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Gabor Balazsi

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Mirna Kheir Gouda

By Daniel Dunaief

Mirna Kheir Gouda arrived in Commack from Cairo, Egypt, in 2012, when she was entering her junior year of high school. She dealt with many of the challenges of her junior year, including taking the Scholastic Aptitude Test, preparing for college and adjusting to life in the United States.

Her high school counselor at Commack High School, Christine Natali, suggested she apply to Stony Brook University. Once she gained admission, she commuted by train to classes, where she planned to major in biology on the road to becoming a doctor.

She did not know much about research and wanted to be involved in it to learn, especially because Stony Brook is so active in many fields.

“After some time conducting research, I came to be passionate about it and it was no longer just another piece of my resume, but rather, part of my career,” she explained in an email.

She reached out to Gábor Balázsi, a relatively new faculty member at the time, who suggested she consider joining a lab.

Balázsi uses synthetic gene circuits to develop a quantitative knowledge of biological processes such as cellular decision making and the survival and evolution of cell populations.

Balázsi knew Kheir Gouda from the 2015 international Genetically Engineered Machine team, which consisted of 14 members selected from 55 undergraduate students.

“Having this iGEM experience,” which included deciding on a project, raising funds, carrying out the project and preparing a report in nine months, was a “very promising indication” that Kheir Gouda would be an “excellent student,” Balázsi explained in an email.

Kheir Gouda chose Balázsi’s laboratory, where she worked with him and his former postdoctoral fellow Harold Bien, who offered her guidance, direction and encouragement.

As a part of the honors program, Kheir Gouda had to conduct an independent research project.

She wanted to “work on a project that involved adaptations and I always thought, ‘What happens when the environment changes? How do cells adapt?’”

She started her project by working with a mutant gene circuit that was not functioning at various levels, depending on the mutation. She wanted to know how cells adapt after beneficial but costly function loss.

An extension of this research, as she and Balázsi discussed, could involve a better understanding of the way bacterial infections become resistant to drugs, which threaten their survival.

“The idea for the research was hers,” Balázsi explained in an email. Under Bien’s mentorship skills, Kheir Gouda’s knowledge “developed quickly,” Balázsi said.

Balázsi said he and Kheir Gouda jointly designed every detail of this project.

Kheir Gouda set up experiments to test whether a yeast cell could overcome various mutations to an inducer, which regains the function of the genetic gene circuit.

Seven different mutations caused some type of loss of function of the inducible promoter of the gene circuit function. Some caused severe but not complete function loss, while others led to total function loss. Some were more able to “reactivate the circuit” rescuing its function, while others used an alternative pathway to acquire a resistance.

The presence of the resistance gene was necessary for cell survival, while the circuit induction was not necessary. At the end of the experiment, cells were resistant to the drug even in the absence of an inducer.

“This synthetic gene circuit in yeast cells can provide a model for the role of positive feedback regulation in drug resistance in yeast and other cell types,” Balázsi explained.

Kheir Gouda said she and Balázsi worked on the mathematical modeling toward the end of her research.

“What our work suggests is that slow growth can turn on quiescent genes if they are under positive feedback regulation within a gene network,” Balázsi wrote.

This mathematical model of limited cellular energy could also apply to cancer, which might slow its own growth to gain access to a mechanism that would aid its survival, Balázsi suggested. 

Recently, Kheir Gouda, who graduated from Stony Brook in 2018, published a paper about her findings in the journal Proceedings of the National Academy of Sciences, which is a prestigious and high-profile journal for any scientist.

“Because PNAS has a lot of interdisciplinary research, we thought it would be a good fit,” Kheir Gouda said. The work she did combines evolutionary biology with applied math and synthetic biology.

The next steps in this research could be verifying how evolution restores the function of other synthetic gene circuits or the function of natural network modules in various cell types, Balázsi suggested.

Kheir Gouda’s experience proved positive for her and for Balázsi, who now has eight undergraduates working in his lab. “The experience of mentoring a successful undergraduate might help make me a better mentor for other undergraduates and for other graduate students or postdoctoral researchers, because it helps set goals based on a prior example,” Balázsi said.

He praised Kheir Gouda’s work, appreciating how she learned new techniques and methods while also collaborating with a postdoctoral fellow in Switzerland, Michael Mahart, who is an author on the paper.

“It is unusual for an undergraduate to see a research project all the way through to completion, including a publication in PNAS,” marveled Balázsi in an email. He said he was excited to have mentored a student of Kheir Gouda’s character.

Kheir Gouda has continued on a research path. After she graduated from Stony Brook, she worked for a year on cancer research in David Tuveson’s lab at Cold Spring Harbor Laboratory. She then transitioned to working at the Massachusetts Institute of Technology for Assistant Professor of Chemical Engineering Kate Galloway. Kheir Gouda, who started working at MIT in October, plans to continue contributing to Galloway’s effort until she starts a doctoral program next fall.

Kheir Gouda said her parents have been supportive throughout her education.

“I want to take this opportunity to thank them for all the sacrifices they made for me,” Kheir Gouda said.

She is also grateful for Balázsi’s help.

He has “always been a very supportive mentor,” she explained. She would like to build on a career in which she “hopes to answer basic biology questions but also build on research and clinical tools.”

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Gábor Balázsi. Photo from SBU

By Daniel Dunaief

Take two identical twins with the same builds, skill sets and determination. One of them may become a multimillionaire, a household name and the face of a franchise, while the other may toil away at the sport for a few years until deciding to pursue other interests.

What causes the paths of these two potential megastars to diverge?

Gábor Balázsi, an associate professor in biomedical engineering at Stony Brook University, asked a similar question about a cellular circuit in the hopes of learning more about cancer. He wanted to know what is it about the heterogeneity of a cancer cell that makes one susceptible to treatment from chemotherapeutic drugs and the other resistant to them. Heterogeneity comes from molecular differences where the original causes may be subtle, such as two molecules colliding or a cell being closer to the tumor’s surface, while the consequences can create significant differences, even among cells with the same genes.

In research published this week in the journal Nature Communications, Balázsi used two mammalian cell lines that were identical except that each carried a different synthetic gene circuit that made one more heterogeneous than the other. He subjected the two cell lines, which would otherwise perform the same function, to various levels of the same drug to determine what might cause one to be treatable and the other to become resistant. 

Through these mammalian cells, Balázsi created two circuits, one of which kept the differences between the cells low, while the other caused larger differences. Once inserted in the cell, these gene circuits created uniform and variable populations that could serve as models for low and high heterogeneity in cancer.

Working with Kevin Farquhar, who recently graduated from Balázsi’s lab, and former Stony Brook postdoc Daniel Charlebois, who is currently at the Department of Physics at the University of Alberta, Balázsi tried to test how uniform versus heterogeneous cell populations respond to treatment with different drug levels. 

Using the two synthetic gene circuits in separate but identical cell lines, the Stony Brook scientists, with financial support from the National Institutes of Health and the Laufer Center for Physical and Quantitative Biology at SBU, could re-create high and low stochasticity, or noise, in drug resistance in two cell lines that were otherwise identical.

While the work is in its preliminary stages and is a long way from the complicated collection of genes responsible for various types of cancer, this kind of analysis can test the importance of specific processes for drug resistance.

“Only in the last decade or so have we come to realize how much heterogeneity (genetic and nongenetic differences) can exist within a tumor in a single patient,” Patricia Thompson-Carino, a professor in the Department of Pathology at the Renaissance School of Medicine at SBU, explained in an email. “Thinking of cancer in a single patient as several different diseases is a bit daunting, though currently, this heterogeneity and its direct effects on how the cancer behaves remains poorly understood.”

Indeed, Thompson-Carino added that she believes Balázsi’s work will “shed light on cancer cell responses to therapy. With the rise in cancer therapies designed to specific targets and the resistance that emerges in patients on these therapies, I think [Balázsi’s] work is of extremely high value” which may help with the puzzle of how nongenetic or epigenetic heterogeneity affects responses to treatment, she continued.

In the future, researchers and clinicians may look to develop new ways of biomarker analysis that considers the variability, rather than just the average level of a biomarker.

Balázsi suggested that looking only at the variability of cells is analogous to observing an iron block sinking in water. Someone might conclude that all solids sink in liquids. Similarly, scientists might decide that cellular variability always promotes drug resistance from observations when this happens. To gain a fuller understanding of the effect of variability, however, researchers need to equalize the averages. They then need to explore what happens at various levels of drug treatment.

Current therapies do not target heterogeneity. If such future treatments existed, doctors and scientists could combine ways of treating heterogeneity with attacking cancer, which might work in the short term or prevent cancer from recurring.

Balázsi suggests his paper is a part of his attempt to address three different areas. First, he’d like to figure out how to categorize patients better, including the variability of biomarkers. Second, he believes this kind of analysis will assist in creating future combinations of treatments. By understanding how the variability of cancer cells contributes to its reaction to therapies, he might help create a cocktail of treatments, akin to the effort that helped with the treatment of HIV in the lab.

Third, he’d like to obtain cancer samples and allow them to evolve in a lab, where he can check to see how they respond to treatment levels and administration scheduling. This effort could allow him to determine the optimal drug combination and dosing for a patient.

For the work that led to the current Nature Communications paper, Balázsi explored how mammalian cells respond to various concentrations of a drug. Over 80 percent of the genes in these cells are also present in human cells, so the mechanisms he discovered and conclusions he draws should apply to human cancer cells as well.

He concluded that cells with more heterogeneity, where the cells deviate more from the average, resist drugs better when the drug level is high. These same cells, show greater sensitivity when the drug is low.

Balázsi recognizes that the work he’s exploring is a “complex problem” and that it requires considerable additional research to understand and appreciate how a therapy might kill one cancer cell, while the same treatment in the same environment doesn’t have the same effect on a genetically identical cell.

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Gábor Balázsi. Photo by Dmitry Nevozhay

By Daniel Dunaief

An especially hot July day can send hordes of people to Long Island beaches. A cooler July temperature, however, might encourage people to shop at a mall, catch a movie or stay at home and clean out clutter.

Similarly, genes in yeast respond to changes in temperature.

Gábor Balázsi, the Henry Laufer associate professor of physical and quantitative biology at Stony Brook University, recently published research in the Proceedings of the National Academy of Sciences on the effect of temperature changes on yeast genes.

“We are looking at single cells and at genetic systems and we can dissect and understand gene by gene with a high level of detail,” said Balázsi, who used synthetic genetic systems to allow him to dissect and understand how temperature affects these genes.

Understanding the basic science of how genes in individual cells respond to temperature differences could have broad applications. In agriculture, farmers might need to know how genes or gene circuits that provide resistance to a pathogen or drought tolerance react when the temperature rises or falls.

Similarly, researchers using genetically designed biological solutions to environmental problems, like cleanups at toxic spills, would need to understand how a change in temperature can affect their systems.

Lingchong You, an associate professor of biomedical engineering at Duke University, believes the research is promising.

“Understanding how temperature will influence the dynamics of gene circuits is intrinsically interesting and could serve as a foundation for the future,” You said. Researchers “could potentially design gene circuits to program the cell such that the cell will somehow remember its experience with the fluctuating temperatures,” which could provide clues about the experience of the cell.

Balázsi suggested the goal of his work is to understand the robustness of human control over cells in nonstandard conditions.

While other researchers have explored the effects of gene expression for hundreds of genes at different temperatures, Balázsi looked more precisely at single genes and human-made synthetic gene circuits in individual cells. He discovered various effects by inserting a two-gene circuit into yeast.

At the whole-cell level when temperatures rise from 30°C to 38°C, some cells continued growing, albeit at a slower rate, while others stopped growing and started to consume their proteins.

For the second type of cells, changing temperatures can lead to cell death. If the temperature comes down to normal levels soon enough, however, researchers can rescue those cells.

“How this decision happens is a question that should be addressed in the future,” Balázsi said.

While the dilution of all proteins slows down, the chemical reactions in which they participate speed up at a higher temperature, much like children who become more active after receiving sugar at a birthday party.

At another level, certain individual molecules change their movement between conformations at a higher temperature. Proteins wiggle more between different folding conformations even if they don’t change composition. This affects their ability to bind DNA.

Balázsi said he is fortunate that he works through the Laufer Center for Physical and Quantitative Biology, which partly supported the work, where he was able to find a collaborator to do molecular dynamic simulations. Based on the pioneering experiments of postdoctoral fellow Daniel Charlebois, with help from undergraduate researcher Sylvia Marshall, the team collected data for abnormal behaviors of well-characterized synthetic gene circuits. They worked with Kevin Hauser, a former Stony Brook graduate research assistant, who explained how the altered conformational movements affected how the protein and cells behaved.

The way proteins fold and move between conformations determines what they do.

Gábor Balázsi with his daughter Julianna at West Meadow Beach
Photo from Gábor Balázsi

Taking his observations and experiments further, Balázsi found that proteins that were unbound to a small molecule didn’t experience a change in their conformation. When they were linked up, however, they demonstrated a new behavior when heated. This suggests that understanding the effects of temperature on these genetic systems requires an awareness of the proteins involved, as well as the state of their interaction with other molecules.

While Balázsi explored several ways temperature changes affect the yeast proteins, he acknowledged that other levels or forces might emerge that dictate the way these proteins change.

Additionally, temperature changes represent just one of many environmental factors that could control the way the genetic machinery of a cell changes. The pH, or acidity, of a system might also change a gene or group of genes.

A main overarching question remains as to how much basic chemical and physical changes combine with biological effects to give predictable, observable changes in the behaviors of genes and living cells.

Balázsi may test other cell types. So far, he’s only looked at yeast cells. He would also like to know the order in which the various levels of reactions — from the whole cell to the molecular level — occur.

He is interested in cancer research and possibly defense applications and would like to take a closer look at the way temperature or other environmental factors impact human disease processes and progression or think about their relevance for homeland security or biological solutions to renewable energy.

Balázsi recognizes that he and others in this field have numerous hurdles to overcome to find acceptable appreciation for the application of synthetic gene circuits.

“It’s not so simple to engineer these cells reliably,” he said. “Some roadblocks need to be eliminated to convince people it’s feasible and useful.”

Balázsi suggested that the field of virology might benefit from pursuing some of these research questions. Viruses move from the environment or even from other hosts into humans. Avian influenza, for example, can begin inside a bird and wind up affecting people. These viruses “might have different expression patterns in birds versus humans,” he said.

Ultimately, he added, this kind of scientific pursuit is “multipronged and the applications are numerous.”

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Thomas Allison, 2017 Discovery Prize winner, with James H. Simons, chairman of the Simons Foundation and Dr. Samuel L. Stanley Jr., president of Stony Brook University. Photo from Stony Brook University

Once a year, Stony Brook University takes science to the competitive level with their Discovery Prize competition.

At the event, which took place April 13, four competitors presented their research to a panel of judges. The competition was established in 2014 with a donation from the Stony Brook Foundation board of trustees. This year at the university’s Charles B. Wang Center Theatre the panel of judges consisted of 2016 Nobel Laureate in physics from Princeton, F. Duncan Haldane, UC Berkeley’s director of the nuclear science division, professor Barbara Jacak, and chairman of the Simons Foundation and a member of the National Academy of Sciences, James H. Simons.

After a tough competition, Thomas Allison, assistant professor in the departments of chemistry and physics, won the $200,000 prize. Allison said all his competitors — Gabor Balazsi, associate professor at the Laufer Center for physical and quantitative biology; Matthew Reuter, assistant professor in the department of applied mathematics and statistics; and Neelima Sehgal, assistant professor in the department of physics and astronomy — did a great job.

Allison won for his concept called “Molecular Movies.” The technology he is working on will record the movement of molecules, which in turn can lead to the development of better high-tech devices.

“I was honored to be a part of it,” he said. “Obviously the result is great, and in general, it’s a great thing at Stony Brook.”

The competition is produced in collaboration with the Alan Alda Center for Communicating Science and is described as a “Shark Tank” meets “TED Talk” type of event. Each contestant presents his or her research in approximately 10 minutes, and they must describe their project from the scientific approach to the potential impact of their research in a way an everyday person would understand it. 

Allison said he has been working on his research for three years and was a bit nervous before his presentation. However, before the event contestants received coaching from communication experts at the Alan Alda Center, which he said was a big help.

“I just tried in the end to be clear, explain my project and what we’re trying to do, so I guess that got me through it,” he said.

When it comes to describing his project to a layperson, Allison said it all depends on how much a person is familiar with electrons.

“Mostly it’s just basic science,” he said. “You can think of it kind of like a microscope, so once you have this tool, then you can use the tool to try to make devices.”

Allison said his tool would be beneficial with any technology that uses molecules with electrons moving around because molecules are “excited” by light. He said the application could help in developing better technology such as solar cells, which are used for light absorption to produce electricity from sunlight, that use organic molecules instead of silicon.

“I’m not going to make a better solar cell,” Allison said. “What I would like to do is make a tool so that people who work on these things can make better solar cells or something. So it’s more about making the tool.”   

After winning the prize, Allison said he will be able to pay for a new electron detector. The detector uses UV lights that make the electrons come out. He said the detector he has right now can only measure the energy of an electron and not its angle. However, a new one will be able to measure both at the same time, providing measurements that are more effective.

He said he has the same goal as those who are working on much larger scale projects, but he can achieve the same results with a less expensive light source as well as instruments.

The prize money will also allow him to hire a post doctorate student to work on the project, and the professor is glad that he now has the funding to spend more time in the lab and less time applying for grants.

“I’m looking forward to doing experiments, and the discovery fund was a big boost,” Allison said.

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