For two UB scientists, love means studying daughter’s rare disease

Few people in the world would have understood what it meant. But when doctors diagnosed 2-year-old Yuna Lee with FOXG1 syndrome, her parents recognized the disease immediately.

The rare genetic disorder explained Yuna’s seizures. It explained why Yuna hadn’t yet learned to talk. It explained why she struggled to sit up on her own when other children her age could walk and run.

Yuna’s mother and father, Soo-Kyung Lee and Jae W. Lee, are biologists at UB. Even before Yuna was born, Soo-Kyung had devoted much of her career to understanding the development of the central nervous system. As part of her work, Soo-Kyung had used genes in the FOX family, including FOXG1, as tools in her research.

Mutations in the gene, like the one Yuna has, typically aren’t inherited. They happen randomly in the womb. Consequences include severe abnormalities in brain development, leading to symptoms like life-threatening seizures and reduced communication between the left and right sides of the brain.

Only about 650 people in the world are known to have FOXG1 syndrome. That Yuna, the daughter of a biologist who had knowledge of the gene, would be one of them: What were the odds?

The diagnosis left the Lees heartbroken. But it was also empowering.

“I was sad that she had the mutation in the FOXG1 gene because we knew the consequences. But I was happy to know the target,” says Soo-Kyung, Empire Innovation Professor and Om P. Bahl Endowed Professor of Biological Sciences in the College of Arts and Sciences.

“At least we knew what it was,” says Jae, professor of biological sciences.

Following Yuna’s diagnosis, both Soo-Kyung and Jae — who is also an expert in genetics — shifted their research to focus on FOXG1.

The eventual goal: to design a treatment to help their daughter and other children with FOXG1 syndrome. Such a therapy would not reverse problems in early brain development — medicine can’t turn back the clock — but it could, perhaps, alleviate some symptoms, improving their lives and health.

With COVID-19 posing a grave threat to public health, the Lees have had to put their research largely on hold due to social distancing measures. Many scientists around the world are doing the same, but for the Lees, the lost time carries an exceptionally personal weight. Each day that passes is one that may have brought them closer to a treatment for their daughter.

“The pandemic literally stopped our work, and this is so frustrating,” Jae says. “I hope we can see a treatment or a successful vaccine soon for coronavirus.”

When it’s safe to restart their research program, the Lees, who joined the UB faculty in 2019, will be more than ready.

“We are so lucky,” says Nicole Johnson, president and co-founder of the FOXG1 Research Foundation. Her 8-year-old daughter, Josie, has FOXG1 syndrome. “The Lees are not only the top neurobiologists on FOXG1. They have the passion of parents. It’s so unique. You don’t find that a lot, and it’s a very incredible opportunity we have.”

Yuna — now 10 years old — is a joyful child. She hasn’t learned to talk yet, but she communicates with a huge smile for the people she loves.

On weekdays, before the pandemic, Yuna would go to school. On weekends, she would play with her family, including her brother, Joon, an exuberant 7-year-old. They would read books, sing songs, talk about the world, and tap the keys of a grand piano in their sun-filled home. They hug stuffed animals — and each other.

Yuna is able to grab and examine toys with ease, and she has an eye for detail, spotting things that are out of place, like a tiny sticker that’s fallen onto a colorful play mat. She can’t eat, walk or get dressed on her own, but she is always learning, always growing.

Soo-Kyung remembers how Yuna surprised her one day when Yuna was about 4. They were lying down, playing together, and Soo-Kyung closed her eyes for a moment. When she opened them again, she saw Yuna sitting up on her own. It was the first time Yuna had reached that milestone, and, “I thought I was dreaming,” Soo-Kyung recalls.

“I was afraid that it might not have happened,” Soo-Kyung says. “But she did it again and again, and now, she’s so natural, so it was incredible. We had gone through so many physical therapy sessions. The physical therapist will say, ‘Use your shoulder and arm to prop her up,’ and it kept failing. And when we asked the physical therapist ‘How long does it take?’ they said, ‘You never know, and there’s no guarantee that she will be able to do it.’

“But she did it. This was something that is not meaningful to other children, but this is a great challenge and great achievement for Yuna.”

The Lees hope their research can help Yuna accomplish even more.

The FOXG1 gene helps guide development of the human brain, carrying instructions for making a protein called forkhead box G1 (FOXG1) that, in turn, regulates the activity of other genes.

In utero, FOXG1 contributes to development of the telencephalon, a region of the embryonic brain that gives rise to structures including the cerebrum, the largest part of the brain. The cerebrum controls language, voluntary movement, learning, thinking, memory and sensory perception.

With funding from the FOXG1 Research Foundation and National Institutes of Health, the Lees are seeking to further elucidate FOXG1’s role in human development. Their research has already explored one of the most pressing questions for families like their own: Does the FOXG1 gene remain active after children are born?

“If the gene does not continue to do its job after birth, then what’s the point of the research? There would be no chance to recover the protein needed for continued brain development,” Johnson says. “But what the Lees have figured out is that the protein persists after birth in mice.”

So if gene therapy could coax targeted brain cells to produce more of the FOXG1 protein in its normal form, perhaps that would help to alleviate some symptoms.

Any such treatment could be years away, but the Lees are working toward it. Their research explores a variety of questions: Will gene therapy work for FOXG1 syndrome, and if so, at what ages will treatment be effective? Will all patients benefit, or only some? Could there be other innovative therapeutic options for FOXG1 syndrome?

To study these problems, the scientists are breeding mice with FOXG1 mutations that mirror those found in human patients, including children of families the Lees have connected with through the FOXG1 Research Foundation. While some mutations disable the gene completely, others cause only a partial loss of function. The mouse models will illuminate how such variations impact brain anatomy, learning and cognition, and enable research on how therapies might work in different conditions.

The Lees are also collaborating with scientists at other institutions to study FOXG1 using “mini-brains” — lab-grown organoids that are made from human cells and mimic important qualities of early brain development.

The research could prove fruitful in understanding not only FOXG1, but other neurological diseases, too.

“FOXG1 studies can impact autism spectrum disorder, and that’s probably the largest umbrella I can think of,” Jae says. “But also, FOXG1 is upregulated in many human tumors, including brain tumors, and it contributes to the tumor formation. FOXG1 also has strong implications in schizophrenia. Thus, FOXG1 studies will lead to better understanding of various human diseases.”

“If we understand how FOXG1 operates in building the brain or maintaining human brain functions, it will lead us to the wider network of genes and biological processes that have implications in human brain function and human brain diseases,” Soo-Kyung says.

When Yuna was diagnosed with FOXG1 syndrome in 2012, she was one of maybe 20 or so people in the world known to have a FOXG1 mutation, Jae says.

The early years were exceedingly difficult. Yuna’s seizures were terrifying. She had trouble swallowing milk, and she slept terribly.

Soo-Kyung, who often stayed up with her daughter, suffered too. Sleep-deprived and working to keep Yuna alive, Soo-Kyung developed vestibular neuritis, a condition that causes vertigo and dizziness. Lights and sounds began to bother Soo-Kyung, and for a while, she had to sleep in a bedroom closet to shut them out. She became depressed.

Life became more manageable as Yuna grew and the seizures subsided, but the Lees still struggle daily to balance parenthood with their careers as scientists. The pandemic has added to the stress.

One thing that has helped over the years: meeting other families struggling with FOXG1. As genetic sequencing becomes faster and cheaper, the number of known patients has increased dramatically, topping 650, according to the FOXG1 Research Foundation’s statistics.

Many parents connect through online communities where they ask questions, share feelings and celebrate children’s milestones. Soo-Kyung and Jae are active in a support group on Facebook, often providing insight on scientific issues. Jae has also created a FOXG1 network for families from South Korea, where he and Soo-Kyung grew up. And both Lees are heavily involved with the FOXG1 Research Foundation, which has funded their work with nearly $1 million through 2020.

“They’ve become family,” Johnson says. “They are incredibly passionate about what they do, and that comes across in every conversation you have with them.”

The Western New York community has also been supportive. Soo-Kyung and Jae came to UB less than a year ago from the Oregon Health and Science University, and already, they say, colleagues and the local community have embraced their work.

“We are extremely happy to be in Buffalo, and we love our department,” Jae says. “It’s really collegial, really great support. And the community support is outstanding too.”

This summer, the Lees and the FOXG1 Research Foundation will host the second FOXG1 Syndrome Science Symposium. They planned to bring scientists from around the world to Buffalo, but due to the coronavirus pandemic, the conference will take place virtually.

The new format won’t stop the event from building community. Families of children with FOXG1 mutations are expected to attend, in addition to researchers from all over the world. Having the symposium online means people from distant locations will be able to easily take part.

The conference will bridge two worlds, Soo-Kyung says. Scientists will “meet” people directly impacted by their work, and parents will have the chance to learn about the latest research on FOXG1.

It is, in a way, a microcosm of the Lees’ life, in which science, community, family, caretaking and love have become entwined.

Reflecting on the meaning of her work, Soo-Kyung sometimes thinks back to a message she received many years ago after publishing research on a different health topic, the creation of motor neurons during fetal development. The first email she got was from a father asking if her work could provide insights into his son’s debilitating motor neuron disease.

“Although I could not give him any satisfying answer at the time, the agony, love and commitment in his message deeply resonated with me and inspired me to think of science from the viewpoint of parents who are looking for answers to their children’s health issues,” Soo-Kyung said in 2018 in a comment she wrote in response to a New York Times story about her research and family.

“A decade later, when we learned about Yuna’s condition, I was reminded of his message, and I felt lucky and privileged to be able to use my skills as a scientist to help Yuna and children with her conditions. As Yuna grows, I learned to love Yuna as she is, not who she might have been, and to dream big dreams for Yuna, and that’s what keeps me going.”