Harald Zur Hausen DSc, MD
German Cancer Research Centre, Heidelberg, Germany
After defining cancers in which the Epstein-Barr virus (EBV) could be found, his research team made a series of key observations that linked human papillomaviruses (HPV) to cervical cancer. This malignancy is a common cancer of women, particularly in the developing world, where in many countries it accounts for even more deaths, and at an earlier age, than breast cancer (1). Prof. zur Hausen's contributions include: 1) finding there are multiple HPV genotypes; 2) molecularly cloning HPV16 and HPV18 genomes and showing their DNA is present in a majority of cervical cancers; 3) observing a portion of the HPV genome is integrated in tumors, with preferential retention and expression of the E6 and E7 genes, thus implicating them as the principal viral oncogenes and suggesting that their continued expression contributed to the tumorigenic phenotype.
Prof. zur Hausen received his MD in 1960 from the University of Dusseldorf. After receiving further medical training, he was a research fellow first at the University of Dusseldorf 1962-1965, and then at the Children's Hospital of Philadelphia, 1966-1969, where he worked under Prof. Werner Henle. In 1969, he returned to Germany, at the University of Wurzburg, as a Senior Scientist at the Institute for Virology. During 1972-1977, he was the Chairman and Professor in the Institute for Clinical Virology at the University of Erlangen-Nurnberg, and then during 1977-1983 the Chairman and Professor at the Institute for Virology at the University of Freiburg. From 1983 until 2003, he was the Scientific Director and Chairman of the Management Board of the German Cancer Research Center (DKFZ) in Heidelberg. In 2003, he became an emeritus professor at the German Cancer Research Center.
Professor zur Hausen's five most important publications are listed below as citations 2-6. He has received many prestigious awards for his research, as listed in his curriculum vitae. These include, among others, the Robert Koch Prize and Medal in 1975, the Charles Mott Prize from the General Motors Cancer Research Foundation in 1986, the Paul Ehrlich-Ludwig Darmstatter Prize in 1994, the Virchow Medal from the University of Wurzburg in 2000, the San Marino Prize for Medicine in 2002.
Prof. zur Hausn's laboratory has made several particularly noteworthy findings in papillomavirus research. The earliest was the recognition that there are multiple HPV genotypes, particularly that the HPVs that caused non-genital warts and those that caused genital warts might be distinct (2,3). Prior to his studies, it was believed that there might be a single HPV, as it had been shown in the first part of the 20th century that cutaneous warts could be induced with filtrates from genital or laryngeal warts.
His most important finding was the identification and molecular cloning of the HPV16 and HPV18 genomes, and the associated demonstration that a majority of cervical cancers contained DNA that hybridized under stringent conditions to probes from HPV16 or HPV18 and that an even higher proportion of cervical cancers would hybridize to these probes under less stringent conditions (4,5). These observations strongly implied: 1) papillomaviruses were etiologically involved in this cancer; 2) infection by more than one HPV type could result in cervical cancer; and 3) there were additional related HPV types that also caused cervical cancer. Indeed, subsequent research has indicated that infection by more than 10 other HPVs that are phylogenetically related to HPV16 and HPV18 are also in cervical cancer. HPV16 and 18 are the most oncogenic, accounting for about 70% of cervical cancer (6).
The third critical finding was that the HPV DNA was integrated into the host genome in cervical cancer cell lines and the associated demonstration that the viral E6 and E7 genes were preferentially retained and expressed in the tumors (6). These observations provided a mechanism for the efficient transfer of viral DNA progeny cells, implied that viral gene expression might be required for maintenance of the tumorigenic phenotype, and that E6 and E7 probably represented key viral oncogenes.
Except for the recognition that there are multiple HPV types, which was also made at the same time by Gerard Orth's group (7,8), Prof. zur Hausen and his colleagues probably deserve exclusive credit for the above accomplishments with HPV. I believe the quality and uniqueness of his scientific contributions merit his receiving the Gairdner Award as an individual. His work is even more noteworthy because it was carried out when there was considerable skepticism whether viruses in general, and EBV and HPV in particular, caused any common cancers. The findings related to HPV16 and HPV18 formed the basis for subsequent epidemiologic studies confirming that infection by a subset of HPV types, most notably HPV16 and HPV18, accounts for virtually all cervical cancers (9). In addition to the role of HPV in cervical cancer, other evidence has led to the conclusion that a substantial proportion of several additional types of cancer are also caused by HPV infection (reviewed in (10)). These include various genital cancers (such as vulvar and penile cancers), anal cancers, and head-and-neck cancers. Almost all the HPV-positive cancers contain HPV16 or HPV18. The epidemiologic and molecular studies in the field were aided greatly by Prof. zur Hausen's policy of rapidly distributing upon request the HPV DNA genomes that his laboratory had cloned.
Prof. zur Hausen has continued to run a highly productive laboratory since making the above seminal findings, publishing an average of more than 5 papers per year. Some of the more important findings made during this period include: 1) finding that most Buschke-Loewenstein tumors, which are large but low-grade malignant penile tumors, contain HPV6 or HPV11, which usually do not cause malignancy at other sites; determining that E6 and E7 expression in cervical cancer cell lines is required for maintaining the transformed phenotype; finding that HPV DNA in cervical tumors may be integrated near the c-Myc oncogene and be associated with its activation; the isolation of several new HPV types and their clinical importance; epidemiological studies delineating the prevalence of genital HPV infection and the risk of progression dysplasia or cancer; identification of cellular transcription factors that interact with the main HPV promoter; and the role of AP-1, Fos, and Fra-1 in regulating HPV transcription. He has also been a highly sought after and effective spokesman for the papillomavirus research community and for the role of viruses in human cancer.
It would be particularly appropriate for Prof. Zur Hausen to receive the Gairdner award at this time. His pioneering research has now led to at least two important clinical applications. The rationale for developing the preventive papillomavirus vaccine, which has recently been licensed, depended directly on Prof. zur Hausen's research linking papillomaviruses to cervical cancer. The vaccine even targets the HPV types that Professor zur Hausen cloned. The use of HPV DNA testing as a primary cervical cancer screening technique is also derived from Prof. zur Hausen's research. Although the importance of this clinical advance is less widely appreciated, it could also have substantial public health implications. The vaccine only has the potential to protect the next generation of women, as it not expected to reduce the risk of cancer in women who are already infected with the HPV types in the vaccine. At any time, there are more than 3 million currently infected women in the world who, if cervical cancer screening implementation is not changed, are destined to die of their disease. There is great hope that an inexpensive, but robust, HPV DNA test will soon be available that could be used to help the current generation of infected women in the developing world, where 80% of cervical cancers occur.