01 April 2014 - PROFILE RALF BARTENSCHLAGER

Award Winner, without Airs and Graces

The hepatitis C research success story is also his story: Ralf Bartenschlager, a virologist at the Heidelberg Medical Faculty of Heidelberg University, has been researching the hepatitis C virus for over twenty years. He developed a cell culture system without which the new, highly effective drugs for this disease would not exist today.

Ralf Bartenschlager, Virologe am Universitätsklinikum Heidelberg

Ralf Bartenschlager, Heidelberg© DZIF

The hepatitis C virus (HCV) was first identified in 1989 through molecular cloning. Now, 25 years later, this viral infection, which if left untreated can lead to liver cirrhosis and liver cancer, is curable in 90 percent of cases. There are different drugs available to fight this infection, a success which could not have been envisaged during the first years after the discovery of the virus when it escaped closer investigation because it could not be cultivated in cell cultures. Ralf Bartenschlager pioneered the development of a reproducible cell culture system on the basis of a minigenome. “This minigenome, which Volker Lohmann and I created, was the result of five years of research work,” Bartenschlager remembers. “On several occasions we had been close to giving up”, the virologist admits, “because the word ‘patience’ is not part of my vocabulary. Nevertheless, I do have a certain ability to tolerate frustration,” he says with a smile. And in the end their efforts were rewarded – the cell culture system they developed formed the basis for all drugs available against hepatitis C today: A testing system for antiviral agents.

Ralf Bartenschlager had an interest in viruses right from the start. In 1990, in his PHD thesis at the University of Heidelberg, the young biologist investigated the P protein of the hepatitis B virus. As a post-doctorate, he initially worked at the Center for Molecular Biology of the University of Heidelberg before joining the pharmaceutical company Hoffmann-La Roche in Switzerland in 1991. His task: “To establish an HCV programme!” And he did this with great dedication. Four years later, he changed back to the university, because he did not only want to be a researcher, but also a dedicated father. “Had I stayed with Roche, I would have had to move across the globe with my three children several times by now.” This was too risky for him and so Bartenschlager, now 55 years old, declined Roche’s offer to move to England and accepted a call by the University of Mainz. He was allowed to take his reagents with him and develop them further. His first big breakthrough came in 1999 with the minigenome and his ‘habilitation’, the qualification to assume a professorship. In 2001, he was then appointed as Professor of Molecular Virology.

“My decision to take up an endowed professorship, funded by the Chica und Heinz Schaller Foundation, at the Ruperto Carola University of Heidelberg in 2002, was an easy one, even though I had several other offers at the time,” he says very modestly in passing. He is still sure, “Heidelberg definitely has the best campus, such a high concentration of life sciences within walking distance from each other is unique.” In addition to this, EMBL and the German Cancer Research Center are in close proximity. In Heidelberg, Bartenschlager took his next big step together with a Japanese researcher: He developed a complete replication system for the virus in cell culture based on an infectious HCV molecular clone that had been isolated by his Japanese colleague. The entire life cycle of the virus, from cell penetration to its replication and release, could now be reconstructed in the laboratory.

In the last years, further drugs against hepatitis C were developed with Bartenschlager’s cell culture system. For a long time, interferon and the virostatic agent ribavirin had been standard therapy, but in 2011 the protease inhibitors telaprevir and boceprevir came onto the market. Most recently these were followed by a new protease inhibitor (Simeprevir) and the polymerase inhibitor sofosbuvir. Besides these, the so-called NS5A inhibitors, which are highly potent and fast-acting, are also close to approval. NS5A is an HCV protein which plays an important role in viral replication. “With all these drugs we are basically done with drug development for hepatitis C,” the virologist thinks. However: “We still cannot say whether resistances may become a problem in daily treatment.” Thus, careful analysis is required. Also, adverse events of the different combination therapies, the use of these new therapies in hepatitis C patients with advanced liver disease, as well as monitoring treatment with biomarkers still require considerable further research.

Ralf Bartenschlager still sees a couple of important tasks ahead for the DZIF and his collaborative work with this association. “For example, we do not know exactly how the NS5A inhibitors work, even though many people will be treated with them in the near future.” And he believes that this knowledge is essential. There is also another important future task regarding HCV research: There is no vaccine against this infection, which often cannot be treated especially in developing countries: The drugs are available, but not affordable for those who need them most.

Besides hepatitis C, he is, of course, also involved in research on other hepatitis viruses. As Co-coordinator of the DZIF Thematic Translational Unit Hepatitis, he is carefully following the development of a new drug candidate called Myrcludex B. This is also being developed at the University of Heidelberg under the supervision of Prof Stephan Urban. Clinical studies will soon show whether Myrcludex B is efficacious in patients and will have a chance of getting into the market.

There cannot be much time left for hobbies and family with such a successful research career, can there? “It does fall a little short” Bartenschlager admits. However, his two daughters are already independent, and he shares a passion for sports with his ten year old son, so they get to do things together at weekends.

Most recently, a further new research perspective has opened up: Since 2014, Ralf Bartenschlager has also been Head of the newly established Division “Virus-associated Carcinogenisis” at the German Cancer Research Center. Both hepatitis B and C virus infections can cause liver cancer if they are not treated in time.

The virologist was recently awarded the financially generous Lautenschläger Research Award for his outstanding scientific achievements. It will probably not be his last award.



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