Profile of Yosef Shiloh

In the summer of 1977, Yosef Shiloh, then a graduate student, visited an Israeli Moroccan Jewish family with several children affected by ataxia-telangiectasia (A-T), a rare and complex genetic disorder characterized by cerebellar degeneration, immunodeficiency, cancer predisposition, premature aging, genome instability, and radiation sensitivity. The visit had a profound impact on Shiloh, inspiring him to dedicate his doctoral research—and, ultimately, his scientific career—to studying A-T.

Portrait of Yosef Shiloh. Image credit: Shoshana Shiloh (Tel Aviv University, Tel Aviv, Israel).

In 1995, Shiloh’s group identified the gene that is defective in individuals affected by A-T, ATM (A-T, mutated). The gene was found to encode the protein ATM, which is critical for many cellular functions, notably the cellular response to DNA damage. Now an emeritus professor of human molecular genetics and biochemistry at Tel Aviv University, Shiloh was elected to the National Academy of Sciences in 2023 and continues to explore A-T. His Inaugural Article (IA) (1) uncovers pathways underlying the premature senescence of ATM-deficient cells, a phenomenon that triggers inflammation and is relevant to fibrotic lung disease, a symptom of A-T and aging.

On the Path Toward Science

Shiloh was born in Haifa, Israel, where he was raised by parents who had immigrated to Israel. He says, “My elementary school was run by teachers with a deep social commitment. This was crucial, as the 1950s were mostly years of austerity in Israel. It was clear I should strive for the best education.”

His teachers during his formative years left a lasting influence. Shiloh remained in contact with his first-grade teacher, Esther Klin, until her passing in 2021. Another key figure was his high school chemistry teacher, Bracha Orgad, who inspired Shiloh’s interest in science. Shiloh says, “She was a legendary figure, remembered by countless number of her students, many of whom went on to careers in science, education, medicine, and industry.”

Focus on A-T

Shiloh attended the Technion Israel Institute of Technology, where he studied chemistry and biology, graduating in 1974 with a bachelor’s degree in biology with distinction. Before pursuing a Master’s degree in human genetics at the Hebrew University of Jerusalem, he married Shoshana Shiloh, a social psychologist who is now a professor emeritus at Tel Aviv University. “Shoshi and I have shared a life of intertwined careers,” he says. “Part of her research resonated with mine, as it focused on the psychosocial aspects of genetic counseling and genetic testing—topics that grew increasingly important with the rapid progress of The Human Genome Project.”

Shiloh’s first mentor at Hebrew University was cytogeneticist Maimon Cohen, who supervised Shiloh’s Master’s thesis (2, 3). While Shiloh was considering a topic for his doctoral thesis, Cohen invited him along on the fateful visit to the family afflicted with A-T. “A-T seemed to be a cruel, extremely complex disease, with a broad array of symptoms, all of which apparently boiled down to one gene with autosomal recessive inheritance,” Shiloh recalled in an interview published in EMBO Reports (4).

The encounter prompted Shiloh to focus his doctoral research on A-T, under the supervision of molecular virologist Yechiel Becker and in collaboration with microbiologist Bernard Strauss at the University of Chicago, where Shiloh completed two internships. He says, “The combined inspiration from these two great scientists made it clear to me that I should pursue an academic career and conduct research in an environment of academic freedom.” Shiloh’s doctoral work resulted in several papers detailing the cellular characteristics of A-T cells, especially their abnormal response to double-strand breaks in DNA (5) and their premature senescence (6).

Discovery of the A-T Gene

Shiloh was introduced to recombinant DNA technology during his postdoctoral work in the lab of geneticist Samuel Latt at Harvard Medical School (7). “Sam was a scientific pioneer, a mentor, and an educator,” Shiloh says. “Our last meeting took place on my final day in his lab. He passed away three years later. Before I left his office, he said something I’ll never forget: ‘You’ll identify the A-T gene—you’ll do it!’ He said it with such certainty. When we landed back in Israel, those words were still ringing in my ears.”

In 1985, Shiloh became a senior lecturer of human genetics at Tel Aviv University, where he advanced to his current position. He established his research group with lab manager Yael Ziv, who remains a colleague. Shiloh says, “Yael has always been at the heart of everything we do, offering her scientific expertise and guiding the team since day one.” Reflecting further, he adds, “At some point, it hit me that part of my career has been spent standing on the shoulders of giants, and the other part—largely standing on the shoulders of my team.”

The 1980s were a pivotal time for advancing the positional cloning approach to identify disease-related genes. The work was slow and labor-intensive. Furthermore, A-T presented a special challenge: Studies showed that the disease could result from mutations in four different genes. Nevertheless, in 1988, the effort to identify the A-T genes gained momentum in many labs, including Shiloh’s, after University of California, Los Angeles geneticist Richard Gatti’s team localized one A-T gene (ATA) to the long arm of human chromosome 11. Shiloh’s group and others proceeded to perform long-range mapping and cloning of that region (8).

A pivotal moment in this journey was Shiloh’s sabbatical year in the lab of molecular geneticist Francis Collins, a leader in human genome research who later established the National Human Genome Research Institute and led the National Institutes of Health. At the time, Collins led a research group at the University of Michigan. Shiloh says, “I had the opportunity to learn gene hunting first-hand, again benefiting from the inspiration of a leading colleague.”

In late 1994, while testing a candidate gene against DNA samples from a family with A-T, Shiloh and Ziv realized that they had identified the ATA gene. “Before rushing to announce our finding,” Shiloh recalls, “I had to make a tough decision. I felt we needed to determine whether this gene wasn’t just one of the four A-T genes, but rather the one and only A-T gene.”

Shiloh’s methodical approach was shaped by his training as a human geneticist, having spent significant time in the clinic with families affected by genetic disorders. “I knew that if this was the sole A-T gene, it could immediately allow for prenatal diagnosis of A-T worldwide. The necessary molecular information was in our hands if this was the only A-T gene.” Shiloh’s group agreed to delay publishing the finding until they conducted additional experiments, despite hearing rumors that another group had also identified the same gene. After five months, they confirmed that the identified gene, which they named ATM, was indeed the sole A-T gene, as it exhibited severe, inactivating mutations in affected individuals across all four previously presumed A-T gene groups (9).

ATM Protein: A Central Hub in Cellular Physiology

To study the function of the protein product of ATM, Shiloh and his team shifted gears to protein chemistry. In 1998, they, along with the group of hematologist/oncologist Michael Kastan, published back-to-back papers identifying the first known physiological substrate of ATM, which was found to be a protein kinase enzyme—the p53 protein—and demonstrated ATM activation in response to DNA double-strand breaks (10, 11). Subsequent research identified additional ATM targets and demonstrated the functional significance of their ATM-mediated phosphorylation within the expanding DNA damage response signaling network (12–15). A fan of classical music, Shiloh compares ATM to a symphony orchestra conductor. “Specifically,” he says, alluding to the protein’s multifarious interactions, “ATM conducts a piece equivalent to Mahler’s 8th Symphony, ‘A Symphony of a Thousand’.”

These insights helped expand the field of genome stability beyond DNA repair biochemistry and into signal transduction. Transitioning to systems biology, the group explored ATM-dependent dynamics within the phosphoproteome (16) and the gene expression landscape (17). ATM, however, proved to be more than just a hub for DNA damage response. As Shiloh explains, “Thanks to work in many labs including ours, ATM turned out to be a multifunctional, homeostatic protein kinase with critical roles not only in responding to DNA damage but also in regulating oxidative stress, mitochondrial homeostasis, and other metabolic pathways.”

A central question in the A-T field remains: Which ATM function loss is responsible for each specific A-T symptom? Shiloh says, “Incredibly, we still do not fully understand A-T’s most devastating symptom, the debilitating and relentless cerebellar degeneration.” Many explanations have been proposed, including Shiloh’s own (18). Once again shifting gears, this time to neurobiology, Shiloh’s lab has launched a long-term effort using engineered mice and cerebellar organotypic cultures to better understand the symptom, which overwhelmingly affects patients’ lives.

Genome Instability, Cellular Senescence, and Aging

Recently, Shiloh and his team extended his earlier work on the premature senescence of A-T primary fibroblasts (6), further exploring the pathways responsible for the phenomenon (19). His IA (1) reports the use of lung fibroblasts from ATM-deficient mice to provide a detailed model of this process. The IA is dedicated to the memory of biochemist Judith Campisi, who was a pioneer in the field of cell senescence. Campisi mentored the paper’s first author, Majd Haj, during an internship in her lab.

For his achievements during five decades of research, Shiloh has received a wide array of awards and honors. These include the EMET Prize in Life Sciences, Israel (2005), the American Association for Cancer Research G.H.A. Clowes Award for Outstanding Accomplishments in Basic Cancer Research (2011), the Israel Prize in Life Sciences (2011), and the Olav Thon International Prize in Mathematics, Natural Sciences, and Medicine (2015), which he shared with Campisi.

Shiloh is proud of Shoshi’s and his children’s accomplishments: His son, Amir, works in Israel’s cybersecurity industry, and his daughter, Ruthy, is a senior scientist at Schneider Children’s Medical Center of Israel. In 2024, Shiloh and his daughter participated in a multisite study on the effect of various ATM mutations on treatment outcomes in A-T patients with hematological malignancies (20), following the publication of his daughter’s paper on another rare disease, H-syndrome. He says, “It seems both Shilohs agree on the power of studying rare disorders to provide novel insights into health and disease.”