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

Nobel Prize in Chemistry · 2004

Aaron Ciechanover

He helped discover how cells tag unwanted proteins for destruction, knowledge that led to new drugs for a deadly blood cancer.

The Nobel citation: “for the discovery of ubiquitin-mediated protein degradation”
Born
October 1, 1947, Haifa, British Protectorate of Palestine (now Israel)
Affiliation at the time
Technion - Israel Institute of Technology, Israel

Chemistry prize

2004

Shared with 2 other laureates.

Age that year

57years

Born in 1947.

Headline credited impact

60,000–95,000people benefited

Patients treated with the proteasome-blocking cancer drug bortezomib worldwide (2003-2025). How it was built

Sources cited

31

Fact-checked September 24, 2026.

  • He and his doctoral supervisor, Avram Hershko, became Israel's first Nobel laureates in a natural science when they shared the 2004 chemistry prize.
  • The key protein turned up when the team boiled an extract of young red blood cells: the hemoglobin cooked into sludge, but the tiny protein they were after kept working.
  • The 1978 paper that started the field was rejected by the Journal of Biological Chemistry, and the journal that printed it misspelled his name as 'Ciehanover'.
  • He was orphaned at 16 and finished high school while living with an aunt in Haifa, spending weekends with his older brother in Tel Aviv.
  • As a navy doctor after the 1973 war, he sailed on a small missile boat from Haifa around Africa to Eilat, because the Suez Canal was blocked.

The breakthrough

Finding the cell's 'kiss of death' tag for unwanted proteins

Cells constantly make proteins, and they must also destroy them: worn-out ones, badly folded ones, and control proteins whose job is done. In the 1970s most scientists assumed this happened in the lysosome, a bag of digestive enzymes, and paid it little attention. But one puzzle stood out. Breaking down proteins inside cells used energy, even though breaking things apart should release energy.

Avram Hershko's team in Haifa, with Ciechanover as his graduate student, studied the puzzle in extracts of young red blood cells, which have no lysosomes. They split the extract into two parts and found that neither worked alone. When hemoglobin spoiled every attempt to purify one part, a colleague suggested boiling it. The hemoglobin cooked into sludge, but a small, heat-proof protein stayed active. In 1979 and 1980, working in Irwin Rose's lab in Philadelphia, they showed that the cell spends energy to fasten many copies of this protein, soon identified as ubiquitin, onto proteins it wants gone. A relay of three enzymes, called E1, E2 and E3, does the tagging. A protein shredder called the proteasome then destroys whatever carries the tag.

Think of an office where only papers with a red 'shred' sticker go into the shredder. Hundreds of different E3 enzymes decide which papers get stickers, so the cell can remove exactly the right protein at the right moment.[2],[5],[6],[8],[9]

“I also learnt to become a long books author rather than a short story writer”
Aaron Ciechanover, Nobel autobiography (2004), on what his mentors taught him: stick with one deep problem instead of chasing quick results.[2]

What it meant for humanity

Before this work, protein breakdown looked like simple garbage disposal. Ciechanover, Hershko and Rose showed it is a precise control system, and medicine followed. Cells use ubiquitin tags to switch off proteins that drive cell division, repair DNA and run immune defenses, and to weed out faulty proteins. The Nobel Prize's official explainer notes that up to 30% of newly made proteins fail the cell's quality checks and are destroyed this way. When the system goes wrong, disease follows. In cervical cancer, a papillomavirus protein hijacks a tagging enzyme to destroy p53, the cell's guard against cancer. In cystic fibrosis, the most common mutation makes a chloride channel fold badly, and quality control destroys it before it can work.

The clearest benefit so far is for people with multiple myeloma, a cancer of the bone marrow. Myeloma cells make huge amounts of antibody protein, some of it faulty, so jamming the proteasome hits them especially hard. Bortezomib (Velcade), the first drug to do this, was approved in the United States in 2003. By 2014 it had approval in more than 90 countries and had reached more than 550,000 patients. In a large trial, adding it to standard treatment cut the risk of death by 31%. A second proteasome blocker had reached about 200,000 patients by 2021. Scientists later found that lenalidomide, another myeloma drug, works by redirecting a tagging enzyme onto proteins the cancer needs. Drug makers now design 'degrader' drugs that aim the cell's own tagging machinery at disease proteins, and dozens were in clinical trials by 2024.

  • Bortezomib, the first drug to block the proteasome, won US approval for relapsed multiple myeloma in 2003. By 2014 more than 90 countries had approved it, and more than 550,000 patients had received it.[13],[19]
  • In the VISTA trial of 682 myeloma patients who could not have a stem-cell transplant, adding bortezomib cut the risk of death by 31% and raised median survival from 43 to 56 months.[17]
  • At the Mayo Clinic, patients who got at least one newer drug (thalidomide, lenalidomide or bortezomib) after relapsing from a stem-cell transplant lived about twice as long after relapse: 31 vs 15 months.[24]
  • A 2014 study found that lenalidomide, another myeloma drug, works by making a ubiquitin-tagging enzyme mark two proteins that myeloma cells depend on for destruction.[20]
  • Drugs designed to aim the tagging system at disease proteins had dozens of candidates in trials by 2024. In a 2025 phase 3 trial, one, vepdegestrant, held off breast cancers with ESR1 mutations longer than a standard drug (5.0 vs 2.1 months).[21],[25]
  • Lab studies help explain why myeloma is so sensitive: its cells churn out antibody protein, some of it misfolded, and blocking the proteasome lets that faulty protein pile up until the cells die.[26]

Impact in numbers

The main value of this discovery is understanding. It revealed a regulated destruction side of cell life, which Ciechanover estimates has almost 2,000 parts, and which shapes cell division, immunity, DNA repair, cancer and brain disease. Most of that cannot be counted in lives. We count one downstream result: proteasome-blocking drugs for multiple myeloma. We estimate that 1.3 to 2.1 million patients received bortezomib from 2003 to 2025, and that 70,000 to 190,000 of them suffered severe nerve damage from it. We credit Ciechanover with only 5% of each, and Hershko and Rose should get the same, because other scientists characterized the proteasome and companies and clinical researchers built and tested the drugs. The benefit is usually added time, not a cure: in one major trial median survival rose by about 13 months. We do not count lenalidomide, whose link to the tagging system was found years after it came into use, or the newer designed degrader drugs, most of which are still in trials.

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 the proteasome-blocking cancer drug bortezomib worldwide (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

    Same whole-outcome range as the Hershko and Rose profiles. Company counts: >300,000 bortezomib patients by Sept 2012 and >550,000 by Oct 2014. For Nov 2014-2025 (~11 yr) assume 60,000-120,000 new patients a year, about 30-60% of the ~188,000-196,000 new myeloma cases a year worldwide (GLOBOCAN). Low: 550k + 11 x 60k = 1.21M; high: 550k + 11 x 120k = 1.87M; rounded 1.2M-1.9M. Carfilzomib (~200,000 by 2021) is left out, since most of its users had bortezomib first. 'Benefited' here means treated: in VISTA, bortezomib cut death risk 31% (median survival 56 vs 43 months), but not every patient responds. Share 0.05, same for Hershko and Rose (0.15 together): the drug targets the proteasome, which others characterized, and companies and trialists developed it. Credited: about 60,000-95,000.[13],[14],[15],[16],[17],[19]

    Sources: Takeda Pharmaceutical Company; Johnson & Johnson (Janssen); Amgen; PubMed (US National Library of Medicine); PubMed (US National Library of Medicine); PubMed (US National Library of Medicine)

  • HarmLow confidenceRippleModeledHealth

    Patients with severe (grade 3 or worse) nerve damage from bortezomib worldwide (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.[18],[27],[28],[29],[30],[31]

    Sources: Journal of Cell Biology (PMC full text); Journal of Clinical Oncology (PubMed record); PubMed (US National Library of Medicine); 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

We found no misuse of the discovery itself. The harms lie in side effects of the drugs built on it, plus a question of credit. Bortezomib often damages the nerves of the hands and feet. In one trial, severe nerve damage affected 16% of patients given the drug by vein and 6% of those given it under the skin. Carfilzomib, a later proteasome blocker, carries warnings of heart failure and heart attacks, some fatal. These drugs buy time more often than they cure: myeloma still killed an estimated 121,000 people worldwide in 2022. On credit, the prize left out Alexander Varshavsky, who shared the 2000 Lasker Award with Hershko and Ciechanover. Six weeks after the announcement, 29 researchers in the field signed a letter in Science titled 'Varshavsky's contributions'.

  • Moderate

    Nerve damage from bortezomib

    Peripheral neuropathy, damage to the nerves of the hands and feet, is a common side effect of bortezomib. In a 2011 trial, severe (grade 3 or worse) neuropathy hit 16% of patients given the drug by vein and 6% given it under the skin. A 2014 retreatment study reported 6%.[13],[18]

  • Moderate

    Heart risks of carfilzomib

    The US label for carfilzomib (Kyprolis), a second-generation proteasome blocker, warns of new or worsening heart failure, heart muscle damage and heart attacks, including deaths, sometimes in patients whose hearts were normal before treatment.[15]

  • Minor

    Questions over who was left out of the prize

    Alexander Varshavsky shared the 2000 Lasker Award with Hershko and Ciechanover. The Lasker citation credits his work with Ciechanover showing the system at work in living cells, and his discovery of the first rules for which proteins get destroyed. In November 2004, 29 researchers signed a Science letter titled 'Varshavsky's contributions'.[9],[22]

Against the odds

Ciechanover grew up in a Jewish state, and he has said plainly that he never suffered persecution. His family's story shows why that was new. His parents left Poland as teenagers in the mid-1920s. He has said they were escaping rising antisemitism, and his Nobel memoir adds Zionist and religious reasons. Relatives who stayed in Poland were murdered in the Holocaust. He was born in Haifa in October 1947, months before Israel declared independence, into a war that he notes killed more than 1% of the new state's population. His father, a member of the pre-state Haganah defense force, worked in the Arab part of the city throughout the fighting, and the family waited on the balcony each day for him to come home. Then came personal loss. His mother died in 1958 and his father in 1964, leaving him an orphan at 16 with no money of his own. An aunt and his older brother took him in, and he chose medicine partly because it was a practical way to earn a living. After medical school he served three years as a military doctor, starting just after the 1973 Yom Kippur War. He turned down American offers to return to the Technion, where, he writes, the life sciences were long treated like stepchildren. In 2007 he cited insecurity, including Hezbollah rocket fire the year before, as one cause of Israel's scientific brain drain.

  • —

    Discrimination

    His parents emigrated from Poland to Palestine as teenagers in the mid-1920s. He has said they were escaping rising antisemitism; his memoir also stresses Zionist and religious motives.[2],[8]

  • —

    Family killed

    Members of his parents' families who stayed in Poland were murdered in the Holocaust, a loss he says overshadowed his parents' lives in Palestine during the war years.[2]

  • 1948

    War

    He was born in October 1947 into the war surrounding Israel's founding, which by his account killed more than 1% of the new state's population. His father, a Haganah member, risked his life going to work in the Arab part of Haifa.[2]

  • 1964

    Other

    His mother died in 1958 and his father in 1964, leaving him an orphan at 16 without financial support. An aunt and his older brother raised him through high school and medical school.[2],[8]

  • 1973

    War

    He served three years as a military physician, starting in the navy just after the 1973 Yom Kippur War, including a long voyage around Africa on a missile boat through waters bordered by hostile states.[2],[8]

  • 2006

    War

    In a 2007 interview he cited insecurity, including Hezbollah rocket attacks on Israel the year before, as one reason some Israeli scientists leave or hesitate to return.[7]

Jewish background

Both parents JewishCulturally Jewish

Ciechanover was born in Haifa to Bluma (née Lubashevsky) and Yitzhak Ciechanover, Jewish parents from religious families who had moved from Poland to British-ruled Palestine as teenagers in the mid-1920s. He describes a liberal modern Orthodox upbringing, with synagogue every Saturday, a kosher kitchen and all the Jewish holidays. As an adult he has taken regular lessons with a rabbinical scholar on Jewish law and medical ethics, and he collects Jewish cantorial music. He has called religion a matter of culture and morality, and has criticized religious leaders who use it to control people. Since the Nobel he has often spoken in small Jewish communities abroad.[2],[7],[8],[23]

Key dates

  1. October 1, 1947

    Born in Haifa, in British-ruled Palestine, to Jewish parents who had moved there from Poland in the 1920s.[1],[2]

  2. 1964

    His father dies, six years after his mother. Orphaned at 16, he moves in with an aunt in Haifa to finish high school.[2]

  3. October 1972

    While a medical intern, begins thesis research with the young biochemist Avram Hershko at the Technion in Haifa.[2],[3]

  4. 1973

    Starts three years of military service, first as a doctor in the navy's missile-boat fleet just after the Yom Kippur War, then in a medical research unit.[2],[3],[8]

  5. 1975

    Receives his M.D. from the Hebrew University and Hadassah medical school in Jerusalem, after an M.Sc. in 1970.[3],[4]

  6. November 1976

    Chooses research over a surgical career and begins doctoral studies on protein breakdown in Hershko's lab.[2]

  7. 1978

    Reports a heat-stable protein, APF-1, needed for energy-driven protein breakdown. It is later shown to be ubiquitin.[5],[12]

  8. 1980

    With Hershko and Irwin Rose, shows that cells attach many copies of APF-1 to proteins marked for destruction.[2],[5]

  9. 1981

    Earns his D.Sc. at the Technion and begins a postdoctoral fellowship with Harvey Lodish at MIT.[2],[3]

  10. 1984

    Turns down US offers and returns to the Technion's Faculty of Medicine to run his own lab.[2],[3],[7]

  11. 2000

    Shares the Albert Lasker Basic Medical Research Award with Hershko and Alexander Varshavsky.[9]

  12. May 2003

    US regulators approve bortezomib (Velcade), the first drug to block the proteasome, for relapsed multiple myeloma.[13],[19]

  13. 2003

    Receives the Israel Prize for biology.[11]

  14. October 6, 2004

    Awarded the Nobel Prize in Chemistry with Hershko and Rose for the discovery of ubiquitin-mediated protein degradation.[1],[4],[10]

Sources

  1. 1.Aaron Ciechanover - Facts · NobelPrize.org (Nobel Prize Outreach)
  2. 2.Aaron Ciechanover - Biographical (from Les Prix Nobel 2004) · NobelPrize.org, 2005
  3. 3.Aaron Ciechanover - Curriculum Vitae · NobelPrize.org, 2005
  4. 4.The Nobel Prize in Chemistry 2004 - Press release · NobelPrize.org (Royal Swedish Academy of Sciences), 2004
  5. 5.The Nobel Prize in Chemistry 2004 - Popular information · NobelPrize.org (Royal Swedish Academy of Sciences), 2004
  6. 6.Intracellular Protein Degradation: From a Vague Idea thru the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting (Nobel Lecture) · NobelPrize.org, 2004
  7. 7.Transcript of an interview with Aaron Ciechanover (Lindau, July 2007) · NobelPrize.org, 2007
  8. 8.A conversation with Aaron Ciechanover (Ushma S. Neill) · Journal of Clinical Investigation 123(10):4093-4094, 2013
  9. 9.Ubiquitin system for regulated protein degradation - 2000 Albert Lasker Basic Medical Research Award · Lasker Foundation, 2000
  10. 10.Nobel Prize Winners Mark 20th Anniversary · Technion - Israel Institute of Technology, 2024
  11. 11.Aaron Ciechanover - Faces of the Technion · American Technion Society
  12. 12.A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes (Ciehanover A, Hod Y, Hershko A; Biochem Biophys Res Commun 1978) - PubMed record · PubMed (US National Library of Medicine), 1978
  13. 13.FDA Approves VELCADE (bortezomib) Retreatment in Patients with Multiple Myeloma · Takeda Pharmaceutical Company, 2014
  14. 14.Subcutaneous VELCADE Approved In the EU for the Treatment of Multiple Myeloma · Johnson & Johnson (Janssen), 2012
  15. 15.FDA Approves New KYPROLIS (carfilzomib) Combination Regimen With DARZALEX FASPRO and Dexamethasone For Patients With Multiple Myeloma At First Or Subsequent Relapse · Amgen, 2021
  16. 16.The global multiple myeloma incidence and mortality burden in 2022 and predictions for 2045 (Mafra A et al., J Natl Cancer Inst 2025) · PubMed (US National Library of Medicine), 2025
  17. 17.Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone (San Miguel JF et al., J Clin Oncol 2013) · PubMed (US National Library of Medicine), 2013
  18. 18.Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma (Moreau P et al., Lancet Oncol 2011) · PubMed (US National Library of Medicine), 2011
  19. 19.United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy (Kane RC et al., Clin Cancer Res 2006) · PubMed (US National Library of Medicine), 2006
  20. 20.Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells (Krönke J et al., Science 2014) · PubMed (US National Library of Medicine), 2014
  21. 21.Targeted protein degradation: from mechanisms to clinic (Tsai JM et al., Nat Rev Mol Cell Biol 2024) · PubMed (US National Library of Medicine), 2024
  22. 22.Varshavsky's contributions (letter; Baumeister W et al., Science 2004;306:1290-2) - PubMed record · PubMed (US National Library of Medicine), 2004
  23. 23.Ageing, God and Lindau: An Interview with Aaron Ciechanover · Lindau Nobel Laureate Meetings, 2014
  24. 24.Improved survival in multiple myeloma and the impact of novel therapies (Kumar SK et al., Blood 2008) · PubMed (US National Library of Medicine), 2008
  25. 25.Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer (Campone M et al., N Engl J Med 2025) · PubMed (US National Library of Medicine), 2025
  26. 26.Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition (Meister S et al., Cancer Res 2007) · PubMed (US National Library of Medicine), 2007
  27. 27.[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
  28. 28.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
  29. 29.Development of proteasome inhibitors as research tools and cancer drugs (Goldberg AL) · Journal of Cell Biology (PMC full text), 2012
  30. 30.Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib (Richardson PG et al.) · Journal of Clinical Oncology (PubMed record), 2006
  31. 31.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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