Research Profile

by Hanna Kurlanda-Witek


Harald zur Hausen

Nobel Prize in Physiology or Medicine in 2008 for “his discovery of human papilloma viruses causing cervical cancer”.

Harald zur Hausen was born on 11 March 1936 in Gelsenkirchen-Buer, the youngest of four children. He was interested in science as a child, but the bombing raids of the Second World War forced schools to close, disrupting his primary school education. Zur Hausen studied medicine at the University of Bonn and attended courses in biology for the first two years of study. He spent a year at the University of Hamburg and at the Medical Academy in Düsseldorf, graduating in 1960. By this time, zur Hausen was convinced he wanted to become a researcher, yet he decided to obtain his medical license. During the next two years of his medical internship he became particularly interested in gynaecology and obstetrics, but eventually chose to focus on research at the Institute of Microbiology at the University of Düsseldorf. The four years zur Hausen spent there were not particularly fruitful and often frustrating. Zur Hausen studied the influence of the vaccinia virus on modifications in mouse chromosomes, but as no one else at the institute was working on the topic, he lacked guidance and appropriate hands-on training in molecular biology. Luckily, the laboratory of the virologists Werner and Gertrude Henle at the University of Philadelphia wrote to the Institute, offering a position for a German fellow. The Institute’s director couldn’t think of anyone to recommend and threw the letter away, but later casually mentioned it to zur Hausen. He recalls, “I fished the letter out of the trash can, and went to Philadelphia.” Much later, zur Hausen wrote to the Henles that this turned out to be the most important decision of his scientific life.

Zur Hausen and his young family moved to Philadelphia in 1966, where he joined the Henles’ laboratory at the Children’s Hospital. He began to work on the Epstein-Barr virus (EBV), a herpes virus, which had been cultured and identified by Michael Epstein and Yvonne Barr in the UK in 1964. Epstein had attended a lecture given by Denis Parsons Burkitt, who had identified a head and neck cancer in African children, now known as Burkitt’s lymphoma. Epstein believed the disease could be caused by a virus and asked Burkitt for a tissue sample. The Henles received cell cultures from Epstein and colleagues. What was puzzling was that the virus was undetectable in cells from thawed biopsies of Burkitt’s lymphoma. Zur Hausen suspected that the host cells incorporate the DNA of the virus, which becomes undetectable by the immune system and, with time, activated in a small number of cells. During his fellowship in Philadelphia, he also worked on adenovirus type 12 to acquaint himself with modern-day molecular methods and established the presence of EBV in Burkitt’s lymphoma cells using an electron microscope. Zur Hausen returned to Germany in 1969 to start his own research group at the Institute for Virology at the University of Würzburg. He was set on focusing on EBV and how its DNA is present in every cell of Burkitt’s lymphoma. In 1970, the group published their results in Nature in a paper titled, “Presence of EB virus nucleic acid homology in a “virus-free” line of Burkitt tumour cells”. This was the first study that demonstrated that a virus can become part of a cell’s genome and can then induce the cell to develop into a tumour. Three years later, another important paper was published, showing that EBV DNA also caused nasopharyngeal cancer and existed in epithelial carcinoma cells.

In 1972, zur Hausen became professor and chairman of the Institute of Clinical Virology, a new research institute in Erlangen-Nuremberg. Here, zur Hausen shifted his focus to cervical cancer, a topic that sparked his interest while still a research fellow in Philadelphia. At that time, the dominant view among virologists was that cervical cancer was caused by the herpes simplex type 2 virus. Zur Hausen wondered whether the human papilloma virus (HPV), responsible for ordinary skin warts, could also cause cervical cancer, a leading malignant cancer in women. There were some hints in papers that linked human warts to cancer, such as the 1967 paper by Rowson and Mahy, where the authors suggested that all human warts were caused by the papilloma virus, but because the virus will not grow in tissue cultures and is very difficult to isolate from warts themselves, this line of study was treated as a dead end by most virologists. Famously, in 1974, zur Hausen presented his views at an international conference on cancer in Key Biscayne, Florida, but his results stipulating that the herpes simplex type 2 virus DNA was absent in cervical cancer biopsies, but that the cancer may be caused by HPV, was largely rejected. It would be many years before he would be able to back his claims with well-grounded results. Zur Hausen and his team set forth to extract papilloma virus DNA from genital warts, which proved to be a very laborious process, as only fragments of the viral DNA were incorporated in host cells. It was apparent that there were many types of HPV, some which caused cervical cancer, and others which rarely caused such malignant conversions. By this time, zur Hausen was chairman of the Institute of Virology at the University of Freiburg, and it was here that an important sequence of discoveries was made. In 1979, two members of zur Hausen’s team, Lutz Gissmann and Ethel-Michele de Villiers, managed to isolate and clone the virus from a genital wart. However, the virus, HPV-6, was not found in cervical cancer cells, but it was helpful in isolating another virus, HPV-11, from a laryngeal papilloma. HPV-11 was then used as a probe, and matching DNA in 1 out of 24 cervical cancer biopsies was found. Soon afterwards, Mathias Dürst, a student in zur Hausen’s lab, found a new fragment of viral DNA in a cancer biopsy. In 1983, after obtaining a clone of this virus, HPV-16, it was found to exist in more than half of cervical cancer cells. One year later, another high-risk strain, HPV-18, was identified, now known to cause approximately 20% of cervical carcinoma cases. Together, HPV-16 and HPV-18 are responsible for over two-thirds of cancers of the cervix and oropharynx (the back of the throat), half of vulvar and penile cancers and 80% of anal cancers. To date, over 200 types of HPV have been discovered.

Further studies in the second half of the 1980s confirmed the mechanism of two viral oncogenes, E6 and E7 – their transcription in cancer cells and cell transformation, leading to tumour growth in both animal and human cells. Despite the increasing evidence, pharmaceutical companies approached by zur Hausen in the 1980s failed to see the profitability of a vaccine for cervical cancer. The first vaccine against HPV wasn’t approved until over 20 years later, in 2006.

Zur Hausen believes that the vaccine could have been released much earlier. Until the approval of the first vaccine, the only method of cervical cancer prevention was the Pap smear, named after Georgios Papanicolaou, a Greek pathologist, who devised the method of microscopically classifying exfoliated cells from the cervix. Since the introduction of the Pap smear in the United States in the 1940s, cervical cancer rates have dropped by over 60%. Yet, the disease is far from eliminated. Particularly due to poor screening procedures in less developed countries, cervical cancer is the third most prevalent cancer among women, with over 500,000 cases reported worldwide each year, 85% of which occur in less developed countries. According to the World Health Organization, 71 countries have incorporated vaccination against HPV for girls into their national immunisation programmes, and eleven countries have also introduced routine vaccination for boys. The target age group for vaccination is 9-14 years of age, as the time period between infection with HPV and cancer development is approximately 20 years. A new nine-valent vaccine has been introduced in 2014, protecting against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58. It is now known that four out of five women will become infected with HPV at some point in their lives, yet the clear majority of these infections will pass without any symptoms. Only persistent infections may lead to tumours. While the risk rises with some factors such as smoking and immunosuppression, and in those infected with HIV, the presence of HPV is enough to cause cancer over time. Once those vaccinated will reach middle age, further epidemiological studies will demonstrate the efficacy of the vaccine in limiting the spread of HPV. Zur Hausen has also encouraged pharmaceutical companies to lower the cost of the vaccines in developing countries.

Zur Hausen was awarded the Nobel Prize in Physiology or Medicine in 2008. By this time, he had retired from the German Cancer Research Centre (Deutsches Krebsforschungszentrum) in Heidelberg, where he was scientific director for 20 years. However, zur Hausen is still active in research, focusing on infections associated with human cancers. Over 20% of cancer incidence is the result of an infection, caused by either viruses, bacteria or parasites. However, additional genetic or epigenetic modifications are necessary for the cancer to surface; the infectious agents will not cause cancer on their own. It is possible that other common cancers, such as breast or colon cancer, are also caused by infections. One of zur Hausen’s research interests is the link between red meat (particularly dairy cattle) consumption and an increase in colorectal, breast and even lung cancers. His hypothesis is that viral agents present in red meat cause infections of the intestinal tract, which may lead to cancer.

“Keep your eyes open,” zur Hausen advised his audience during his lecture in Lindau in 2011. The field of cancer virology is constantly evolving, and as zur Hausen himself can affirm, sometimes previously overlooked clues and unpopular theories, given time and persistence, can lead to great discoveries. Focusing our attention on the sidelines and dead-ends of a research field could eventually obliterate some types of cancer.


http://www.academia.dk/Blog/wp-content/uploads/harald-zur-hausen.pdf

http://apps.who.int/iris/bitstream/10665/255353/1/WER9219.pdf?ua=1

https://www.cdc.gov/cancer/hpv/statistics/cases.htm

http://www.fiercepharma.com/pharma-asia/interview-nobel-winner-harald-zur-hausen-on-vaccines-and-need-for-basic-research

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2008/hausen-bio.html

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2008/hausen_lecture.pdf

http://www.philly.com/philly/business/jobs/industries/healthcare/20081006_UNCOVERING_A_VIRAL_VILLAIN.html

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-59702010000500004

Adegoke, O., Kulasingam, S., and Virnig, B. (2012). Cervical cancer trends in the United States: a 35-year population-based analysis. Journal of Women’s Health 21(10), pp. 1031-1037.

Huang, M.S., Tarbell, N.J. and Weinstein, H.J. (2012) Chapter 8: Non-Hodgkin Lymphoma. In: Pediatric Radiation Oncology

Tan, S.Y. and Tatsmura, Y. (2015) George Papanicolaou (1883-1962): Discoverer of the Pap smear. Singapore Medical Journal 56(10), 586-587.

zur Hausen, H. (2009) Papillomaviruses in the causation of human cancers – a brief historical account. Virology 384 (2), pp. 260-265.


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