Virologist Professor Dr Ralf Bartenschlager, since 2002 Managing Director of the Department of Infectious Diseases, Molecular Virology, at Heidelberg University Hospital and Medical Faculty Heidelberg, and Coordinator of the ‘Infection, Inflammation and Cancer’ research programme at the German Cancer Research Center since 2014, is to receive the Lasker-DeBakey Clinical Medical Research Award, together with his colleagues Professor Charles Rice at Rockefeller University, New York, and Dr Michael Sofia at Arbutus Biopharma, USA. The Lasker Award, which the New York Lasker Foundation awards annually in four categories, is the most prestigious medical-scientific award in the USA and carries the unofficial title ‘American Nobel Prize in Medicine’. It is endowed with 250,000 USD. The award ceremony will take place on September 23, 2016 in New York. In 1999 Ralf Bartenschlager and this team succeeded for the first time in replicating a slightly modified form of the hepatitis C virus in the lab. This cell culture system was an essential prerequisite for the development of new, highly effective drugs. More than 95 percent of all patients with chronic infection with hepatitis C viruses can now be cured. Further information: www.lasker-bartenschlager.de
‘Today, chronic hepatitis C can be cured in the majority of patients. Without the replication system for this virus that was developed by Ralf Bartenschlager and his team, and that for the first time allowed us to test active agents, we would be in a far different place’, explains Professor Dr Guido Adler, Chief Medical Director of Heidelberg University Hospital, to underline the achievement of the award-winning virologist. Professor Dr Wolfgang Herzog, Dean of the Medical Faculty Heidelberg, adds: ‘It is a great honour that a scientist working in Germany has been chosen for the Lasker-DeBakey Clinical Medical Research Award. Congratulations to Professor Bartenschlager and his team!’ ‘The outstanding work of Ralf Bartenschlager and his team, and the recognition represented by this award, are a great asset to the medical campus in Heidelberg with its research focus on infectious diseases’, says Prof. Dr Hans-Georg Kräusslich, Speaker of the Department of Infectious Diseases and Vice Dean of Research.
The World Health Organization (WHO) estimates that approximately 130 million people worldwide suffer from chronic infection with hepatitis C viruses (HCV). The infection progressively destroys the liver, causing liver cirrhosis and liver cancer. The first drugs to be used in treatment merely controlled the liver inflammation; thanks to new drugs introduced in 2014, which selectively target HCV proteins, more than 95 percent of all patients can now be cured.
25 years of research into the hepatitis C virus
Ralf Bartenschlager began his scientific career shortly after the hepatitis C virus was first described genetically in 1989. After earning his doctorate at the Center for Molecular Biology of Heidelberg University, working in the laboratory of Prof. Heinz Schaller, he accepted a position in the pharmaceutical industry and began his research of HCV, which he continued after his transition to Mainz University Hospital in 1994. In many years of painstaking work, he and his colleague Dr. Volker Lohmann developed the first method for the reliable replication of HCV in human liver cell cultures.
‘For whatever reason, HC viruses isolated from patients don’t replicate in cell cultures, so we knew next to nothing about how they function’, says Bartenschlager. ‘Nevertheless we needed a cell culture system, because viruses are obligate intracellular parasites than can only be replicated and examined in living cells.’ The researchers came up with an ingenious solution: they created genetic HCV ‘mini-genomes’, also known as replicons. The trick was to equip these mini-genomes with a resistance gene that permitted the scientists to isolate those cells—from a pool of millions—in which the replicons replicated permanently and with high efficiency. In the following years, the team continued improving on this system.
For the first time, it was now possible to study the molecular properties of HCV, test potential drugs and identify new points of attack for antiviral therapies. One of them is the viral protein NS5A: ‘For a long time, we didn’t know anything about the function of NS5A. It doesn’t have any enzymatic activity, which is why nobody considered it as a potential drug target’, says the virologist. ‘It was the replicon cell system that proved NS5A to possess many functions, not unlike a Swiss Army Knife. Drugs that incapacitate NS5A are the most potent HCV blockers of all.’ Bartenschlager and his work group identified one mode of action of the protein at Medical Faculty Heidelberg and Heidelberg University Hospital, where he accepted the Chica and Heinz Schaller endowed professorship of ‘Molecular Virology’ in 2002. Nearly all of today’s therapies for chronic hepatitis C are based on a combination of an NS5A-blocker and one of two additional virostatic agents.
Diverse fields of research – numerous awards
‘All hepatitis C drugs available today were developed with this cell culture system. Due to the high cure rate, the development of drugs for HCV is basically complete’, explains Bartenschlager. That is why he has spent the major part of the last ten years gaining a better understanding of the life cycle of HCV. ‘After all, we don’t yet have a vaccination against hepatitis C, and we still don’t understand in detail how the therapies work or whether antiviral therapy resistance is a clinical problem. Fortunately, that doesn’t seem to be the case as much as we can tell for now.’ HCV research relies on further improved replication systems that Bartenschlager developed together with his Japanese colleague Takaji Wakita in 2004. Wakita had discovered a Japanese patient with a highly unusual HCV, whose genome was the first to complete its entire life cycle in cell culture. With the help of this virus isolate, scientists can now also study aspects like the assembly and release of newly formed virus particles, and the early stages of infection, i.e. how HCV enters the liver cell and how it spreads from cell to cell.
In the meantime, Ralf Bartenschlager—who has won the Lautenschläger Research Prize and the Robert Koch Prize in recent years and is a member of the Leopoldina National Academy of Sciences—has moved on to new fields of research. He is a founding member of the German Center for Infection Research (DZIF) and the Heidelberg Cluster of Excellence ‘CellNetworks’. He is heading the ‘Infection, Inflammation and Cancer’ research programme at the German Cancer Research Center since 2014. In addition, he serves as Speaker of the new Transregional Collaborative Research Centre 179 ‘Determinants And Dynamics Of Elimination Versus Persistence Of Hepatitis Virus Infections’, which was approved by the German Research Foundation in 2016. And Prof. Bartenschlager has lately diversified his scientific work in another direction: Among other interests, he is currently investigating the Dengue virus that infects nearly 390 million people worldwide every year and for which there is no specific therapy as yet.
Information on the Lasker Foundation: