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National Institutes of Health

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By Daniel Dunaief

In the typical process of developing cures for medical problems or diseases, researchers explore the processes and causes and then spend years searching for remedies.

Ke Jian Liu. Photo by Jeanne Neville, Stony Brook Medicine

Sometimes, however, the time frame for finding a solution is cut much shorter, particularly when the Food and Drug Administration has already approved a drug treatment for another problem.

This could be the case for hemorrhagic stroke. Caused by a burst blood vessel that leads to bleeding in the brain, hemorrhagic stroke represents 13 percent of stroke cases, but accounts for 50 percent of stroke fatalities.

That’s because no current treatment exists to stop a process that can lead to cognitive dysfunction or death.

A researcher with a background in cancer and stroke, Ke Jian “Jim” Liu, Professor of Pathology and Associate Director or Basic Science at the Stony Brook Cancer Center who joined Stony Brook University in 2022, has found a mechanism that could make a hemorrhagic stroke so damaging.

When a blood vessel in the brain bursts, protoporphyrin, a compound that attaches to iron to form the oxygen carrying heme in the blood, partners up with zinc, a similar metal that’s in the brain and is released from neurons during a stroke. This combination, appropriately called zinc protoporphyrin, or ZnPP, doesn’t do much under normal conditions, but could be “highly toxic” in hypoxic, or low-oxygen conditions.

“We have done some preliminary studies using cellular and animal stroke models,” said Liu. “We have demonstrated on a small scale” that their hypothesis about the impact of ZnPP and the potential use of an inhibitor for the enzyme that creates it ‘is true.’”

These scientists recently received a $2.6 million grant over five years from National Institute of Neurological Disorders and Stroke, which is a branch of the National Institutes of Health.

Focusing on a key enzyme

After Liu and his colleagues hypothesized that the ZnPP was toxic in a low-oxygen environment, they honed in on ways to reduce its production. Specifically, they targeted ferrochelatase, the enzyme that typically brings iron and protoporphyrin together.

Iron isn’t as available in this compromised condition because it has a positive charge of three, instead of the usual plus two.

Liu discovered the role of zinc in research he published several years ago.

When a hemorrhagic stroke occurs, it creates a “perfect storm,” as the enzyme favors creating a toxic chemical instead of its usual oxygen carrying heme, Liu said. He is still exploring what makes ZnPP toxic.

The group, which includes former colleagues of Liu’s from the University of New Mexico, will continue to explore whether ZnPP and the enzyme ferrochelatase becomes an effective treatment target.

Liu was particularly pleased that currently approved treatments for cancer could be repurposed to protect brain cells during a hemorrhagic stroke. Indeed, with over 80 approved protein kinase inhibitors, which could work to stop the formation of ZnPP during a stroke, Liu and his colleagues have plenty of potential treatment options.

“We’re in a unique position that a clinically available drug that’s FDA approved for cancer treatment” could become a therapeutic solution for a potentially fatal stroke, Liu said.

To be sure, Liu and his colleagues plan to continue to conduct research to confirm that this process works as they suggest and that this possible therapy is also effective.

As with other scientific studies of medical conditions, promising results with animal models or in a lab require further studies and validation before a doctor can offer it to patients.

“This is an animal model, based on a few observations,” said Liu. “Everything needs to be done statistically.”

At this point, Liu is encouraged by these preliminary studies as the subjects that received an inhibitor are “running around,” he said. “You can see the difference with your own eyes. We’re excited to see that.”

Earlier hypotheses for what caused damage during hemorrhagic stroke focused on the release of iron. In research studies, however, using a chelator to bind to iron ions has produced some benefits, but they are small compared to the damage from the stroke. The chelator is “not really making any major difference,” said Liu.

The Stony Brook researcher did an experiment where he compared ZnPP with the damage from other metabolic products.

“ZnPP is several times more toxic than all the other things combined,” which is what makes them believe that ZnPP might be responsible for the damage, he said.

Proof of principle

For the purpose of the grant, Liu said the scientists were focusing on gathering more concrete evidence to support their theory. The researchers are also testing a few of the protein kinase inhibitors to demonstrate that they work.

In their preliminary studies, they chose several inhibitors based on whether the drug penetrates the blood brain barrier and that have a relatively high affinity for ferrochelatase.

“This opens the door for a new phase of the study,” Liu said. “Can we find the best drug that provides the best outcomes? We are not there yet.”

Removing zinc is not an option, as it is a part of 2 percent of the proteome, Liu said. Taking it out would “screw up the entire biological, physiological system,” he added.

Liu speculates that any future drug treatment would involve a relatively small dose at a specific time, although he recognized that any drug could have side effects.

In an uncertain funding climate in which the government is freezing some grants, Liu hopes that the financial support will continue through the duration of the grant.

“Our hope is that at the end of this grant, we can demonstrate” the mechanism of action for ZnPP and can find a reliable inhibitor, he said. “The next step would be to go to a clinical trial with an FDA-approved drug, and that would be fantastic.”

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Stony Brook University. File photo

This month, Stony Brook University anticipates the induction of a new president: an exciting time for students. Who will this new leader be and how will they shape the school? What do they have planned for the bustling university? What expertise do they bring? 

Simultaneously, the fate of the monetary foundation of SBU’s research is uncertain. The new president will be stepping into the role amidst changes that would redefine the school’s research aspirations. New York had previously received $5 billion in funds from the National Institutes of Health–an amount that was cut on Monday. The move was blocked by a federal judge after 22 states, including New York, filed a lawsuit against it.

“[The policy] will devastate critical public health research at universities and research institutions in the United States. Without relief from NIH’s action, these institutions’ cutting edge work to cure and treat human disease will grind to a halt,” the lawsuit reads. 

The plan creates ambiguities on a local level as institutions envision a future without millions in funding. The SUNY system’s downstate flagship university is not excluded. “From working to cure Alzheimer’s disease to improving cancer outcomes, from supporting 9/11 first responders to detecting brain aneurysms, your research is essential to our national security and economic leadership. NIH’s cuts represent an existential threat to public health.” SUNY Chancellor John King wrote in a statement released on Monday.

As much as 60% of the NIH grant budget can be devoted to indirect costs such as infrastructure and maintenance. These costs, known as facilities and administrative costs, help support research and would be lowered to 15%. “[The plan] will cost SUNY research an estimated $79 million for current grants, including more than $21 million over just the next five months.” King wrote.

The new president will be juggling the specific priorities of Stony Brook while navigating federal legalities of policies that will undoubtedly affect one of the institution’s major focuses, research. As president, they will have the power to shape the university in momentous ways, leaving their trace for years to come just as previous presidents have. They will also have to adapt to federal directives. The current changes on the national educational stage would put pressure on any university president and could affect the economy of surrounding areas, particularly as the university is the largest single-site employer on Long Island.. As we await the announcement of this new leader, who will have to navigate national funding in addition to the countless other challenges of assuming the top job, we recognize that their success is our success.

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When the National Institutes of Health funds scientific research, the government is investing in hope. The people with the purse strings believe the scientists have the potential for progress, whether from a fundamental discovery or a breakthrough translational finding. Work in these labs may save and extend the lives of our fathers, mothers, sisters and brothers.

On Sept. 12, a cancer scientist at the Renaissance School of Medicine at Stony Brook University was charged with seven counts of stealing state and federal funds, wire fraud and money laundering when he allegedly funneled more than $200,000 of his research money into his own pockets, in part to pay his mortgage.

Taxpayers are a victim in this alleged fraud. Fellow scientists, who might have otherwise received the funds, are also greatly harmed, along with patients awaiting medical help and the support systems for all those patients. In other words, most of us — in one way or another — have been pickpocketed.

So, what’s supposed to happen now? If Geoffrey Girnun is guilty — due process will determine that and he has pleaded not guilty — he will face prison time, fines and other punishments. Girnun allegedly was self-dealing his grant money into shell companies. Perhaps the system where potential conflicts of interest exist needs a closer look, both from funding agencies and from the university.

It’s also crucial that SBU and the NIH pay especially close attention to this criminal case. They need to know all the details of this alleged fraud so they can monitor other scientists and make sure they close any gaps in the funding process. We, the taxpayers, need to be confident that the money the government invests goes toward the hunt for scientific discovery.

What shouldn’t happen? The NIH shouldn’t turn off the tap for scientists at SBU or elsewhere, or create unrealistic hurdles, to receive funding or reimbursement. As it is, many researchers spend considerable time applying for funds and, once they receive them, justifying every penny. Slowing that process down would make them less productive, hurting their research and cutting back on their benefits to the whole of humanity.

Scientific studies seek to understand cause and effect — actions and reactions. When doctors treat cancer patients, they try to balance between the need to eradicate cells with cancerous programming and the potential danger of collateral cellular damage to avoid wiping out healthy and productive cells. The treatment for this alleged fraud should do the same, trying to prevent other such corruption without shutting down valuable science.

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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.

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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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