Research Focus

Research Focus -
35 years of progress
and future projects

Foundation for Liver Diseases

Foundation for Liver Diseases

University Clinic for Visceral Surgery and
Medicine (UVCM), Hepatology
Murtenstrasse 35
3008 Bern


Research: past 35-years and future moves

 



 
 

Summary

  • 1970: The only possible treatment for liver diseases: Prednisone
  • 2015: Hepatitis A is avoidable, hepatitis B is avoidable and treatable, hepatitis C is treatable, haemochromatosis is diagnosed by molecular genetics and treatable. Liver transplantation has become a routine surgical procedure.


This remarkable progress in the last 35 years has been made possible only thanks to research. Medical research covers essentially three main areas – all of which are present in our institute:

  • Basic research
  • Translational research
  • Clinical research


The Institute of Hepatology in Bern has always made major contributions and has introduced groundbreaking ideas to the field of hepatology. Only time will tell us, which of our current research projects will prove to be of most importance.

 


Cancer and angiogenesis

A new tumour suppressor and new treatment with an old drug promise greater understanding and better treatment of a deadly cancer.

 

Patients with advanced liver disease - especially due to hepatitis B or C - have an increased risk of developing hepatocellular carcinoma (HCC). The incidence of HCC is increasing: The mortality due to HCC has virtually doubled in the last ten years. Unfortunately, only a small percentage of patients can be cured. To improve this, we need new approaches in research. Our laboratory is working in two directions:

  • Basic research to provide a better understanding of the mechanisms driving HCC development.
  • Pre-clinical and clinical studies to improve treatment. Here, we focus on the vascular supply of the tumour; this approach has been shown to be very promising for other types of cancer and we could show that this might also be the case in HCC.

Through basic research we have discovered a new protein called Hint2, which plays an important role in the development of HCC. If the amount of this protein is comparatively low, the chances of survival for patients are small. The protein is localized in mitochondria (the power plants of liver cells) and plays an important role in the metabolism of a DNA building block, called adenosine. If a cell has less of this protein it will be more resistant to stress signals and - as a consequence - has a growth advantage. We try to understand the role of this tumour suppressor in cancer using new technologies, such as microarrays and proteomics and also work with animals, which lack the corresponding gene.

Tumour growth in Rat model of HCC

In order to develop new treatment methods we need an experimental rat animal model of HCC; tumour growth is measured by means of a magnetic resonance tomography (MRT). We could show that medicines, which have been used in the prevention of rejection after liver transplantation are also able to inhibit tumour growth and improve survival rates in animals. This is achieved by inhibition of new blood vessel formation. Consequently the tumour is deprived of its oxygen and nutrient supply (oxygen loss) and “starved out”. The effectiveness of these drugs is greater when combined with conventional chemotherapy.
We will follow-up on this approach in different clinical studies carried out in humans, and thus improve the chances for many patients who – until now - cannot be cured.
See article on tumour growth in a rat model of hepatocellular carcinoma, monitored by magnetic resonance imaging.
 


DESI - Desorption Electrospray Ionization - developed in Graham Cook's laboratory

New metabolic analytics for mass spectrometry in clinical laboratories 

Non-alcoholic fatty liver disease or NAFLD comprises a spectrum of conditions from the benign accumulation of triglycerides in hepatocytes (steatosis) progressing to end-stage cirrhosis and then finally hepatocellular carcinoma. The progressive form of NAFLD is non-alcoholic steatohepatitis (NASH), which is defined by the additional features of hepatocyte ballooning and parenchymal inflammation. The earlier diagnosis and detection of NAFLD patients who are at risk of developing NASH allows better targeted treatment. Currently, liver biopsy is a gold standard to precise histological diagnostic NASH including disease stage. However, the evaluation of liver biopsy tissue still lacks surrogate markers which are important for distinguishing NASH from other liver diseases. Moreover the heterogeneity of liver which consists of zonation is more difficult for result interpretations. Then it seems even more important to improve diagnostic methods and to get molecular diagnostic tests in order to help susceptible NAFLD patients prevent NASH developing.


The last 10 years from the rapid development of high-throughput technologies provided lots of knowledge in the field of NAFLD, including genomics, transcriptomics, proteomics and metabolomics. Therefore, OMICs signature biomarkers maybe considered for the diagnosis of this disease. However, these methods has limited by cost-effectiveness for clinical usage. The available analysis using mass spectrometry, in blood or tissue samples, such as metabolomics is certainly the most appropriate tool for use in the clinical setting. Basically, liver homogenates, serum or plasma is used for metabolomics studies, despite the analysis on these samples does not exhibit the distribution of metabolites information in liver tissue.

Recently, a new mass spectrometry imaging (MSI) technique called desorption electrospray ionization (DESI) provides rapid metabolomics information on proteins, lipids, and metabolites without damaging tissue or cellular morphology. Moreover this technique performs the analysis on spatial distribution and localization of metabolites directly from tissue samples. DESI-MSI is an ambient ionization technique which can be applied directly to tissue samples with a simple sample preparation. A single tissue section is imaged in positive and negative ion modes. As the droplets of the electrospray contact the surface of the tissue section, chemical constituents are desorbed and carried towards the inlet of a mass spectrometer. Ionization of the desorbed molecules occurs via the charge imparted onto the droplets. Then, the analyses and metabolomics data are generated using the mass spectrometer. DESI-MSI has been developed for cancer tissue diagnosis in various human tissues including breast, brain, kidney, bladder, gastrointestinal, prostate, and liver cancers. Therefore, regarding the ability to direct analysis of histological tissue sections DESI-MSI has great potential to developing a molecular NASH diagnosis tool. Hence, we intend to gather metabolomics and imaging data to target metabolites in situ. In order to explore the reliable imaging method for NASH diagnosis, we will develop a DESI-MSI analysis method for liver section. Then, we will explore metabolomics changes related to NAFLD and NASH mechanisms which discriminate the molecular diagnosis for non-alcoholic liver disease.


A glance into the past

Prof. R. Preisig (*26.06.1929, † 23.02.2017) was world-famous for his research on bile formation. He was also a co-founder of EASL, the European Association for the Study of the Liver.

Prof. J. Bircher invented the treatment of hepatic encephalopathy with lactulose and provided the basis for the first effective treatment against the cyclophyllid tapeworm Echinococcus multilocularis with Mebendazole.

Prof. G. Paumgartner introduced the non–surgical treatment of gallstones in medicine and started in Bern (together with one of his successors) to describe the transport mechanisms, which contribute to bile formation.

Prof. J. Reichen (*23.01.1946, † 25.07.2017) above all was well known for his research on the metabolism of bile acids and for the discovery of specific factors that contribute to hepatic function in cirrhosis.

Prof. B. Lauterburg has achieved recognition for his research on antioxidants and on the toxicity of medicinal products.
 

A glance at recent actions of the foundation

Supporting young researchers and Research projects:

Dr. Sheida Moghadamrad, Ph.D. on portal hypertension and angiogenesis (Dr. A De Gottardi).
Her work has been recently published in Hepatology (Impact Factor 11.19) - see article and links


Dr. Sheida Moghadamrad was recently awarded the prize Benoit Pochon - March 2015.

Sheida Moghadamrad and Andrea De Gottardi

 

Investment :

MicroScale Thermophoresis (MST) - precise way to quantify biomolecular interactions.


New and efficient technology to measure binding constant for any type of biomolecular interactions, close to native environment.