INTERVIEW

A fundamental researcher

Harald zur Hausen – “Since we already had the genomic key to the HPVs, the idea of developing vaccines was constantly in our mind.”
Harald zur Hausen – “Since we already had the genomic key to the HPVs, the idea of developing vaccines was constantly in our mind.”

The Nobel Prize in Medicine in 2008 turned the spotlight on three European pioneers who have contributed decisively to combating two major infectious scourges. They are French scientists Luc Montagnier and Francoise Barre-Sinoussi, who discovered the HIV viruses responsible for AIDS, and German virologist Harald zur Hausen, who identified human papillomaviruses (HPV) as the cause of cervical cancer. We interviewed the man who helped create the first vaccines against this cancer.

Your Nobel Prize crowns a life spent entirely on fundamental research into cancer, and particularly the infectious viruses that cause it.
What set you on this path?

Back when I was doing my doctorate in medicine in the ’60s, I became interested in what were then the very beginnings of research into the role of viruses in causing cancer. At the time, although the infectious origin of certain cancerous animal tumours had already been certified since the beginning of the century, we were still groping our way down a small number of hypothetical avenues to try and understand the viral processes that might be involved in humans. I started working with Gertrude and Werner Henle in the United States on Burkitt’s lymphoma(1). In 1964 English biologists Michael Epstein and Yvonne Barr identified its association with the EBV herpes virus carrying their name. For me the central issue was the role played by this virus in the genome of epithelial cells. Returning to Germany, I was able to set up a research group at the Würzburg Institute of Virology. We found that, when contamination occurs, DNA of the EBV virus can be identified in Burkitt’s lymphoma cells that are not yet producing viruses. It was an important result, showing that the subsequent growth of tumours resulted from a genomic cause.

It is from here that you directed your research towards cervical cancer?

Yes, it is from this background that I started working on this disease, which is the second most common cause of cancer in women. At the time, its possibly infectious origin was largely attributed to the simplex herpes virus, spread by sexual contact. But the DNA identification techniques then available to us did not yet confirm any result in this direction. Given these failures, my curiosity was roused by reports of ‘minor surgery’ (some dating back to the 19th century) of lesions caused by genital warts, which we associated with another infectious agent, then still poorly understood, the human papillovirus or HPV. Very few of us were then engaged in this path of research. In 1974, at a virology conference in Florida, my presentation on these genital warts, challenging the simplex herpes avenue of research, received a very cool reception…

Our group – I was then in charge of the University of Freiburg Institute of Virology – established a close collaboration with the group working under French researcher Gérard Orth. He shared the same intuition and was studying the hereditary aspect of HPV. Our two groups met several times to share and discuss results. It was a rich experience of cooperative competition.

The search was long. We first succeeded in extracting the DNA of HPV from plantar warts. But to our great disappointment we found no similar traces in the biopsies of genital warts. This finding, however, led us to understand that HPV exists in many different forms. In 1983, a student of our institute, Mathias Dürst, succeeded for the first time in cloning a new specific type, HPV 16, which turned out to be the direct source of infection for nearly half of all cervical cancers. Two years later we isolated HPV 18. Today we have nearly 115 distinct HPVs. But we had already identified the two HPV types that are responsible for 7 out of 10 cervical cancers(2).

In recent years, vaccination against these cancers, unique in its kind, has become increasingly common. Have you been associated with the long journey to this medical breakthrough?

Since we already had the genomic key to the HPVs, the idea of developing vaccines was constantly in our minds. In the ’80s, I approached a German pharmaceutical firm. We negotiated, but its decision-makers concluded that there was not a market. This was a somewhat frustrating period. We had widely disseminated the knowledge we had acquired, including sampling and laboratory protocols. I was a little naive at that time and I did not think in terms of industrial exploitation and technology transfer. Our results and methods were taken up and patented by others. In 1983, I founded the German Cancer Research Center, based in Heidelberg, which I headed for 20 years. Over this period, my cancer research horizons broadened considerably.

Some European media have expressed doubts about the appropriateness and effectiveness of the two preventive vaccines that have become available in recent years. What are your feelings on these reserves?

These vaccines represent a very significant innovation. They open for the first time a way to preventing cancer-linked genetic disorders that are passed on by infection These represent at least one cancer in five. This is a highly complex field of research because the possibilities of primary infection are vast and the actual triggering of the cancer phenomenon may occur very much later.

But such vaccines are as safe as all vaccines currently administered to children or adolescents. An Australian study, monitoring over 200 000 young girls, has found only minimal complications. As to effectiveness, even if this has been demonstrated in the laboratory, it is obviously too early to confirm this in terms of real-life results. Being preventive and nontherapeutic, these vaccines must be administered before the possibility of contamination, that is to say before the first sexual intercourse. The latency period is then very long. The carcinogenic activity of HPV can take more than two decades to declare itself. The real reduction in the incidence of cervical cancer cannot be observed before then.

The resistance of a section of public opinion to vaccination is irrational. In the case of HPV, which is linked to sexual transmission, cultural, social and religious taboos surrounding the permitted onset of sexual activity come into play. However, the immediate benefit of the vaccine against HPV is in preventing contamination and the appearance of lesions. It reduces the need for surgical ablation, often insufficient – 20 % of all lesions go unnoticed – and which can at times seriously reduce a woman’s fertility.

Cause for concern remains, however, the high cost of the vaccine, which is preventing the protection of women from developing countries, where more than 80 % of cervical cancers are identified, accounting for an estimated 250 000 deaths every year. This presents a real challenge for health policy economics. A challenge that emerging countries like China or India may perhaps be able to meet.

You have spent almost your entire research career without leaving the German university system. How do you perceive the concept of a European research area?

On my return from the United States, the German system of foundations gave me great freedom of means to fund research, the objectives of which were far from obvious in terms of results. In the U.S., research is extremely powerful, but it is directed more towards ‘promising’ areas. I would say that, until recently, Europe has often been able to give more room for the emergence of original ideas at the level of fundamental research. I do fear, however, that it may find itself carried away towards a more American style approach.

What role do you attribute to the European research programmes?

The German Cancer Research Center is very active in European projects. I have been involved, at a greater or lesser distance, in many projects in virology, genomics and molecular biology. But there is, I believe, a trap that we need to avoid, which is wanting to interconnect everyone at any cost by multiplying networks. Freedom of choice is essential to scientists. They know where their competitors are and where their allies, and they need to be able to decide themselves how to broaden the scope of their initiatives. Here in Heidelberg, for example, we are hosting for the first time a full team of researchers from Inserm in France who will be doing joint work with our own people. This type of strong interaction between teams of excellence – even if not without problems of cultural and material adaptation – seems very fruitful.

Interview by Didier Buysse.

  1. A form of cancerous tumour endemic among African children.
  2. The term ‘cervical cancer’ applies in medicine to cancer of the neck of the womb.

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