Avram Hershko

Avram Hershko
Hershko in 1994
Avram Hershko
Born	Herskó Ferenc Ábrahám 31 12, 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 (Template:Lang-he; born Herskó Ferenc Ábrahám, December 31, 1937) is a Hungarian-born Israeli biochemist whose groundbreaking research into the mechanisms by which cells break down proteins transformed the understanding of fundamental biological processes. Together with his former graduate student Aaron Ciechanover and American biochemist Irwin Rose, Hershko was awarded the Nobel Prize in Chemistry in 2004 for the discovery of ubiquitin-mediated protein degradation — the process by which cells tag unwanted or damaged proteins with the small molecule ubiquitin for destruction by the proteasome. Born in Hungary, Hershko survived the Holocaust as a child before emigrating to Israel in 1950, where he pursued studies in medicine and biochemistry at the Hebrew University of Jerusalem. He spent the majority of his research career at the Technion – Israel Institute of Technology in Haifa, while also maintaining affiliations with institutions in the United States, including the Fox Chase Cancer Center in Philadelphia and New York University School of Medicine. His work elucidating the ubiquitin system opened major new avenues in the understanding of cell cycle regulation, DNA repair, immune response, and cancer biology, and has had profound implications for drug development.

Early Life

Avram Hershko was born on December 31, 1937, in Karcag, a town in central Hungary, under the name Herskó Ferenc Ábrahám. He was born into a Jewish family during a period of rising antisemitism and political instability across Central Europe. His early childhood was shaped by the catastrophic events of World War II and the Holocaust. During the Nazi occupation of Hungary in 1944, when Hershko was six years old, his family faced persecution. His father was taken to a Nazi forced labor camp. The young Hershko and other family members survived the war, and his father ultimately returned from the labor camp alive.

After the war, the family remained in Hungary for several years during the early period of Communist rule. In 1950, when Hershko was twelve years old, he and his family emigrated from Hungary to the newly established State of Israel. This emigration was part of a larger wave of Jewish immigration to Israel from European countries in the late 1940s and early 1950s. Settling in Israel, Hershko adapted to a new country, language, and culture as a young teenager. Hershko has been recognized by Yad Vashem, Israel's Holocaust remembrance center, as a Holocaust survivor.

The experience of surviving the Holocaust and rebuilding life in a new country profoundly shaped Hershko's outlook and determination. In interviews, he has reflected on the formative influence of these early experiences on his subsequent career in science.

Education

Hershko pursued his higher education at the Hebrew University of Jerusalem, where he enrolled in the Hebrew University–Hadassah Medical School. He earned his M.D. degree from the institution, receiving training in medicine that would provide the biological foundation for his later research career. He subsequently continued his studies at the Hebrew University, completing a Ph.D. in biochemistry. His doctoral research focused on problems of protein metabolism, a subject that would become the central theme of his life's work.

After completing his doctoral studies, Hershko undertook postdoctoral training in the United States, which exposed him to the American research environment and established connections that would prove important for his later collaborative work. He then returned to Israel to join the faculty at the Technion – Israel Institute of Technology in Haifa, where he would build his laboratory and conduct the research that led to his most significant scientific contributions.

Career

Early Research at the Technion

Upon joining the Technion – Israel Institute of Technology, Hershko established a research program in the Department of Biochemistry in the Rappaport Faculty of Medicine. His early research interests centered on the mechanisms by which cells regulate the turnover of intracellular proteins — the processes by which proteins are synthesized and then broken down within cells. At the time, the field of protein degradation was relatively neglected compared to the study of protein synthesis, as most researchers focused on how cells make proteins rather than how they dispose of them. The prevailing view in molecular biology held that protein degradation was a largely nonspecific, unregulated process. Hershko challenged this assumption and sought to understand the specificity and regulation of intracellular protein breakdown.

During the 1970s, Hershko began investigating energy-dependent protein degradation in cell-free systems — laboratory preparations of broken-open cells that retained the ability to break down proteins. This approach, using reticulocyte (immature red blood cell) lysates, proved instrumental in the biochemical dissection of the degradation machinery. The use of reticulocyte lysates was a key methodological choice: these cells lack lysosomes, which were then considered the primary sites of protein degradation, yet still exhibited ATP-dependent protein breakdown. This observation pointed toward the existence of a previously unknown, energy-requiring proteolytic system in the cytoplasm.

Collaboration with Aaron Ciechanover

One of the most consequential developments in Hershko's career was his mentorship of Aaron Ciechanover, who joined his laboratory as a graduate student. Together, Hershko and Ciechanover began systematically fractionating the reticulocyte lysate to identify the components responsible for ATP-dependent protein degradation. Their biochemical approach — separating the cell extract into different fractions and testing which combinations restored proteolytic activity — was painstaking but ultimately revelatory.

Through this fractionation work, they identified a small, heat-stable protein that was required for the degradation process. This protein, initially called APF-1 (ATP-dependent Proteolysis Factor 1), was later identified as ubiquitin, a 76-amino-acid protein that had been previously described but whose function was unknown. The discovery that ubiquitin was covalently attached to protein substrates destined for degradation was a critical insight, revealing that the cell uses a specific molecular "tag" to mark proteins for destruction.

Work at the Fox Chase Cancer Center with Irwin Rose

A pivotal chapter in the ubiquitin story unfolded at the Fox Chase Cancer Center (then 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 with expertise in enzymology. This collaboration proved enormously productive. Rose's biochemical expertise complemented Hershko's and Ciechanover's ongoing work, and together the three researchers made rapid progress in elucidating the enzymatic cascade responsible for ubiquitin conjugation.

During their collaborative summers at Fox Chase — a pattern that 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 known as E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase), which work together in a hierarchical fashion to covalently link ubiquitin chains to proteins designated for degradation. Key publications from this period include landmark papers in the Proceedings of the National Academy of Sciences, including a 1980 paper describing the proposed mechanism of ATP-dependent protein breakdown and a 1984 paper further characterizing components of the system.

The discovery of the E1–E2–E3 enzymatic cascade was of particular significance because it explained how the ubiquitin system achieves substrate specificity. While there is only one E1 enzyme in most organisms, there are multiple E2 enzymes and hundreds of E3 ligases, each capable of recognizing different target proteins. This hierarchical arrangement allows the ubiquitin system to selectively target thousands of different proteins for degradation in a highly regulated manner.

Elucidation of the Ubiquitin–Proteasome System

The work by Hershko, Ciechanover, and Rose established the biochemical framework for what became known as the ubiquitin–proteasome system (UPS). In this pathway, proteins that need to be destroyed — whether because they are damaged, misfolded, or no longer needed — are tagged with chains of ubiquitin molecules 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 acts as the cell's protein-disposal machinery.

The elucidation of this system fundamentally changed the understanding of cellular regulation. It revealed that protein degradation is not a passive, nonspecific process but rather a tightly controlled mechanism that plays essential roles in virtually every aspect of cell biology. The ubiquitin–proteasome system was found to regulate 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 the roles of ubiquitin-mediated degradation in cell cycle control. He and his colleagues demonstrated that the timely destruction of specific regulatory proteins, such as cyclins, by the ubiquitin system is essential for the orderly progression of cells through the stages of division. This work established direct connections between the ubiquitin system and cancer biology, since errors in the regulation of cell division are a hallmark of cancer.

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. In addition to his position at the Technion, he held an adjunct professorship in the Department of Pathology at New York University School of Medicine, reflecting his connections to the American biomedical research community. His regular summer visits to the Fox Chase Cancer Center in Philadelphia were also a defining feature of his research career, enabling the transatlantic collaboration that produced the Nobel Prize–winning discoveries.

Hershko has been a fellow of the American Philosophical Society, one of the oldest learned societies in the United States.

Continued Research and Cancer Biology

In the decades following the initial discovery, Hershko continued to investigate the molecular details and biological functions of the ubiquitin system. His laboratory at the Technion pursued studies on the roles of specific E3 ubiquitin ligases in cell cycle regulation and on the mechanisms that control the activity of the ubiquitin system itself. The recognition that the ubiquitin–proteasome pathway is central to the regulation of protein levels in cells had major implications for understanding diseases, particularly cancer.

The ubiquitin–proteasome system became one of the most active areas of biomedical research in the early 21st century, in large part because of its relevance to drug development. The proteasome inhibitor bortezomib (marketed as Velcade), approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma, was a direct therapeutic application of the basic science discoveries made by Hershko and his collaborators. Hershko has spoken publicly about the significance of basic research for the development of new therapies, noting that the practical applications of the ubiquitin system could not have been predicted at the outset of the work.

Hershko has also engaged in efforts to communicate science to broader audiences. He participated in an iBiology lecture series discussing lessons from a life in science.

Personal Life

Avram Hershko has three children. He has resided in Israel for most of his life since emigrating from Hungary in 1950. In interviews, he has discussed his family, including his grandchildren, and his life in Haifa. He is a survivor of the Holocaust, having endured the Nazi persecution of Hungarian Jews as a child, and his father survived internment in a forced labor camp.

Hershko's personal history as a Holocaust survivor and immigrant to Israel has been an important part of his public identity. He has participated in events and programs related to Holocaust remembrance and has been recognized by Yad Vashem in the context of survivor testimony and memory preservation.

Recognition

Avram Hershko has received numerous awards and honors in recognition of his contributions to biochemistry and cell biology. His most significant recognitions include:

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

The Israel Prize for biochemistry, awarded by the Israeli government, recognizing 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 the roles of this system 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 — a molecular mechanism by which the cell breaks down and recycles proteins. The award ceremony took place in Stockholm, Sweden, in December 2004, and the three laureates shared the prize equally.

Hershko was also elected a fellow of the American Association for Cancer Research (AACR) Academy, 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 is considered one of the most significant advances in cell biology and biochemistry in the late 20th century. Prior to their work, protein degradation was viewed as a relatively unimportant and unregulated cellular process. Their research demonstrated that the controlled destruction of proteins is as essential to cellular life as their synthesis, and that failures in this system underlie numerous diseases.

The ubiquitin–proteasome system has become central to modern molecular biology and medicine. As of the early 21st century, the field of ubiquitin research encompasses thousands of researchers worldwide and has led to the identification of hundreds of E3 ubiquitin ligases, each with distinct substrate specificities and biological roles. The system is implicated in the pathogenesis of cancer, neurodegenerative diseases (including Parkinson's disease and Alzheimer's disease), immune disorders, and viral infections.

In the realm of therapeutics, the development of proteasome inhibitors such as bortezomib for the treatment of multiple myeloma represented a direct translation of the basic science discoveries made by Hershko and his colleagues into clinical medicine. More recently, the concept of targeted protein degradation has given rise to new drug discovery approaches, including proteolysis-targeting chimeras (PROTACs), which 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 — beginning as a mentor-student relationship and evolving into a long-term scientific collaboration — has also been noted as an example of productive mentorship in science.

Beyond his scientific achievements, Hershko's personal story — from Holocaust survivor to Nobel laureate — represents 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 the establishment of Israel as a center of scientific research.