Avram Hershko

Avram Hershko
Hershko in 1994
Avram Hershko
Born	Herskó Ferenc Ábrahám 12/31/1937
Birthplace	Karcag, Hungary
Nationality	Israeli
Occupation	Biochemist
Employer	Technion – Israel Institute of Technology
Known for	Ubiquitin-mediated protein degradation
Education	M.D., Ph.D., Hebrew University of Jerusalem
Children	3
Awards	Weizmann Prize (1987), Wolf Prize in Medicine (2001), Nobel Prize in Chemistry (2004)

Avram Hershko (אברהם הרשקו (Hebrew: אברהם הרשקו); born Herskó Ferenc Ábrahám, December 31, 1937) is a Hungarian-born Israeli biochemist. His research into how cells break down proteins transformed our understanding of fundamental biological processes. In 2004, he won the Nobel Prize in Chemistry alongside his former graduate student Aaron Ciechanover and American biochemist Irwin Rose for discovering ubiquitin-mediated protein degradation. This is the process by which cells tag unwanted or damaged proteins with ubiquitin, a small molecule, marking them for destruction by the proteasome.

Born in Hungary, Hershko survived the Holocaust as a child. He emigrated to Israel in 1950, where he studied medicine and biochemistry at the Hebrew University of Jerusalem. Most of his research career took place at the Technion – Israel Institute of Technology in Haifa. He also maintained affiliations with American institutions: the Fox Chase Cancer Center in Philadelphia and New York University School of Medicine.

His work on the ubiquitin system opened up major new directions for understanding cell cycle regulation, DNA repair, immune response, and cancer biology. That work also had profound implications for drug development.

Early Life

Avram Hershko was born on December 31, 1937, in Karcag, a town in central Hungary. His birth name was Herskó Ferenc Ábrahám. He was born into a Jewish family during a period of rising antisemitism and political instability across Central Europe. World War II and the Holocaust shaped his early childhood profoundly.

In 1944, when Hershko was six, Nazi Germany occupied Hungary. His family faced persecution. His father was sent to a Nazi forced labor camp. The young Hershko and other family members survived the war. His father came back alive.

The family stayed in Hungary for several years after the war ended, through the early Communist period. Then in 1950, when Hershko was twelve, he and his family left Hungary for the newly established State of Israel. This was part of a larger wave of Jewish immigration to Israel from Europe in the late 1940s and early 1950s. As a young teenager, Hershko had to adapt to a new country, language, and culture. Yad Vashem, Israel's Holocaust remembrance center, has recognized him as a Holocaust survivor.

Surviving the Holocaust and rebuilding life in a new country shaped everything. In interviews, he's reflected on how these early experiences influenced his later career in science.

Education

At the Hebrew University of Jerusalem, Hershko enrolled in the Hebrew University–Hadassah Medical School. He earned his M.D. degree there, getting training in medicine that would provide the biological foundation for his later research. He then continued at Hebrew University, completing a Ph.D. in biochemistry. His doctoral research focused on protein metabolism, which would become the central theme of his life's work.

Following his doctorate, Hershko did postdoctoral training in the United States. This exposed him to the American research environment and built connections that would prove crucial for his later collaborative work. He then returned to Israel and joined the faculty at the Technion – Israel Institute of Technology in Haifa, where he'd establish his laboratory and conduct the research that led to his most significant discoveries.

Career

Early Research at the Technion

Hershko set up a research program in the Department of Biochemistry at the Rappaport Faculty of Medicine when he joined the Technion. His early work centered on how cells regulate the turnover of intracellular proteins. He studied the processes by which proteins are synthesized and then broken down inside cells. Protein degradation was a relatively neglected area of study back then. Most researchers focused on protein synthesis rather than protein disposal. The field assumed that protein degradation was largely nonspecific and unregulated. Hershko challenged that assumption. He wanted to understand the specificity and regulation of intracellular protein breakdown.

Starting in the 1970s, Hershko investigated energy-dependent protein degradation in cell-free systems. These were laboratory preparations of broken-open cells that still had the ability to break down proteins. Reticulocyte lysates, prepared from immature red blood cells, proved instrumental in dissecting the degradation machinery biochemically. Using reticulocyte lysates was a clever methodological choice. These cells lack lysosomes, which were then thought to be the main sites of protein degradation, yet they still showed ATP-dependent protein breakdown. That observation pointed toward an unknown, energy-requiring proteolytic system in the cytoplasm.

Collaboration with Aaron Ciechanover

A major turning point came when Aaron Ciechanover joined Hershko's laboratory as a graduate student. Together they began systematically fractionating the reticulocyte lysate to identify the components responsible for ATP-dependent protein degradation. They separated the cell extract into different fractions and tested which combinations restored proteolytic activity. It was painstaking work, but ultimately revelatory.

Through fractionation work, they found a small, heat-stable protein required for degradation. It was called APF-1 (ATP-dependent Proteolysis Factor 1) initially, but was later identified as ubiquitin. This was a 76-amino-acid protein that had been previously described, though nobody knew what it did. Their discovery was critical: ubiquitin was covalently attached to protein substrates destined for destruction. The cell uses a specific molecular "tag" to mark proteins for destruction.

Work at the Fox Chase Cancer Center with Irwin Rose

A key chapter in the ubiquitin story took place at the Fox Chase Cancer Center (then called the Institute for Cancer Research) in Philadelphia, Pennsylvania. In the summer of 1979, Hershko and Ciechanover traveled to Fox Chase to work in the laboratory of Irwin Rose, an American biochemist specializing in enzymology. This collaboration proved enormously productive. Rose's biochemical expertise complemented the work by Hershko and Ciechanover. Together the three made rapid progress in elucidating the enzymatic cascade responsible for ubiquitin conjugation.

During their collaborative summers at Fox Chase, which continued for several years, the team worked out the multi-step enzymatic mechanism by which ubiquitin is activated and attached to target proteins. They identified the cascade of enzymes now called E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase). These enzymes work together in a hierarchical fashion to covalently link ubiquitin chains to proteins designated for degradation. They published landmark papers in the Proceedings of the National Academy of Sciences. A 1980 paper described the proposed mechanism of ATP-dependent protein breakdown. A 1984 paper further characterized components of the system.

The E1–E2–E3 enzymatic cascade mattered because it explained how ubiquitin achieves substrate specificity. Most organisms have only one E1 enzyme, but multiple E2 enzymes and hundreds of E3 ligases exist, each recognizing different target proteins. This hierarchical arrangement lets the ubiquitin system selectively target thousands of different proteins for degradation in a highly regulated way.

Elucidation of the Ubiquitin–Proteasome System

The work by Hershko, Ciechanover, and Rose established the biochemical framework for the ubiquitin–proteasome system (UPS). In this pathway, proteins that need destruction get tagged with chains of ubiquitin molecules. Whether damaged, misfolded, or no longer needed, these proteins are marked through the sequential action of E1, E2, and E3 enzymes. The polyubiquitinated proteins are then recognized and degraded by the proteasome, a large multi-subunit protease complex that serves as the cell's protein-disposal machinery.

This work fundamentally changed how we understand cellular regulation. It showed that protein degradation isn't passive or nonspecific. Rather, it's a tightly controlled mechanism playing essential roles in virtually every aspect of cell biology. The ubiquitin–proteasome system regulates cell division, DNA repair, quality control of newly synthesized proteins, immune responses, signal transduction, transcription, and many other processes.

Hershko's subsequent research continued to explore ubiquitin-mediated degradation in cell cycle control. He and colleagues demonstrated that timely destruction of specific regulatory proteins, such as cyclins, by the ubiquitin system is essential for orderly progression through cell division stages. This work connected the ubiquitin system directly to cancer biology, since errors in cell division regulation are a cancer hallmark.

Appointments and Affiliations

Throughout his career, Hershko held his primary appointment as Distinguished Professor in the Rappaport Faculty of Medicine at the Technion – Israel Institute of Technology in Haifa, Israel. He also served as an adjunct professor in the Department of Pathology at New York University School of Medicine, reflecting his ties to the American biomedical research community. His regular summer visits to the Fox Chase Cancer Center in Philadelphia were a defining feature of his research career. Those visits enabled the transatlantic collaboration that produced the Nobel Prize–winning discoveries.

The American Philosophical Society, one of the oldest learned societies in the United States, elected him a fellow.

Continued Research and Cancer Biology

After the initial discovery, Hershko continued investigating the molecular details and biological functions of the ubiquitin system. His Technion laboratory pursued studies on specific E3 ubiquitin ligases in cell cycle regulation and on mechanisms controlling ubiquitin system activity. The recognition that ubiquitin–proteasome pathway is central to protein level regulation had major implications for understanding diseases, particularly cancer.

By the early 21st century, ubiquitin–proteasome research became one of the most active areas of biomedical research, largely because of its relevance to drug development. Bortezomib (marketed as Velcade), a proteasome inhibitor approved by the U.S. Food and Drug Administration for treating multiple myeloma, was a direct therapeutic application of the basic science discoveries made by Hershko and his collaborators. He's spoken publicly about how basic research matters for developing new therapies. The practical applications of the ubiquitin system couldn't have been predicted at the work's outset.

He's also worked to communicate science to broader audiences. An iBiology lecture series featured him discussing lessons from a life in science.

Personal Life

Avram Hershko has three children. Since emigrating from Hungary in 1950, he's made Israel his home. In interviews, he's discussed his family, including his grandchildren, and his life in Haifa. He's a Holocaust survivor. As a child, he endured Nazi persecution of Hungarian Jews. His father survived internment in a forced labor camp.

His personal history as a Holocaust survivor and immigrant to Israel has been central to his public identity. He's participated in Holocaust remembrance events and programs. Yad Vashem has recognized him in the context of survivor testimony and memory preservation.

Recognition

Avram Hershko has received numerous awards and honors for his contributions to biochemistry and cell biology. The most significant recognitions include:

The Weizmann Prize in 1987 for his contributions to science in Israel.

The Israel Prize for biochemistry, awarded by the Israeli government in recognition of his outstanding contributions to science in Israel.

The Wolf Prize in Medicine in 2001, which he shared with Aaron Ciechanover and Alexander Varshavsky for their discovery of the ubiquitin system of intracellular protein degradation and its roles in cellular regulation.

The Nobel Prize in Chemistry in 2004, shared with Aaron Ciechanover and Irwin Rose, "for the discovery of ubiquitin-mediated protein degradation." The Nobel Committee's citation recognized that the trio had discovered one of the cell's most important cyclical processes. They'd revealed a molecular mechanism by which the cell breaks down and recycles proteins. The award ceremony took place in Stockholm, Sweden, in December 2004. The three laureates shared the prize equally.

The American Association for Cancer Research (AACR) Academy elected him a fellow, recognizing his contributions to cancer research through the elucidation of the ubiquitin system.

Legacy

The discovery of ubiquitin-mediated protein degradation by Hershko, Ciechanover, and Rose stands as one of the most significant advances in cell biology and biochemistry in the late 20th century. Before their work, protein degradation seemed like a relatively unimportant and unregulated cellular process. Their research showed something different: controlled protein destruction is as essential to cellular life as protein synthesis. Failures in this system underlie numerous diseases.

The ubiquitin–proteasome system is now central to modern molecular biology and medicine. As of the early 21st century, thousands of researchers worldwide work in ubiquitin research. They've identified hundreds of E3 ubiquitin ligases, each with distinct substrate specificities and biological roles. The system is implicated in cancer pathogenesis, neurodegenerative diseases like Parkinson's and Alzheimer's, immune disorders, and viral infections.

Therapeutically, proteasome inhibitors such as bortezomib for multiple myeloma represented a direct translation of Hershko's basic science discoveries into clinical medicine. More recently, targeted protein degradation has given rise to new drug discovery approaches. Proteolysis-targeting chimeras (PROTACs) harness the ubiquitin system to selectively destroy disease-causing proteins.

Hershko's career also exemplifies the value of international scientific collaboration. His regular summer visits to Fox Chase Cancer Center, where he worked with Irwin Rose, and his adjunct position at NYU School of Medicine illustrate the transatlantic scientific networks that facilitated the ubiquitin discoveries. The partnership between Hershko and Ciechanover, which began as a mentor-student relationship and evolved into a long-term scientific collaboration, has been noted as an example of productive mentorship in science.

Beyond his scientific achievements, Hershko's personal story tells us something profound. From Holocaust survivor to Nobel laureate—that's a narrative of resilience and intellectual achievement. His journey from wartime Hungary through immigration to Israel and ultimately to the highest recognition in science reflects the broader history of the 20th century and Israel's emergence as a center of scientific research.