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Portrait of Avram Hershko
Photo: Sharon Gabay, שרון גבאי · CC BY-SA 3.0 via Wikimedia Commons

Nobel Prize in Chemistry · 2004

Avram Hershko

A child survivor of the Holocaust, he helped discover how cells tag unwanted proteins for destruction, work behind new cancer drugs.

The Nobel citation: “for the discovery of ubiquitin-mediated protein degradation”
Born
December 31, 1937, Karcag, Hungary
Affiliation at the time
Technion - Israel Institute of Technology, Israel

Chemistry prize

2004

Shared with 2 other laureates.

Age that year

67years

Born in 1937.

Headline credited impact

60,000–95,000people benefited

Patients treated with proteasome-inhibitor drugs, mostly for multiple myeloma (2003-2025). How it was built

Sources cited

38

Fact-checked September 24, 2026.

  • At six he was deported from the Szolnok ghetto on one of the few trains bound for forced labor in Austria instead of Auschwitz. He, his mother and brother survived.
  • Much of the ubiquitin system was discovered in an old two-floor monastery in Haifa, which housed the Technion's new medical school for more than 15 years.
  • His lab first nicknamed ubiquitin 'Red', because it came from the red, hemoglobin-rich part of the blood-cell extract they were studying.
  • He chose medicine partly because his older brother, already a medical student, could hand down his textbooks for free.
  • Aaron Ciechanover, who shared the 2004 Nobel Prize with him, did much of the prize-winning work as Hershko's graduate student.

The breakthrough

Ubiquitin: the cell's 'destroy this protein' label (1978-1983)

Proteins are the tiny machines that do most jobs in your cells. Cells build them all the time, but they must also destroy them: worn-out or badly made proteins, and control proteins whose job is done. Since the 1950s scientists had known something odd. Breaking down a cell's own proteins used energy, even though breaking a protein apart normally releases energy. As a young researcher in San Francisco around 1970, Hershko saw this too and spent a decade chasing the reason. Back in Haifa he worked with extracts of immature red blood cells, a test-tube system from Alfred Goldberg's lab that digests proteins using energy. In 1978 he and his graduate student Aaron Ciechanover found that the process needed a small, heat-proof protein, later identified as ubiquitin. In 1980, working with Irwin Rose, they showed what it does: the cell attaches many ubiquitin molecules to a protein it wants gone. Together they work like a shipping label that says 'to the shredder'. The labelled protein is then fed into a barrel-shaped shredder called the proteasome, found by other scientists, and cut into small pieces. By 1983 Hershko, Ciechanover and their colleagues had found the three kinds of enzymes that attach the label, called E1, E2 and E3. The E3 enzymes choose which proteins get tagged, and cells have hundreds of them. That is how a cell can remove exactly the right protein at exactly the right moment.[3],[4],[5],[6],[8],[9]

“Maybe the lesson from this story is that it is dangerous to consult experts.”
Avram Hershko, From his Nobel autobiography (2004), recalling how a Technion protein expert told his team that their heat-stable factor, later identified as ubiquitin, could not be a protein. Tests showed it was one.[2]

What it meant for humanity

Hershko's work revealed a control system that touches almost every part of cell life. The ubiquitin label helps decide when cells divide, how they repair damaged DNA, how they discard faulty new proteins and how the immune system spots infected cells. When the system goes wrong, people get sick. The human papillomavirus, a cause of cervical cancer, tricks one E3 enzyme into tagging p53 for destruction, a protein that normally stops damaged cells from growing. In cystic fibrosis, the most common faulty form of the CFTR protein is caught by the cell's quality check and destroyed. The biggest practical result so far is a new kind of cancer drug. Building on this knowledge of protein breakdown, a small company co-founded by the biochemist Alfred Goldberg created bortezomib (Velcade), which blocks the proteasome. Cells of multiple myeloma, a bone-marrow cancer diagnosed in about 196,000 people a year worldwide, make huge amounts of faulty antibody protein and are unusually sensitive to it. The US approved bortezomib in 2003. In a 2005 trial of patients whose myeloma had returned, 80% of those given bortezomib were alive after one year, compared with 66% of those given high-dose dexamethasone. More than 550,000 patients had received it by 2014, and about 200,000 had received a second proteasome blocker, carfilzomib, by 2021. Along with other new drugs, these helped raise five-year survival for US myeloma patients from about 39% for those diagnosed in 2001 to about 62% for those diagnosed in 2015. In a 2018 interview Hershko said that industry, not he, developed the drug, but that it was based on their research. In May 2026 US regulators approved vepdegestrant, the first PROTAC: a drug designed to make an E3 enzyme tag a cancer-driving protein for destruction.

  • Bortezomib, the first proteasome-blocking drug, won accelerated US approval in 2003 after only phase II trials. Hershko later said industry developed it, but that it was based on his team's research.[17],[18],[33]
  • In a 669-patient trial in relapsed myeloma, 38% responded to bortezomib versus 18% to high-dose dexamethasone, and one-year survival was 80% versus 66%.[19]
  • By the makers' counts, more than 550,000 patients had been treated with bortezomib by October 2014, and about 200,000 had received carfilzomib by December 2021.[20],[23]
  • US five-year survival for myeloma rose from about 39% for patients diagnosed in 2001 to about 62% for those diagnosed in 2015, as bortezomib and other new drugs came into use.[25],[26]
  • Proteasome-blocking chemicals also became standard laboratory tools. One early compound, MG132, had been used in more than 4,000 studies by 2012.[17]
  • In May 2026 the US approved vepdegestrant, the first PROTAC drug, for some advanced breast cancers. It recruits an E3 enzyme to tag the estrogen receptor with ubiquitin for destruction.[15],[34]

Impact in numbers

Hershko's main gift was knowledge: he showed how cells choose which proteins to destroy, a system now known to help control cell division, DNA repair, immunity and protein quality. Much of that value cannot be counted. The clearest countable result is proteasome-blocking drugs for multiple myeloma, which we estimate were given to 1.2 to 1.9 million patients from 2003 to 2025. We count patients treated rather than lives saved, because myeloma remains incurable and these drugs extend life rather than cure. We credit Hershko with 5% of that outcome, the same as each co-laureate, because the proteasome itself was found by others, company scientists invented and developed the drug, and clinicians proved it worked. We also count a harm: severe nerve damage in a minority of bortezomib patients, often temporary. Newer ubiquitin-based medicines, such as the first protein-degrader drug approved in 2026, are too new to count.

HealthFundamental science

Each number is the laureate’s credited share of a real-world outcome, cumulative to 2025. The whole outcome, the share of credit, and the reasoning are shown so you can check the arithmetic. Outcomes shared with other laureates are counted once on the impact page.

  • Medium confidenceRippleModeledHealth

    Patients treated with proteasome-inhibitor drugs, mostly for multiple myeloma (2003-2025)

    60,000–95,000

    people benefited, credited share

    That is 5% of 1.2–1.9 million people benefited since 2003.

    How this number was built

    Bortezomib (US approval 2003) had treated >85,000 patients by Feb 2008, >450,000 by Dec 2013 and >550,000 by Oct 2014 (company figures): ~63,000/yr in 2008-13, ~120,000/yr in 2014. For Nov 2014-2025 (~11 yr) we assume 60,000-120,000 new patients/yr, about 30-60% of the ~196,000 new myeloma cases a year worldwide (GLOBOCAN 2024). Low: 550k + 11 x 60k = 1.21M; high: 550k + 11 x 120k = 1.87M; rounded 1.2M-1.9M. Carfilzomib (~200,000 patients by 2021) is not added, since most users had already had bortezomib. 'Benefited' means treated; not all respond. Share 0.05: the proteasome was found by others, bortezomib was invented at ProScript and proven by clinicians, and Goldberg credits the whole protein-degradation field. The three 2004 laureates get 0.15 together, 0.05 each.[17],[20],[21],[22],[23],[24]

    Sources: Journal of Cell Biology (via PubMed Central); Takeda Pharmaceutical Company; Johnson & Johnson; Millennium Pharmaceuticals via US Securities and Exchange Commission; Amgen; International Agency for Research on Cancer, Global Cancer Observatory

  • HarmLow confidenceRippleModeledHealth

    Patients with severe (grade 3+) nerve damage from bortezomib (2003-2025)

    3,150–8,000

    people harmed, credited share

    That is 5% of 63,000–160,000 people harmed since 2003.

    How this number was built

    Shared outcome; same range for Hershko, Ciechanover and Rose. Base: the 1.2M-1.9M bortezomib patients of the benefit claim; over 400,000 had been treated by 2012 (Goldberg), mostly by vein twice weekly. Grade 3+ neuropathy on that schedule: 9% in the phase 3 APEX trial with a dose-modification guideline (Richardson 2009), 13% in phase 2 trials without one (Richardson 2006), 16% by vein in Moreau 2011 and 15.6% pooled over four randomised trials (Liu 2019), so 9-16%. Later patients mostly get it under the skin: 3.4% pooled (Liu 2019); Hu 2017's risk ratio of 0.4 x 16% = 6.4%, near Moreau's 6%, so 3.4-6.4%. Low: 400k x 9% + 0.8M x 3.4% = 63,000; high: 400k x 16% + 1.5M x 6.4% = 160,000. Most severe cases (64-71%) improved or resolved after dose cuts or stopping, so these are serious episodes, not all permanent. Share 0.05 each, matching the benefit claim: about 3,150-8,000 credited.[17],[27],[28],[36],[37],[38]

    Sources: Journal of Cell Biology (via PubMed Central); Journal of Clinical Oncology (via PubMed); Lancet Oncology (via PubMed); Zhongguo Shi Yan Xue Ye Xue Za Zhi (PubMed record); International Journal of Clinical Pharmacology and Therapeutics (PubMed record); British Journal of Haematology (PubMed record)

The double edge

The discovery itself has no known harmful use, and we found no misconduct linked to Hershko. The drugs built on it are cancer treatments with serious side effects. Bortezomib often damages nerves in the hands and feet: in early trials about 13% of patients developed severe nerve damage, though most severe cases improved after the dose was cut or stopped. A 2011 trial found that injecting it under the skin rather than into a vein cut severe cases from 16% to 6%. With carfilzomib, a later proteasome blocker, heart and blood-vessel problems were reported in about 18% of trial patients, serious ones in about 8%. Cost is a barrier too: in 2007 NICE, which guides NHS spending in England and Wales, backed bortezomib only if the maker refunded the full cost for patients who did not respond. The prize also drew debate. Alexander Varshavsky, who shared the 2000 Lasker Award and 2001 Wolf Prize with Hershko, was left out of the Nobel, and 29 researchers in the field wrote to Science about his contributions.

  • Moderate

    Nerve damage from bortezomib

    In early trials of twice-weekly intravenous bortezomib, 35% of patients developed new nerve damage and about 13% had severe (grade 3 or 4) cases. Of 35 patients with severe cases or who stopped treatment because of it, 71% improved or returned to baseline. A 2011 trial found severe cases fell from 16% to 6% when the drug was injected under the skin.[27],[28]

  • Moderate

    Heart problems with carfilzomib

    A 2018 review of 24 studies with 2,594 myeloma patients found heart and blood-vessel side effects in 18.1% of patients given carfilzomib, and serious ones (grade 3 or higher) in 8.2%. Higher doses carried more risk.[29]

  • Minor

    High cost of the drugs

    Bortezomib earned over two billion dollars a year by 2012. In 2007 NICE, which guides NHS spending in England and Wales, recommended it for first relapse only if the manufacturer refunded the full cost for patients who had less than a partial response after up to four cycles.[17],[30]

  • Minor

    Dispute over who was left out of the prize

    Alexander Varshavsky shared the 2000 Lasker Award with Hershko and Ciechanover and the 2001 Wolf Prize with Hershko, whose jury credited both with revealing the system's mechanism and functions. He was not included in the 2004 Nobel. Nature noted the Nobel committee does not explain such choices, and 29 researchers wrote to Science about his contributions.[12],[13],[31],[32]

Against the odds

Hungary was already restricting its Jews when Hershko was born. A 1920 law capped Jewish university places, and laws passed from 1938 to 1941 pushed Jews out of many jobs and defined them by race. Jewish men were drafted into forced-labor units. In 1942 Hershko's father, a teacher at Karcag's Jewish school, was sent with one to the Russian front, where most of the men died. Captured by the Soviets, he was held as a forced laborer until 1946, and his family did not know for four years whether he was alive. After Germany occupied Hungary in March 1944, about 437,000 Jews were deported in eight weeks, most to Auschwitz. Six-year-old Avram, his mother, brother, paternal grandparents and aunts were held in a ghetto in Karcag and then in a crowded ghetto in Szolnok. In what Hershko calls a random event, they were put on one of the few trains that went to Austria instead. Historians count 2,567 people sent from Szolnok to the Strasshof camp near Vienna in late June 1944, part of a diversion of about 15,000 Hungarian Jews to forced labor that followed talks between Adolf Eichmann and the rescue negotiator Rezső Kasztner. The family worked near Vienna until Soviet troops freed them in spring 1945. His mother's parents were murdered, as were almost two-thirds of Karcag's Jews. In 1950 the family moved to Israel as poor immigrants and had to learn Hebrew.

  • 1938

    Discrimination

    Hungary's 1920 numerus clausus law limited Jewish university enrollment. Three main anti-Jewish laws passed from 1938 to 1941 set job quotas, defined Jews by race and banned marriage with non-Jews.[14]

  • 1942

    Persecution

    His father was taken into a Jewish forced-labor unit and sent to the Russian front, where most of his group died. Captured by the Soviets, he was a forced laborer until 1946; for four years the family did not know whether he was alive.[2],[14]

  • 1944

    Holocaust survivor

    At six he was confined with his family in the Karcag and Szolnok ghettos, then deported to forced labor in a village near Vienna rather than to Auschwitz. They were freed by the Soviet Army in spring 1945.[2],[14],[16]

  • 1944

    Family killed

    His maternal grandparents were murdered in the Holocaust, along with almost two-thirds of the Jews of Karcag.[2]

  • 1950

    Poverty

    The family arrived in Jerusalem as poor immigrants who had to learn Hebrew. His parents still paid for a private school, which Hershko suspected took most of his father's salary.[2]

Jewish background

Both parents JewishIdentified as Jewish, secular

Hershko was born Herskó Ferenc into a Jewish family in Karcag, Hungary. His father, Moshe, taught at the town's Jewish elementary school; his mother, Shoshana (Margit), gave English and piano lessons. The family was persecuted as Jewish: his father was sent to a Jewish forced-labor unit, and Avram, his mother and brother were deported in 1944. His mother's parents were murdered in the Holocaust. In 1950 the family moved to Israel, where he took the name Avram and studied subjects ranging from mathematics to Talmud at school. His career has been based at the Technion in Haifa. We found no statement by him about his religious practice.[2],[35]

Key dates

  1. December 31, 1937

    Born Herskó Ferenc in Karcag, Hungary, a town with nearly 1,000 Jews. His father teaches at the Jewish elementary school.[1],[2],[35]

  2. 1942

    His father is taken into a Jewish forced-labor unit and sent to the Russian front. Captured by the Soviets, he returns only in 1946.[2]

  3. 1944

    Held in the Karcag and Szolnok ghettos, then deported with his mother and brother to forced labor near Vienna. Soviet troops free them in spring 1945.[2],[16]

  4. 1950

    The family emigrates to Israel and settles in Jerusalem.[2],[35]

  5. 1956

    Enters the Hebrew University-Hadassah Medical School, then Israel's only medical school. In 1960 he starts research with the biochemist Jacob Mager.[2]

  6. 1969

    Earns his PhD after an MD and army service as a physician, then joins Gordon Tomkins in San Francisco, where he finds that breaking down a specific enzyme needs energy.[2],[4],[11]

  7. 1971

    Returns to Israel to head biochemistry at the Technion's new medical school in Haifa, housed in an old monastery.[2],[7]

  8. 1978

    With his student Aaron Ciechanover, finds that protein breakdown needs a small heat-stable protein, APF-1, later identified as ubiquitin. He spends 1977-78 in Irwin Rose's lab.[2],[5],[6]

  9. 1980

    Hershko, Ciechanover and Rose report that many copies of APF-1 are attached to proteins marked for breakdown. The same year others identify APF-1 as ubiquitin.[5],[6],[8]

  10. 1983

    His lab isolates the three enzymes, E1, E2 and E3, that attach ubiquitin to target proteins.[5],[9]

  11. 1995

    Reports the cyclosome, a large ubiquitin-tagging complex that marks cyclins for destruction so cells can finish dividing.[4],[10]

  12. 2000

    Shares the Lasker Award for Basic Medical Research with Aaron Ciechanover and Alexander Varshavsky.[11],[12]

  13. 2003

    The US approves bortezomib (Velcade), the first drug that blocks the proteasome, for multiple myeloma.[17],[18]

  14. October 6, 2004

    Awarded the Nobel Prize in Chemistry with Aaron Ciechanover and Irwin Rose for the discovery of ubiquitin-mediated protein degradation.[1],[3],[6]

Sources

  1. 1.Avram Hershko - Facts · NobelPrize.org (Nobel Prize Outreach)
  2. 2.Avram Hershko - Biographical (from Les Prix Nobel 2004) · NobelPrize.org, 2005
  3. 3.The Nobel Prize in Chemistry 2004 - Press release · NobelPrize.org (Royal Swedish Academy of Sciences), 2004
  4. 4.The Ubiquitin System for Protein Degradation and Some of Its Roles in the Control of the Cell Division Cycle (Nobel Lecture, 8 December 2004) · NobelPrize.org, 2004
  5. 5.The Nobel Prize in Chemistry 2004 - Popular information · NobelPrize.org (Royal Swedish Academy of Sciences), 2004
  6. 6.Advanced information on the Nobel Prize in Chemistry, 6 October 2004: Ubiquitin-mediated proteolysis · Royal Swedish Academy of Sciences (via NobelPrize.org), 2004
  7. 7.Transcript from an interview with Avram Hershko (Lindau, July 2007) · NobelPrize.org, 2007
  8. 8.Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis (Hershko A, Ciechanover A, Heller H, Haas AL, Rose IA) · Proceedings of the National Academy of Sciences (via PubMed), 1980
  9. 9.Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown (Hershko A, Heller H, Elias S, Ciechanover A) · Journal of Biological Chemistry (via PubMed), 1983
  10. 10.The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis (Sudakin V et al., Hershko A) · Molecular Biology of the Cell (via PubMed Central), 1995
  11. 11.Avram Hershko - faculty profile · Technion Rappaport Faculty of Medicine
  12. 12.2000 Winners - Lasker Awards · Lasker Foundation, 2000
  13. 13.Avram Hershko - Wolf Prize Laureate in Medicine 2001 · Wolf Foundation, 2001
  14. 14.The Holocaust in Hungary · United States Holocaust Memorial Museum, Holocaust Encyclopedia
  15. 15.FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer · US Food and Drug Administration, 2026
  16. 16.Jews in a 'Judenrein' City: Hungarian Jewish Slave Laborers in Vienna (1944-1945) (Frojimovics K, Kovács É) · Hungarian Historical Review 4, no. 3, 2015
  17. 17.Development of proteasome inhibitors as research tools and cancer drugs (Goldberg AL) · Journal of Cell Biology (via PubMed Central), 2012
  18. 18.Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy (Kane RC, Bross PF, Farrell AT, Pazdur R) · The Oncologist (via PubMed), 2003
  19. 19.Bortezomib or high-dose dexamethasone for relapsed multiple myeloma (Richardson PG et al., APEX trial) · New England Journal of Medicine (via PubMed), 2005
  20. 20.FDA Approves VELCADE (bortezomib) for Injection for Previously Untreated Patients with Mantle Cell Lymphoma · Takeda Pharmaceutical Company, 2014
  21. 21.New VELCADE Data Highlight Treatment's Versatility and Its Continued Role as a Backbone of Multiple Myeloma Therapy · Johnson & Johnson, 2013
  22. 22.Millennium over-delivers on 2007 goals and financial guidance (press release, Form 8-K Exhibit 99.1) · Millennium Pharmaceuticals via US Securities and Exchange Commission, 2008
  23. 23.FDA Approves New KYPROLIS (carfilzomib) Combination Regimen With DARZALEX FASPRO and Dexamethasone · Amgen, 2021
  24. 24.Multiple myeloma fact sheet (GLOBOCAN 2024) · International Agency for Research on Cancer, Global Cancer Observatory
  25. 25.Cancer Stat Facts: Myeloma · National Cancer Institute, SEER Program
  26. 26.Improved survival in multiple myeloma and the impact of novel therapies (Kumar SK et al.) · Blood (via PubMed Central), 2008
  27. 27.Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib (Richardson PG et al.) · Journal of Clinical Oncology (via PubMed), 2006
  28. 28.Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma (Moreau P et al.) · Lancet Oncology (via PubMed), 2011
  29. 29.Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis (Waxman AJ et al.) · JAMA Oncology (via PubMed), 2018
  30. 30.Bortezomib monotherapy for relapsed multiple myeloma (Technology appraisal guidance TA129) · National Institute for Health and Care Excellence (NICE), 2007
  31. 31.Molecular kiss of death · Nature News, 2004
  32. 32.Varshavsky's contributions (letter; Baumeister W et al., 29 authors) · Science (via PubMed), 2004
  33. 33.Avram Hershko Talks Cancer Research, Winning the Nobel and His Grandchildren · Jewish Journal, 2018
  34. 34.The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer (Lin X, Xiang H, Luo G) · Drug Discovery Today (via PubMed), 2026
  35. 35.Avram Hershko · Jewish Virtual Library
  36. 36.[Incidence and risk of peripheral neuropathy caused by intravenous and subcutaneous injection of bortezomib] (Liu ZQ et al., meta-analysis of 4 RCTs; Chinese with English abstract) · Zhongguo Shi Yan Xue Ye Xue Za Zhi (PubMed record), 2019
  37. 37.Efficacy and safety of subcutaneous versus intravenous bortezomib in multiple myeloma: a meta-analysis (Hu B et al.) · International Journal of Clinical Pharmacology and Therapeutics (PubMed record), 2017
  38. 38.Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline (Richardson PG et al.) · British Journal of Haematology (PubMed record), 2009

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