When the parents of an 8-year-old Israeli boy reached out to Tel Aviv University, a research team at the Gray Faculty of Medical and Health Sciences stepped up. Their mission: to find answers for a devastating genetic condition with no known cure. The result is a breakthrough mouse model that mimics the disease with striking accuracy — and may pave the way for life-saving treatments.

The study was led by Prof. Moran Rubinstein and Prof. Karen Avraham, Dean of the Faculty. Other participants included students Mor Yam, Julan Nasir, Daniel Gelber, Shir Kavin, Roni Gal, Mor Ovadia, Mor Bordinik-Cohen, and Eden Peled — all from the Gray Faculty of Medical and Health Sciences at Tel Aviv University or the Sagol School of Neuroscience — as well as Dr. Moran Heusman-Kedem and Prof. Aviva Fattal-Valevski from the Pediatric Neurology Institute at Dana-Dwek Children’s Hospital, Tel Aviv Medical Center, and Prof. Christopher McKinnon and Prof. Wayne Frankel from Columbia University in the United States.

Prof. Avraham explains: “We were approached by the parents of an Israeli child named Adam, now 8 years old, who is one of approximately 40 people worldwide suffering from an extremely rare genetic disease. It’s a mutation in a gene called GRIN2D, which causes developmental epilepsy, severe delays in motor and cognitive development, and sometimes even premature death.”

Eden Maimon Benet, Adam’s mother, adds: “At Tel Aviv University, we met a remarkable all-women team that took on the mission: to find a cure for our son. I believe the fact that they got to know Adam and our family personally only deepened their dedication and commitment. When Adam was two years old, we embarked on this long journey together — and today, we can already see real light at the end of the tunnel.”

How Do You Study a Disease No One Understands?

In the first stage, the researchers aimed to better understand the disease’s characteristics. To do so, they created a mouse model with a mutation similar to that found in human patients. However, due to the severity of the disease, most of the mice did not survive their first weeks of life — before any meaningful research observations could be made. This led the team to conclude that while the model mimics the human disease, it poses a major challenge: too few mice could be generated for scientific study.

To overcome this, they used genetic engineering tools to create a strain of mice that carry the mutation but do not develop symptoms. These serve as carriers, with half of the offspring born healthy and the other half born with the disease. The affected mice exhibited symptoms similar to those seen in children with the disease. Most lived only a few weeks, and only a few survived up to three months. The researchers observed their behaviour and development at four key stages: at two weeks old (infancy), three weeks (when mice transition to solid food — roughly equivalent to a one-year-old child), four weeks (roughly age six in children), and five weeks (the onset of sexual maturity).

“Because the disease is so rare, we don’t yet fully understand how it progresses with age,” Prof. Rubinstein says. “The mouse model helped us characterize symptoms at various stages. The tests we conducted revealed interesting findings: neurological symptoms — including epilepsy, hyperactivity, and severe motor impairments — appeared as early as infancy. Cognitive impairments, on the other hand, showed up later and worsened gradually. In addition, their lifespan was short — most of the affected mice did not survive to sexual maturity.”

What Happens in the Brain?

In a follow-up experiment, the researchers monitored communication between neurons in the brains of the model mice, focusing on the cerebellum — the brain region responsible for motor control. The tests showed that by just two weeks of age, pathological changes were already present, expressed as reduced neuronal activity. Later in life, activity levels returned to normal; however, the communication between neurons became impaired. Finally, the researchers identified structural changes in the neurons themselves. All these findings help shed light on the mechanism driving the disease.

EEG recordings conducted on the affected mice revealed a unique brain activity pattern that also characterizes the disease in humans. “In most types of epilepsy, seizures are caused by disruptions in brain activity, but between seizures, brain activity is relatively normal,” explains Prof. Rubinstein. “In this disease — in both children and mice — brain activity is consistently disrupted. Moreover, using specific markers we developed, we identified the same abnormal parameters in both mice and humans — a finding that most clearly demonstrates the validity of the model.”

From Testing to Treatment

After confirming that the mouse model accurately mimics the human disease, the researchers began testing the effects of various drugs on the progression of symptoms. They found that ketamine — a drug previously proposed for treating this condition — actually worsened the seizures. In contrast, memantine, another drug currently used for this disease, led to partial improvement in brain function. The same was true for phenytoin, an anti-seizure medication, which also improved some markers of brain activity.

New Hope for Rare Disease Patients

“Modeling the disease using a mouse model is a key tool in making clinical decisions for treating rare diseases,” explains Dr. Heusman-Kedem, who adds: “The model allows us to test the efficacy of known drugs, as well as the safety and effectiveness of innovative treatments — before administering them to patients. For example, the results found in the mouse model helped clarify that memantine may help prevent seizures. Using a mouse model provides critical insights for developing new treatment strategies for rare diseases, where the number of patients is too small to establish broad statistical conclusions. In such cases, animal studies can offer major breakthroughs and support the development of personalized medicine.”

“In this study, we created a mouse model of a rare genetic disease caused by a mutation in the GRIN2D gene,” concludes Prof. Rubinstein. “The model allowed us to better understand how the disease progresses and to test the effectiveness of several existing drugs. We’re now continuing the research and exploring additional therapies — both pharmaceutical and genetic — and we’ve reached promising results, including improvements in cognition and motor function and increased lifespan in the affected mice. We sincerely hope our work brings hope and real progress to families and children battling this rare and devastating disease — and to those affected by other brain conditions with similar mechanisms.”

The study was conducted in the laboratories of Prof. Yossi Yovel from the School of Zoology and Prof. Lilach Hadany from the School of Plant Sciences and Food Security at TAU's Wise Faculty of Life Sciences. It was led by students Dr. Rya Seltzer and Guy Zer Eshel, in collaboration with scientists from the Plant Protection Institute at the Volcani Institute. The paper was published in the journal eLife.

This study follows the dramatic discovery published by the same researchers about two years ago, which generated worldwide interest: plants under stress emit sounds—at ultrasonic frequencies, above the range of human hearing, but detectable by many animals. The researchers state: “That discovery opened the door to extensive research on acoustic communication between plants and animals. In the present study, we began to explore this subject.”

Prof. Yovel explains: “After proving in the previous study that plants produce sounds, we hypothesized that animals capable of hearing these high-frequency sounds may respond to them and make decisions accordingly. Specifically, we know that many insects, which have diverse interactions with the plant world, can perceive plant sounds. We wanted to investigate whether such insects actually detect and respond to these sounds.”

Prof. Hadany adds: “We chose to focus on female moths, which typically lay their eggs on plants so that the larvae can feed on them once hatched. We assumed the females seek an optimal site to lay their eggs — a healthy plant that can properly nourish the larvae. Thus, when the plant signals that it is dehydrated and under stress would the moths heed the warning and avoid laying eggs on it? To explore this question, we conducted several experiments would the moths heed the warning and avoid laying eggs on it? To explore this question, we conducted several experiments.”

Prof. Yossi Yovel and Prof. Lilach Hadany

In the first experiment, aiming to isolate the auditory component from other plant features like color and scent, the researchers presented the female moths with two boxes: one contained a speaker playing recordings of tomato plants in a state of dehydration, while the other was silent. The moths showed a clear preference for the ‘noisy’ box, which they likely interpreted as a living plant (even if under stress). Conclusion: the moths do indeed perceive and respond to a playback of plant-emitted sounds. When the researchers neutralized the moths’ hearing organs, this preference disappeared and they chose both boxes equally — clear evidence that the preference was specifically based on listening to sounds, and not on other stimuli.

In the second experiment, the female moths were presented with two healthy tomato plants – one with a speaker playing sounds of a drying plant, and one that was silent. Again, they showed a clear preference – but this time for the silent plant, from which no distress sounds were heard, and therefore probably serves as a better site for laying eggs.

In another experiment, the moths again faced two boxes—one silent and the other containing male moths, which also emit ultrasonic sounds at a frequency similar to plant sounds. This time, the females showed no preference and laid their eggs equally on both boxes. The researchers concluded that when deciding where to lay their eggs, the females specifically respond to plant-emitted sounds — and not, for example, to sounds made by males.

The researchers conclude: “In this study, we revealed the first evidence for acoustic interaction between a plant and an insect. We are convinced, however, that this is just the beginning. Acoustic interaction between plants and animals doubtlessly has many more forms and a wide range of roles. This is a vast, unexplored field — an entire world waiting to be discovered.”

The program's initiator, Prof. Dalit Rom-Shiloni from the Department of Biblical Studies, Chaim Rosenberg School of Jewish Studies and Archaeology, explains: "The Orit of Beta Israel includes the Five Books of the Torah, as well as the Books of Joshua, Judges, and Ruth. So far, we have documented four Orit books, including the two from the 15th century, as well as 13 other sacred books. All the sacred books of Ethiopian Jewry are written in Ge'ez, a language known only to the Kessim, and each manuscript has its own fascinating story. They have been passed down through generations from father to son, and some were given to Kessim by their teachers — Jewish monks who taught the sacred traditions in Ethiopia. The books were carefully guarded and preserved, with some of their owners even risking their lives to bring them to Israel. Today, most of these books are privately owned by Kessim and their families and used as “living books” in the prayer houses of Ethiopian Jewish communities across Israel. Until now, they were inaccessible to interested individuals of the general public, nor to the research world, and we intend to locate as many books as possible for preservation, digitization, and academic study."

To this end, a unique traveling workshop was held in June 2024, with participants including: Prof. Rom-Shiloni, anthropologist Prof. Erica Weiss, linguist Dr. Anbessa Teferra, and students from the Orit Guardians program — all from Tel Aviv University, alongside representatives of the Ethiopian Jewry Heritage Center and the National Library, as well as three international experts in ancient Ethiopian sacred texts: Prof. Loren Stuckenbruck (Ludwig Maximilian University of Münich), Dr. Sophia Dege-Müller and Ted Erho (University of Hamburg). The international experts examined and dated the books using palaeography — based on script forms. To their astonishment, they found that two of the Orit books were written as early as the 15th century — the oldest discovered so far in the hands of Beta Israel. Prof. Rom-Shiloni explains: "Our discovery is causing a stir among experts in the field worldwide. While we are familiar with similar Ethiopian texts from this period or even earlier, all of those are Christian texts, not Jewish. Now, for the first time, it has been revealed that Kessim from Beta Israel possess Orit books that are over 600 years old."

In total, the workshop yielded four Orit books — two from the 15th century and two from the 18th century, as well as 13 other sacred books from the 17th to 20th centuries. All the discovered books were documented with their owners’ consent and remain in their possession — so they can continue to serve as “living books” in their communities. The documentation now enables academic research and the establishment of a digital archive at the National Library.

Prof. Youval Rotman, Academic Director of the Koret Center and faculty member in the Department of Jewish History at Tel Aviv University, added: "This is an extraordinary finding. Discovering ancient manuscripts is rare, and when they are the oldest of their kind in existence, the find is all the more exceptional. This discovery was made thanks to the Orit Guardians' emphasis on studying the textual knowledge and interpretive tradition preserved and orally transmitted over centuries within the various Beta Israel communities. The uniqueness of the program lies not only in mapping manuscripts and training students for their research but also in doing so as an integral part of the knowledge preserved within the community — thereby continuing and expanding it. The young researchers form personal connections and earn the trust of the Kessim as successors to the tradition and oral interpretation. In doing so, they connect communal-social knowledge to academic knowledge — and this is our great pride. The program unearths hidden treasures that have so far dwelt within the four walls of local synagogues, then documents and studies them and makes them accessible. Imagine a situation in which the great Bible commentaries were passed down orally through generations."

Prof. Rom-Shiloni concludes: "Through the traveling workshop of the Orit Guardians program we discovered 17 sacred books of Beta Israel held by Kessim across Israel and still used as “living books” in the prayer houses of Ethiopian Jewry. Among them, we discovered two Orit books — the Torah of Beta Israel — written in the 15th century, the earliest found so far in the hands of Jewish Kessim.
Alongside the excitement, we believe our discovery is only the tip of the iceberg. It is likely that many more sacred books of Beta Israel are held by families and Kessim around the country, and we will continue searching for them. It is important to emphasize that all manuscripts located (like those found through the workshop) will remain in the possession of their owners, while being photographed and documented to make them accessible to interested members of the community, the broader public, and researchers in Israel and around the world. Another, especially urgent task of the Orit Guardians is documenting the scholarly oral traditions of the Kessim in Ethiopia, which includes translation from Ge’ez to Amharic and interpretation of the Orit and other holy books. This heritage, transmitted only orally from generation to generation, has never been set down in writing. Today, only 18 senior Kessim, who were trained in Ethiopia and hold this knowledge, remain active in Israel, and they are aging. If we do not act quickly, we might lose this precious cultural treasure."