A Visa lottery winner finds her path to medical school

Growing up in Albania, Sonola Burrja never imagined that she would move to Mamaroneck, New York, and study in the United States. But when her family won the U.S. government’s Diversity Immigrant Visa program lottery in 2018, the plan changed.

“The plan was that my younger brother and I get educated outside of Albania, which would probably result in our … not going back, [but]when we won the U.S. lottery, my parents saw it as a great opportunity for the entire family to stay together,” says Burrja, who graduated from Fordham College at Rose Hill in May.

Now, just five years after moving to New York, she’s a first-year student at Albert Einstein College of Medicine in the Bronx. And she can’t imagine not having gone to Fordham, where she joined the pre-health program, majored in biological sciences, minored in German, and was part of the University’s inaugural group of ASPIRES scholars. Partially supported by the National Science Foundation, the program—which stands for Achievement in STEM through a Program of Immersive Research Experience and Support—provides a select group of undergraduates with scholarships for their four years at Fordham, guidance in and out of the lab, and funding for their undergraduate research. 

Conducting Ethical Research

Through ASPIRES, Burrja began collaborating with professors and conducting research almost right away—albeit not in the way she expected. It was March 2020, when COVID-19 spread to the United States, so her plan to conduct in-person research had to be put on hold in favor of a virtual research project.

“I was supposed to meet up with a researcher at Fordham that week that everything got shut down,” she recalls. Instead, she spent the summer working with Rachel Annunziato, Ph.D., a psychology professor and associate dean for strategic initiatives at Fordham College at Rose Hill, studying statistical data on diabetes and COVID-19 comorbidity.

Burrja went on to earn three undergraduate research grants from Fordham to support her work with biology professor Marija Kundakovic, Ph.D. She joined the Kundakovic Lab to study the epigenetic effects of hormones in female brains. 

“I never knew that there were so many differences between female and male brains—and that somebody at Fordham was actually tackling this issue,” Burrja says, explaining why she asked Kundakovic to be her mentor. “I really thought it was very interesting because some conditions, for example, depression and anxiety, have a sex bias of females during their reproductive stage. There are some huge differences, and we still don’t know enough about this topic—and the brain generally is a very unexplored area.”

To help her navigate the ethical questions that need to be taken into consideration when conducting research, Burrja took Ethics and Research, a course that allowed her to “discuss some very difficult dilemmas” and think deeper “about some issues that don’t really come into our lives, but if you go into medicine or if you go into actually doing research, those issues might come up—and there are actual consequences to being on one side or the other.”

And they will come up: Burrja plans to become a doctor. She’s not yet sure what her specialty will be, but one thing in particular is a must.

“The patient interaction part is something that I would not want to sacrifice,” she says. “I would like to be able to speak with them and just be an advocate for them, especially working with underserved populations.”

Read more “20 in Their 20s” profiles.

Devin Rocks is still at least a year away from earning his Ph.D. in biology. But the Rockaway Park, Queens, native is already making a splash in the academic world, thanks to his work examining the role that fluctuating sex hormones can have on mental disorders such as anxiety and depression.

This spring, the Organization for the Study of Sex Differences honored Rocks with the Elizabeth Young New Investigator Award, and the Society for Behavioral Neuroendocrinology awarded him its Welcome Initiative Award. In January, the Society for Neuroscience bestowed upon him the Trainee Professional Development Award.

The awards recognize both the promise that Rocks has as a scientist and the work he’s conducted at Fordham under the guidance of Marija Kundakovic, Ph.D., assistant professor of biology. Kundakovic’s lab has been focused on an acute problem: Women are twice as likely to have anxiety and depression than men, but little research has been done on the molecular level to figure out why—until now. In January, Kundakovic was awarded nearly $1.9 million in grant funding from the National Institute of Mental Health for her research.

Rocks, who graduated from Fordham College Rose Hill in 2017 with a B.S. in integrative neuroscience and is on track to earn a Ph.D. in biological sciences in 2022, has been a part of the research from the beginning. He was one of five co-authors of a 2019 paper published in the prestigious journal Nature Communications that showed how a microscopic cell component called chromatin changes its shape during the mouse ovarian cycle—especially when females experience a change in estrogen. Because the changes occur inside the brain area implicated in anxiety and depression, it may affect women’s vulnerability to an increased risk for these disorders.

“The chromatin is basically the packaging material of the DNA. The chromatin can either be open, which allows the genes to be turned on, or it can be closed, in which case the genes are turned off,” he said.

“The studies showed that, over the rodent estrous cycle, which is the rodent equivalent of the menstrual cycle, the fluctuating sex hormones are affecting whether this chromatin is open or closed and affecting certain genes.”

It’s not known exactly how the opening or closing of chromatin causes depression or anxiety, but connecting the two events together is an important step in the research.

Since that 2019 paper was published, Rocks has been conducting follow-up research that involves introducing a gene known as Egr1 into the brains of laboratory mice to mimic the changes that normally only happen during the estrous cycle. The results will be published as part of his dissertation.

“We can give mice extra copies of this gene in the brain region that we study, the ventral hippocampus, and this can mimic the effect you’d see from the fluctuating hormones. This gene seems to be playing an important master regulatory role,” he said.

Kundakovic, who joined Fordham in 2015 and began working with Rocks when he was in his junior undergraduate year, said “functional” studies that rely on live animals are vital to verifying studies that use computational analysis to predict whether one change (a change in estrogen) is connected to something happening in the brain (a change in chromatin structure) and behavior.

“You can do a big data-computational type analysis, and say, ‘Give me the predicted regulator of these chromatin changes that we are seeing.’ [In 2019], we did that, and we found a really good candidate in Egr1,” she said.

“What Devin did was he took the candidate that we have, and he was able to do a manipulation of the animals in which he could functionally relate the changes and say, ‘This is the regulator of the behavior.’”

Rocks still has more research to do. Now that he knows that introducing Egr1 into mouse brains can change their behavior, he’s planning to conduct experiments that show exactly how Egr1 affects chromatin.

“We want to see which changes in chromatin and gene expression that we see happening in normal animals over their estrous cycle are being regulated directly by Egr1,” said Rocks, who also teaches techniques in molecular biology to first-year graduate students.

The awards he received are gratifying, he said, given that he’s still completing his education.

“It’s an indication that the community is welcoming me as someone who will contribute to the field in the future and will continue to grow as a scientist, and so I’m really grateful for all of them,” he said.

The most challenging aspect of the research has been utilizing the full spectrum of research techniques required.

“A lot of labs will just do one of the techniques we do, like the genome-wide experiments. Learning how to do them and analyze all that data that comes out of it using bioinformatics analysis, and then also learning how to do animal surgeries—we combine so many different disciplines and techniques,” he said.

“It’s definitely been a challenge to keep up with all of that. It’s also really exciting though. Learning new things is one of my favorite parts of the job.”

Kundakovic was quick to note that when it was announced that Rocks had won the Elizabeth Young New Investigator Award, he was introduced as a “future leader in the field.”

“As someone who’s been working with him for the past five years, since he was an undergraduate, it’s really been my privilege to watch him grow as a person and a scientist,” she said.

“His dedication to his work, his passion; it’s just paid off really well. I think he’s on a really good path.”

“The field of neuroscience has been very male-centric. Most studies were historically done on males, and there wasn’t enough information on the female brain in general. This grant is not only a testament to the excellence of the project proposal, but also to the importance of this topic,” said Kundakovic, who learned she received the grant on Jan. 29. 

Kundakovic studies cellular changes in the brain on a molecular level using a mouse model. Her lab specializes in researching the molecular mechanisms behind hormonal changes during the ovarian cycle and how they can change female brain and behavior. Her research results could lead to the development of sex-specific treatments for mental disorders like anxiety and depression—disorders that are more prevalent in women than in men. 

In recent years, Kundakovic and her team discovered that chromatin, a microscopic cell component, changes its shape during the ovarian cycle, which also changes the way genes are expressed. Over the next five years of grant funding from the NIMH, they will build on their research and try to better understand how chromatin changes in brain cells can impact anxiety-related behavior, especially for female mice, in her project “Epigenetic regulation of brain and behavior by the estrous cycle.” 

“We are trying to understand how chromatin changes within brain cells affect cellular function and contribute to changes in behavior and which specific cells are really critical for changing behavior,” said Kundakovic. “With this new grant, we will be able to identify the specific brain cells that are really responsive to hormonal changes and reveal epigenetic regulators that are possible targets for drug treatment.”

Kundakovic said her research has taken on new meaning during the pandemic, an unprecedented period where more people than usual are struggling with their mental health, especially anxiety and depression. 

“The pandemic may widen the gender gap that we are already seeing in anxiety and depression,” Kundakovic said. “We will have even more women who are affected by these disorders.”

Marija Kundakovic, Ph.D., assistant professor of biology, spearheaded a study that was published in Nature Communications, the third highest-ranked multidisciplinary science journal in the world, earlier this summer. Kundakovic and her colleagues found that chromatin, a microscopic cell component, changes its shape during the ovarian cycle—especially when females experience a drop in estrogen. This changes how our genes behave. Because this occurs inside the brain area implicated in anxiety and depression, it may mediate women’s vulnerability to increased risk for these disorders. 

Now, thanks in part to the research conducted by Kundakovic’s team, scientists are closer to figuring out which molecules should be targeted with drug treatments, particularly for women with anxiety or depression. 

“This is really important for us to show at the molecular level—the molecular basis of this is what we now, with our study, are starting to understand,” Kundakovic said.

Part of the reason why this study is important is that it focuses on the female brain. Tell me more about that. 

The majority of neuroscience experimental studies were done on males. It’s been like that for decades. We know very little about the female brain, and this is particularly a problem for the disorders that are more frequent in women than men, like depression and anxiety. So this is why we basically don’t understand anything about the mechanism that tells us why this sex difference exists. 

Our study was designed to try to understand how—at a molecular level—these fluctuating sex hormone levels might increase the risk of anxiety and depression in women.

Why is there such a stark difference between men and women regarding their risk for anxiety and depression?

When you look at boys and girls before puberty, there’s really no difference in risk for depression. This risk really becomes two times higher in females when they get their first period —when the hormones start fluctuating. And then around perimenopause, this difference becomes even more profound because there are more extreme fluctuations. You can have very high or very low sex hormones. And then after menopause, when women achieve these very stable, low sex hormone levels, the sex difference becomes almost nonexistent. So this really tells us that this is not about low or high hormones, but the fluctuations in hormones that might be increasing women’s vulnerability to anxiety and depression.

What’s an extreme example of hormone fluctuations? 

Postpartum depression, a period when you have very high progesterone and estrogen (sex hormones), and then a drop after pregnancy. It often triggers a serious depression. There are a lot of lines of evidence showing that this drop in sex hormones, particularly estrogen, may increase the risk for anxiety and depression.

There’s another interesting phenomenon. Women who are depressed and on antidepressant treatments often report that just before their period, they experience worsening of their symptoms. The symptoms seem to be in control with the treatment, but all of a sudden, in this particular period, their symptoms worsen.

All these human findings are consistent with our findings in mice (women experience the menstrual cycle; female mice experience a similar process called the estrous cycle), showing that a drop in estrogen during the estrous cycle leads to increased anxiety levels in females.

You studied brain cells from both female and male mice, and also included female mice in different stages of the estrous cycle. What did you find? 

DNA is six-and-a-half feet long in a single cell. You have to package it very nicely so you can put this huge piece of DNA into every cell. The way this is accomplished is through a special structure called chromatin. 

This is important to package our DNA, but not only for that. By opening and closing chromatin, you can turn genes on or off. You have to have this open structure for some factors to bind and to turn the genes on. If this is closed, you can’t do that. People use libraries as an analogy. You can have a huge library. There are certain books you can’t even access. But if something’s accessible, you can potentially read it. That’s how our genome works as well. 

What we show—and this is really the biggest discovery of this study—is that as hormones fluctuate, they’re actually changing the organization of chromatin. This changes gene expression. 

Can you provide an example that explains these chromatin changes? 

Serotonin is a neurotransmitter—a chemical in the brain that has been implicated in anxiety and depression. What we show in our study is that the genes that are important for serotonin function, their expression, and their chromatin organization changes with the estrous cycle. Basically, now we are providing a possible molecular mechanism for why we could have those changes in anxiety levels across the ovarian cycle. 

What’s the difference between chromatin in male and female mice? 

In terms of how many open chromatin regions we have, the numbers are pretty similar. What is different is which regions are open or closed. They change with the estrous cycle, and they differ between males and females, meaning some genes that were closed will open up. And some genes that were open will close. What we didn’t expect is that we would find as many differences across the estrous cycle as we see when we compare chromatin in males and females. 

Women and men currently have the same treatment for anxiety and depression. But might your study results lead to the development of sex-specific treatments for these disorders? 

Yes. We are starting to understand what are the players involved, what are the mechanistic factors—like receptors, regulators of chromatin—that are leading to this opening and closing. It may help us identify a candidate that we could possibly target with drugs. 

Many women take birth control. How can that affect sex hormones and treatment? 

We don’t know enough about that. There are different contraceptives. I think we need more studies in humans to understand how exactly contraceptives would affect this. 

What implications does this research have for transgender people? Or is there not enough data yet? 

That’s another important question that I’m getting more nowadays. What we’re talking about here are biological changes that are induced by hormones. When we talk about transgender people, you might think about certain hormonal treatments that they are receiving. Our brain, even in adulthood, is responsive to these hormones. But sexual differentiation of the brain is very complicated, and it starts very early during life. So as you said, I think we would need more information and funding to try to understand how exactly this would affect transgender people. 

This interview has been edited and condensed for clarity.

Kundakovic, an assistant professor of biological sciences, is conducting research to understand the mechanisms that drive the behavior of genes. Although the genes in humans are similar, individual genes can “express” themselves in different ways, through either alteration of the DNA or of the proteins that hold the DNA together.

“What makes something a brain cell, a skin cell, or a blood cell? The genetics are the same, meaning the set of genes that we have are the same,” she said. But within that set, “different genes are turned on or off. So, depending on which genes you turn on or off, certain cells will function as say, neurons, blood cells, or something else.”

When spread out, human DNA is actually about six-and-a-half feet long, said Kundakovic. To fit it into a microscopic structure called a nucleus, it’s wrapped into a structure called a chromatin. In this process, some DNA is squeezed tightly together; some not. Kundakovic compared the way DNA is wrapped to a library where some books are  accessible while others are stored on shelves that are off limits.

Opening up parts of that “library” i.e., the human genome, to change could lead to developments like cancer or psychiatric disorder, said Kundakovic. There are some life periods with more flexibility and, hence, vulnerability than others, and this is particularly important during human development. The DNA and proteins are susceptible to outside environmental factors that a person might encounter early in life—Kundakovic’s work lies at this level.

Previously at Columbia University, her research showed a connection between exposure to certain kinds of plastics and fetal development. Now, she is looking for connections between abuse and neglect early in life, and depression and anxiety later on in adulthood.

It’s already known that the former often leads to the latter, but researchers don’t fully understand the underlying processes that cause it.

“If there is early-life neglect or abuse, chances are that later in life, the person will be socially isolated. We’re trying to understand whether these two stressful events actually are interacting,” Kundakovic said.

Her current study on mental disorders, which is funded by the Brain and Behavior Research Foundation, is just getting underway.

What makes Kundakovic’s work particularly challenging is the fact that the changes that she’s looking for are in the brain, and therefore, inaccessible in living subjects. So she has to look for clues somewhere other than in brain cells, for example blood cells.

“If I take a blood cell, and I see some differences in autistic children versus control children, or ADHD children versus control children, what does that mean for the brain? It might not exactly reflect what’s happening in the brain, but I do believe there is a lot of potential here,” she said.

“The idea is that environmental exposures like stress or malnutrition can leave a signature in the peripheral tissues that can capture something also happening in the brain.”

In addition to blood cells from living subjects, Kundakovic has also received post mortem brain tissue for a separate project that will compare the epigenome of neuronal and non neuronal cells. This is important because even within the brain, not every cell is identical. Epigenomes vary not only among cells, but also among different individuals. Successful studies require hundreds of patients, and take a long time, particularly since the field of epigenetics is relatively new.

Kundakovic is hopeful that scientists will be able to identify biomarkers for serious psychiatric disorders before the disorders take hold. There will never be just one on/off switch that will predict whether everyone will be afflicted by depression; rather she envisions a panel of markers that will tip off scientists to a person’s risks.

“There will be genetic markers, there will be epigenetic markers, and you might see  brain-imaging markers. We will probably need to have several different tests to be able to predict whether someone will develop this.

“I’m not naïve enough to think epigenetics is everything,” she said. “I just think it’s an important part of neuroscience, and it is very important to understand this in the context of psychiatric disorders.”