Tissue Engineering Group
The Tissue Engineering Group at the University of Bergen is headed by Kamal Mustafa. It studies tissue engineering and regeneration.
This research group aims to develop regenerative therapies based on stem cells and bone regeneration. Preclinical studies on growing cells and different forms of stimulation of cells will be conducted at their laboratories. The group represents a collaboration between researchers and clinicians, both at the national and international level. Its goal is to rehabilitate patients with congenital and acquired bone defects caused by aging, trauma or pathological defects. The group is participating in two big EU projects, VASCUBONE (a tool box for tailor-made vascularized bone implants) and REBORNE (Regenerating Bone Defects using New biomedical Engineering approaches).
The VascuBone project emphasises research that will expand our understanding of differences between stem cells from young and old individuals. In the Reborne project, the group, represented by Professor Emeritus Sølve Hellem, leads and supports a multi-centre study across three countries in which stem cells will be used for jaw bone regeneration. The study is being carried out by PhD candidate Cecilie Gjerde, and it is the first clinical trial involving human subjects to take place in Norway. The first patients have already received transplants at the University of Bergen's Department of Clinical Dentistry. This clinical trial is being carried out in parallel with two orthopaedic studies in different European countries in which more than 20 patients have already been treated. Stem cells from patients included in the studies are being expanded on a continuous basis at GMP-certified laboratories, including at Ulm University in Germany. For all relevant projects, the plan is to transfer the treatment and cell expansion activities to a new GMP-certified ex vivo laboratory in Bergen from 2017. The plastic surgery department at Haukeland University Hospital is also taking part in this group in cooperation with the University Medical Center Utrecht in the Netherlands, where they are now using biomaterial instead of the patient's own bone to close the cleft in paediatric patients with cleft lip and palate. This study will be expanded to include the use of mesenchymal stem cells.
The group is also participating in the Research Council of Norway's Norwegian Nanocellulose Technology Platform (Norcel). Norcel is working on the development of a scaffold based on nanucellulose and 3D printing for use in bone tissue engineering.
The Prostate Cancer Therapy Research Group
The Prostate Cancer Therapy Research Group is led by Karl-Henning Kalland.
The group is endeavouring to develop new cancer therapies, particularly targeting prostate cancer. The work consists of two main parts. The first part consists of the phase 1 clinical trial of cryoimmunotherapy to treat prostate cancer. The trial will begin in 2015, and it will include 20 patients who have prostate cancer with metastases. The strategy is designed to overcome the problem of the heterogeneity of cancer cells, which is caused by both mutations and the ability of cancer cells to be reprogrammed. It includes attacking cancer stem cells. The research biobank linked to the study provides valuable research material.
The other main part is the development of an experimental, stepwise model for prostate cancer development. This model is already being used in a screening programme for new bioactive substances that are being tested especially for their ability to influence stem cells and cancer stem cells. It is an important goal to isolate, cultivate and program stem cells and cancer stem cells for diagnostic and therapeutic development of the protocol in the ongoing phase 1 clinical trial.
The mitochondria/neurology stem cell research group
The Mitochondria/neurology group is led by Laurence Bindoff.
Mitochondria are key players in cellular physiology, not only are they the major producers of cellular energy (ATP), but they also play a role in many vital processes that affect the cell: these include processes such as apoptosis, cancer development, neurodegeneration and even ageing. Mitochondrial energy failure produces a wide range of devastating diseases that affect both adults and children: these diseases can affect any tissue, since all tissues rely on energy they produce, and they are among the commonest inborn errors of metabolism known. Indeed, evidence suggests that even the current prevalence figure of 1:3500 underestimates the problem. Mitochondrial disease phenotypes vary dramatically, even when caused by the same genetic defect; e.g. in diseases caused by mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (POLG), some patients show involvement of the brain and liver while others show only skeletal muscle disease. We have been studying diseases caused by mutations in this protein and find that it is the commonest cause of recessively inherited ataxia (unsteadiness) in Norway with two founder mutations each having a prevalence of 1:100.
We are studying POLG disease using stem-cell like cells transformed from the patient’s own fibroblasts. These “induced pluripotent stem cells” (iPSC) offer a unique opportunity to model human disease in a renewable and tissue specific manner. We also plan to use iPS cells to perform large scale screening of potential therapeutic agents. In this way, we do to expose the patient to any compounds that we have not already tested and found to be helpful. Further, using new technology (CRISPR-cas) that allows us to correct the genetic defect in living cells, the iPSC that are the patient’s own cells, will have the disease causing corrected and this will open the way for potential treatment using stem cells differentiated to whichever tissue is required.
The work on iPSC is performed in specialised laboratories located in the Department of Neurology, Haukeland University Hospital. Currently, there are a postdoctoral fellow (Xiao Liang) and one PhD student (Novin Balafkan) working on different aspects of the project: Novin Balafkan is differentiating cells to cardiomyocytes and hepatocytes (Figure 1) and looking at the levels of mitochondrial DNA as they mature. This is vital since we know that patients with POLG disease loose mtDNA in their cells. Interestingly, this is mostly in neurons and liver cells while skeletal muscle shows other mtDNA defects. Xiao Liang is preparing to differentiate iPSC into neurons and at the same time establishing methods to enable us to screen cells quickly so that we can begin screening compounds as potential therapies (Figure 2, 3). To do this we are investigating the use of flow-cytometry to see if we can develop methods to screen for mitochondria membrane potential.
The Blood Stem Cell Research Group
The Blood Stem Cell Research Group is headed by Bjørn Tore Gjertsen. In cooperation with a large national and international network, the group has produced many important publications on intracellular signal transduction by protein phosphorylation and apoptosis.
Much of the group's research has been related to AML patients. Important prognostic biomarkers have been identified through laboratory experiments and animal testing, and this work has been continued in clinical studies. The group is also involved in other cell therapy-related projects, including in cooperation with the Prostate Cancer Therapy Research Group. Access to stem cell research facilities will bring new possibilities for both in vitro and clinical studies. There is also a leukaemia research group in haematology headed by Øystein Bruserud. This group will also be taking part in the project, but concrete plans have yet to be finalised. The Department of Immunology and Transfusion Medicine has engaged in a considerable amount of stem cell research in cooperation with researchers in the Western Norway health region. It has previously focused on the cryopreservation of cells. Under Tor Hervig's leadership, the plan is now to resume work on a large-scale project on platelets, stem cells and growth factors – a field that is also related to the work carried out by the Tissue Engineering Group.
The Adipose Stem Cell Research Group
Gunnar Mellgren and Jørn V. Sagen are heading the Adipose Stem Cell Research Group. The group's main goal is to identify biological processes that lead to the development of obesity and diabetes.
Different biological processes in fat tissue are an important for the development of obesity and associated co-morbidities such as type 2 diabetes and certain forms of cancer. The group studies these changes using, e.g., microarray technology examination of fat tissue biopsies collected from patients who have undergone bariatric surgery or dietary intervention. This technology makes it possible to identify changes in the expression of all known genes, which may give indications of which biological processes that are important for the development of obesity and metabolic disease. Interesting factors that we identify from patient samples are studied further in different fat cell models in order to determine their role in the development of fat cells. Previous studies have found that the expression of genes that code for certain homeobox transcription factors is reduced in obese individuals and that their expression increases in connection with weight loss.
The stem cell project will give the group an opportunity to study these mechanisms in more detail, also in cells differentiated from mesenchymal stem cells in fat tissue. The group will focus on factors with important for the development and activation of 'brite' or 'beige' fat cells. The traditional thinking has been that the body has white fat cells that store energy and energy expending brown fat cells. In recent years, a third type of fat cell has been identified, called 'beige' or 'brite' ('brown in white') fat cells. Brite fat cells share certain characteristics with the brown fat cells, such as an increased number of mitochondria that consume energy. Identifying factors that regulate the development of 'brite' or 'beige' fat cells may prove to have a great potential in the treatment of both obesity and type 2 diabetes.
The Diabetes Group
The main aim is to discover important changes of signaling pathways in cells, leading to diabetes.
For this purpose, cells from the pancreas, but also other diabetes-relevant organs, are studied. The cells investigated are grown from skin-cells from patients, which are then transformed into induced pluripotent stem cells (iPSC), which in turn are developed into cell types found in pancreas and other diabetes-relevant cell types. Skin-biopsies are performed of individuals from families where a monogenic diabetes (MODY – maturity-onset-diabetes of the young) was diagnosed, where the dysfunction is caused by a single mutation in a gene involved in transcriptional regulation of pancreatic beta cells. But samples are also taken from other patient groups with diabetes or diabetes related syndromes.
Professor Helge Ræder is the leader of the diabetes group.
The work is performed in close collaboration with leading research environments in the US and other groups in Bergen, pursuing the following aims: the use of proteomic, genomic and epigenetics to investigate cells from MODY-patients to identify and validate signaling pathways and regulatory mechanisms (miRNA and post-transscriptional modifications) leading to the development of diabetes. We also would like to test the hypothesis that the re-mutation of single MODY-mutations (via in vitro mutagenesis) will restore the cells ability to produce and secrete insulin and normal cellular functions. Furthermore, we investigate how high blood-sugar levels in mothers with diabetes influence the fetal development and if there is an increased risk for diabetes and miss formation of heart and nervous system of the developing fetus.
The research group receives financial support from Bergen Forskningsstiftelsen, University of Bergen, Helse Vest and Novo Nordisk Fonden.