A major national initiative funded by the German Federal Ministry for Education and Research
Virtual Liver Network
The Virtual Liver will be a dynamic model that represents, rather than fully replicates, human liver physiology morphology and function, integrating quantitive data from all levels of organisation.
The Virtual Liver Network (VLN) represents a major research investment by the German Government focusing on work at the “bleeding edge” of Systems Biology and Systems Medicine. This Flagship Programme is tackling one of the major challenges in the life sciences: that is, how to integrate the wealth of data we have acquired post-genome, not just in a mathematical model, but more importantly in a series of models that are linked across scales to represent organ function. As the project is prototyping how to achieve true multi-scale modelling within a single organ and linking this to human physiology, it will be developing tools and protocols that can be applied to other systems, helping to drive forward the application of modelling and simulation to modern medical practice. It is the only programme of its type to our knowledge that bridges investigations from the sub-cellular through to ethically cleared patient and volunteer studies in an integrated workflow. As such, this programme is contributing significantly to the development of a new paradigm in biology and medicine.
The Virtual Liver Network is made up of seventy research group distributed across Germany, and is establishing links with research groups and international initiatives to supplement its work. The research effort is divided essentially into three major areas of focus:
The Liver Cell: These teams are concentrating on mapping and defining the functions that take place within the cells in the liver, and using this information to develop mathematical and computational models representing them.
Beyond the Cell: Here, research groups consider the mechanisms that are involved in helping individual cells “talk” to each other, coordinating the more complex interactions necessary within organised tissues to establish the basic functions of the liver, with the objective of delivering models representing tissue-level activity.
Integration and Translation: The most challenging part of the programme is establishing methods to integrate the models across all these different levels of liver organisation and function, so called multi-scale modelling which has not yet been achieved in Systems Biology, and translating this work to clinically relevant applications.
After the skin, the liver is the largest organ in the body. Located in the abdomen, just below the diaphragm and slightly to the right of centre, it is divided into two anatomical units: a large right and smaller left lobe, joined by a ligament. It is connected to two large blood vessels, the hepatic artery, carrying blood from the aorta, and the portal vein, carrying blood containing digested nutrients from the entire gastrointestinal tract, the spleen and the pancreas. These blood vessels subdivide into capillaries, which then lead to a lobule.
The liver is the central metabolic organ in human physiology, with functions that are fundamentally important to the detoxification of substances- typically synthetic chemicals- that are foreign to the human body, so-called xenobiotics. It is also responsible for the maintenance of homeostasis and the production of mediators of the acute phase response. Liver toxicity, whether actual or implied is the reason for the failure of a significant proportion of many promising novel medicines that consequently never reach the market, and diseases such as atherosclerosis, diabetes and fatty liver disease, that are a major burden on current health resources, are directly linked to functional and structural disorders of the liver.
Liver tissue is composed of a compact mass of multisided units: the hepatic lobules. Each lobule consists of a central vein surrounded by plates of liver cells. The liver receives blood from two sources: 80% from the intestine via the portal vein and venules, and 20% from the hepatic artery and arterioles. An exchange of materials takes place between the liver cells and the blood, which then passes into the central veins and returns to the general body circulation via the hepatic vein. Sinusoids, spaces between plates of liver cells composed of tributaries of the hepatic artery and portal vein, conduct the blood flow to the central vein. The bile canaliculus carries bile juice from the liver to branches of the bile duct, which convey bile from the lobules to the gall bladder. When an adult is at rest, about two and a half pints of blood flow through the liver each minute.
Two major types of cells populate the liver lobules: parenchymal and non-parenchymal cells. 80% of the liver volume is occupied by parenchymal cells commonly referred to as hepatocytes. Non-parenchymal cells constitute 40% of the total number of liver cells but only 6.5% of its volume. Sinusoidal hepatic endothelial cells, Kupffer cells and hepatic stellate cells are some of the non-parenchymal cells that line the liver sinusoid.
The BMBF is recognised for having taken a major leadership position not only historically in Systems Biology, but now in particular with funding the VLN focusing clearly on demonstrating it has true value in the clinical and industrial setting. The very clear line of sight from molecule to the clinic and the inclusion of ethically cleared patient and volunteer studies as an integral component of this programme is unique, and has provided an early exemplification of Systems Medicine. The strategic vision for the future is to ensure all of this investment in the excellent science and its application to the challenges of 21st Century medicine, the successful outcomes, the groundbreaking demonstration that big science can be delivered if professionally managed, is translated into something that has durability, flexibility and status, perhaps establishing the foundation for the creation of a national Centre of Excellence in Systems Medicine, based on studies of the liver as a first step.