because it creates pressure on the tissue. It is likely pushing against special nodes that generate the heart rhythm.

These studies include exploring the mechanical stress threshold that requires implantation of a pacemaker. By moving the device to a slightly different location, it may not interfere with the heart rhythm.

A resident of Melville and Manhattan, Bluestein is married to Rita Goldstein, who is a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai. 

Bluestein was raised in Israel, where he did his doctoral work. He became intrigued by the study of the flow of blood around and through the heart because he was interested in blood as a living tissue.

As for the ongoing work, Haj-Ali is optimistic about the group’s prospects. The scientists that are a part of this effort “bring something to the table that, in combination, doesn’t exist” elsewhere, he said.

Gabor Balazsi in his lab. Photo by Aleksandrs Nasonovs

By Daniel Dunaief

It started with a bang. When he was young and living with his parents, Gabor Balazsi’s curiosity sometimes got the better of him, at the expense of his parents’ house.

The future Henry Laufer associate professor of physical and quantitative biology at Stony Brook University was holding bare wires in his native home in Transylvania when he plugged in an appliance. The current surged through his body, preventing him from releasing the wires. Fortunately, his mother came in and “unplugged me.”

These days, Balazsi, is much more focused on the kinds of behavior that turns the instructions for a cell into something more dangerous, like cancer or a drug-resistant strain of a disease.

Balazsi recently received a $1.8 million, five-year grant from the National Institutes of Health to study how gene networks change, often to the detriment of human health, as is the case when they are active in cancer or when they are resisting treatment. The grant is called Maximizing Investigators’ Research Award.

“Cancer cells often don’t look the same in a matter of months and drug-resistant microbes may look the same in a matter of days,” Balazsi said. He would like to know “what causes them to change and how can we prevent them from changing to their advantage and our disadvantage?”

In a way, Balazsi is trying to figure out a code that is akin to the popular 1970s game Simon in which a player has to repeat a growing number of flashing lights and sounds. With each turn, the game increases the number of flashing lights and sounds, going from a single red, to red, green, yellow and green until the player can no longer recall the entire code.

He is looking for a similar key to a sequence of events that transforms a cell, except that in the cancer, there are millions of interacting lights, many of which are invisible. The cancer biologist tries to reconstruct the sequence in which some of these lights turned on by observing visible lights that are currently on.

He is exploring the “pattern that leads to the outcome” through changes of networks in yeast cells, he said. He is also hoping to explore pathogenic fungi. The pattern, he said, will change depending on the circumstances, which include the environment and initial mutations.

Scientists who have collaborated with Balazsi suggested his understanding of several scientific disciplines enables him to conduct innovative research.

“He bridges two fields, biology and biophysics, allowing him not only to describe biological processes but also to model them and make predictions that can then be tested,” Marsha Rosner, the Charles B. Huggins professor at the University of Chicago, wrote in an email.

While Balazsi doesn’t treat patients, he is focused on understanding and controlling the processes that lead a cell or group of cells to change from a uniform function and task to a heterogeneous one, where the cells may follow a different path using a previously inactive network of genes.

By understanding what causes these changes, he hopes to find ways to slow their progress or prevent the kind of deviations that lead to combinations that are destructive to humans, such as when the cellular machinery copies itself uncontrollably.

Balazsi and Rosner collaborated on one paper and are continuing to work together. “Our work demonstrates one mechanism by which cells move from a homogeneous population to a more complex population that contains cells that promote cancer,” Rosner explained. “This mechanism is not based on mutations in genes, but rather on changes in the way that genes interact with each other in cells.”

On a fundamental level, Balazsi explained that researchers have developed considerable understanding, but still not enough, of what happens in normal conditions. He is seeking to discover the logic cells use to survive under stressful conditions.

Balazsi would like to determine if there is “anything we can do to decrease the tendency of cells to deviate from normality,” he said.

Balazsi welcomes this new funding, which will give him the freedom to pursue research questions at a basic level. Instead of supporting a single project, this financial support contributes to multiple projects.

The next step in funding his lab will be to approach the National Cancer Institute. Without much experience in applying for cancer grants, Balazsi plans to attend a think tank workshop in June in Seattle. Attendance at this meeting, which is hosted by Sage Bionetworks and the NCI, required an application and selection of participants.

To some degree, Balazsi may be able to relate to the heterogeneity that he hopes to study in cells. A physicist by training, Balazsi explained that he “wandered into biology.” He would like to steer away from major trends that mobilize many researchers. If many people are working on something, he does not want to be enriching big crowds but would prefer to try new things and test new ideas.

A resident of East Setauket, Balazsi lives with his wife Erika and their daughter Julianna, who is 6. Julianna is already doing some experiments at home and is exploring the yard.

When Balazsi was young, his parents tried to encourage him to become a doctor, which didn’t work because he didn’t like blood or hospitals as a child. In addition to his unexpected electric shock, Balazsi also explored how ethanol burns while flowing, which caused some additional damage to his house. “My parents,” he recalled, “weren’t happy.”

As for his work, Balazsi would like his work with these first steps, in understanding cellular processes, will have a translational element for people some time down the road.

“Whatever we do, hopefully, they can be implemented in actual cancer cells that are coming from patients one day,” he said, or they could have some relevance for people who are attempting to fight off “pathogenic microbes.”

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