Harald zur Hausen (1936 to 2023): Discoverer of human papillomavirus infection as the main cause of cervical cancer

In May, we lost Harald zur Hausen, a physician scientist and true pioneer. By molecular cloning the genomes for HPV16 and HPV18 in the mid-1980s, he and his team showed that human papillomavirus (HPV) infection was responsible for the vast majority of cervical cancers, which is one of the most common cancers worldwide. zur Hausen and his team also used cervical cancer cell lines to demonstrate the viral E6 and E7 genes, which are now recognized to be the main viral oncogenes, were preferentially retained and expressed in this cancer, thus providing insight into its virally induced molecular pathogenesis. These seminal discoveries led to zur Hausen being awarded the 2008 Nobel Prize in Physiology and Medicine (1). In addition, he was generous with providing the cloned viral DNAs to other investigators, at a time when this practice was less frequent, and possessed considerable administrative skills, ably leading the German Cancer Research Center (DKFZ) as its director for 20 years from 1983 to 2003.

Harald zur Hausen. Image credit: Beverly Mock (photographer).

The research conducted under zur Hausen’s direction was carried out by a dedicated team that was affiliated with him for many years. The team included Lutz Gissmann, Ethel-Michel DeVilliers—whom he married in 1993—Matthias Dürst, Michael Boshart, Harald Ikenberg, Elizabeth Schwartz, and others.

zur Hausen was born in 1936 in Gelsenkirchen-Buer, Germany (2). Although he was attracted to the idea of doing research, he decided to go to medical school and received his medical degree in 1960 from the University of Düseldorf. After two additional years of clinical training and three years for research at the University of Düseldorf, he decided to focus on virology and obtain more training in the United States. He became a post-doctoral fellow in 1966 at the University of Pennsylvania with the husband and wife team of Gertrude and Werner Henle, who had left Germany in the 1930s because Werner Henle was classified in Germany as non-Aryan and therefore ineligible for a faculty position (3). The study of oncogenic human viruses had only recently begun, with identification in 1964 of Epstein–Barr virus (EBV) from patients with Burkitt lymphoma, although several classes of animal viruses had been shown in the first half of the 20th century to be oncogenic. Zur Hausen’s experience with the Henles, where he studied both Epstein–Barr virus and morphologic cell transformation of hamster cells by an adenovrirus that did not cause cancer in humans, enabled him to start his own laboratory at the University of Wuerzburg in 1969, with the long-term focus to identify and characterize oncogenic viruses in humans. In the next decades, in addition to his research, he was selected for academic positions that carried progressively greater administrative responsibilities, at the University of Erlangen-Nuernberg (1972 to 1977), the University of Freiburg (1977 to 1983), and the DKFZ (1983 to 2003), where he became an emeritus professor in 2003.

The mid-1980s were pivotal for zur Hausen’s research. In the 1970s, zur Hausen and Canadian researchers had independently hypothesized that HPV infection could be an important cause of cervical cancer, which is one of the most common cancers of women worldwide (4, 5). At that time, however, retrospective evidence had suggested Herpes simplex virus type 2 infection could be the major cause, which was dispelled by a large prospective negative study as well as research from zur Hausen (6). Two important positive observations were that benign lesions caused by HPV were associated with several HPV types and that a rare syndrome of widespread warts that sometimes resulted in skin cancers was associated with still other HPV types (7). These findings raised the possibility that unknown HPV types could be responsible for cervical cancer.

The molecular cloning of HPV16 DNA and finding it in a majority of cervical cancer DNAs ushered in a new era of HPV research (8). The identification of HPV18 the next year further embellished the association of HPV with this cancer (9). Epidemiologic support for a causal role for HPV in this cancer required the development of sensitive but rigorous PCR-based systems for HPV DNA detection in small clinical samples of cervical dysplasia (10, 11). This role was widely accepted by the field by the early 1990s and then by others. Another conceptually important finding from zur Hausen was that the HPV16 and 18 E6 and E7 genes were the two viral genes regularly expressed in cervical cancer cell lines (12).

In yet another contribution to the field, the International HPV Reference Center (IHRC) was begun at the DKFZ in 1985, under the leadership of Ethel-Michel de Villiers, at a time when new HPV types appeared to be discovered almost monthly. By performing comparative analysis between putative new HPV types and all known HPV types, the IHRC served as a reliable arbiter of these viral DNAs and assigned authenticated new HPV types a number that was one higher than all previous isolates (13). After running the IHRC for more than 25 years, de Villiers and zur Hausen decided it was time for another institution to run the IHRC, which led to its transfer in 2012 to the Karolinska Institute, where it is led Joakim Dillner (14).

The discovery of HPV16 and 18 led to several other noteworthy advances, including the recognition that chronic HPV infection, predominantly by HPV16 & 18, was associated with several other HPV-associated cancers, including vulvar, vaginal, anal, penile, and oropharynx (15). In the United States, the incidence of oropharynx cancer is higher than cervical cancer, whose reduced incidence and mortality are mainly attributable to pap smear screening and follow-up. In another advance that built on zur Hausen’s work, Peter Howley and his colleagues determined that the E6 and E7 proteins bound and reduced the activity of several tumor suppressor proteins, of which the best known are P53 with E6 and PRB with E7 (16). The recognition of the medical importance of HPV infection led to the successful development of subunit HPV vaccines that can prevent the vast majority of HPV-associated cancers (reviewed in ref. 17). In addition, HPV-based screening for cervical cancer is replacing cytology-based screening because the former has greater positive and negative predictive values (18).

Thus, zur Hausen’s research identifying HPV as the main cause of cervical cancer, led other investigators to determine that HPV infection was associated with several other cancers, improve the molecular and epidemiologic understanding of how the precancers and cancers arise, and develop interventions to prevent their development. Quite a legacy.