Oncology · 1976
Harald zur Hausen hypothesis linking HPV to cervical cancer
In the mid-1970s, the dominant hypothesis in cervical cancer research held that herpes simplex virus type 2 was the causal agent. Epidemiological patterns in sexually active women seemed consistent with a herpesvirus, and the research community was largely oriented in that direction. Harald zur Hausen, then at the University of Erlangen-Nuremberg, took a different view. In 1976 he published his argument that human papillomavirus was the more plausible candidate, based on the biology of HPV's ability to persist episomally and integrate into host DNA.
The hypothesis was not warmly received. Zur Hausen moved to the German Cancer Research Center (DKFZ) in Heidelberg and spent the next seven years systematically cloning HPV types from cervical tumor specimens. His group identified HPV-16 in 1983 and HPV-18 in 1984, finding these specific types in a large proportion of cervical carcinomas while they were absent or rare in normal cervical tissue. The two types together account for roughly 70% of cervical cancers globally.
The molecular mechanism followed over the subsequent decade. Integration of HPV DNA into the host genome disrupts the viral E2 gene, removing repression of the E6 and E7 oncoproteins. E6 targets p53 for proteasomal degradation; E7 binds and inactivates the retinoblastoma protein. The result is loss of two critical tumor suppressor pathways simultaneously. This mechanistic clarity made HPV a more tractable vaccine target than almost any other oncogenic virus.
Zur Hausen shared the 2008 Nobel Prize in Physiology or Medicine with Luc Montagnier and Francoise Barre-Sinoussi, who had discovered HIV. His award attracted some controversy because several members of the Nobel selection committee had undisclosed ties to a company that held licenses related to HPV, but the scientific basis of the award was not disputed. The prophylactic HPV vaccines, Gardasil approved in 2006 and Cervarix in 2009, are built on virus-like particles assembled from the L1 capsid proteins of the high-risk HPV types his group identified.
WHO has set a target of 90% adolescent vaccination coverage globally as the threshold at which cervical cancer would effectively be eliminated as a public health problem. Countries with high vaccine uptake have already documented sharp declines in precancerous cervical lesions in vaccinated cohorts. The vaccines have also been extended to include HPV types responsible for oropharyngeal, anal, vulvar, and penile cancers, expanding the scope of zur Hausen's original observation far beyond its initial cervical focus.
Key People
- Harald zur Hausen — German virologist at DKFZ who identified HPV-16 and -18 in cervical tumors; 2008 Nobel laureate.
- Lutz Gissmann — DKFZ virologist who collaborated with zur Hausen on cloning HPV types from tumor tissue.
- Ian Frazer — Australian immunologist who co-developed the HPV virus-like particle vaccine technology.
- Jian Zhou — Molecular biologist who worked with Frazer to produce the L1-based virus-like particles for vaccine use.
Proc Natl Acad Sci USA, 1983
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