Research into understanding disease at cellular and molecular level
Basic knowledge about cells, their differences and how they communicate with each other, is necessary for understanding what happens when we become sick. In recent years, our understanding of diseases and how they occur at cellular and molecular level has grown exponentially. In particular, the latest advances in genome sequencing have advanced knowledge of genetic components making it possible to pose, and answer, brand new questions. Better understanding of communication networks within and between cells also paves the way for new paths towards the treatment and prevention of diseases. Researchers at the University of Copenhagen are working to decode and understand the mechanisms behind diseases such as diabetes, cancer and malaria. Below are some examples of the new knowledge that researchers have already identified.
Development of insulin-producing beta cells
Insulin is a hormone produced in the pancreas, by what are called beta cells. In people with type 1 diabetes, the beta cells are destroyed by the patient's own immune system. The aim is therefore to develop insulin-producing beta cells. This will require an understanding of the mechanisms that control the formation of beta cells. Researchers from DanStem have shown that the so-called 'notch' signal's ability to inhibit and then stimulate the formation of hormone-producing cells is important for monitoring the development of the beta cells.
- Horn S, Kobberup S, Jørgensen MC, Kalisz M, Klein T, Kageyama R, Gegg M, Lickert H, Lindner J, Magnuson MA, Kong Y-Y, Serup P, Ahnfelt-Rønne J, Jensen JN (2012): Mind bomb 1 is required for pancreatic ß-cell formation. Proceedings of the National Academy of Sciences (PNAS).
Kesavan G, Sand FW, Greiner TU, Johansson JK, Kobberup S, Wu X, Brakebusch C, Semb H. (2009): Cdc42-mediated tubulogenesis controls cell specification. Cell.
Several cancers may be caused by diseased stem cells
The discovery of more and more of the cells that maintain tissue and organs throughout life (the stem cells) offers new perspectives for the treatment of diseases. In order to find new principles for treatment, we must be able to compare cancer cells with their normal cell of origin. This will only be possible with a sufficient understanding of the organ's normal cellular hierarchy. Significant and highly promising new 'drug targets' deal with the micro-environment's importance for tumour growth and metastasis, in particular the signalling pathways and glycosylation.
- Kim J, Villadsen R, Sørlie T, Fogh L, Grønlund SZ, Fridriksdottir AJ, Kuhn I, Rank F, Wielenga VT, Solvang H, Edwards PA, Børresen-Dale AL, Rønnov-Jessen L, Bissell MJ, Petersen OW (2012): Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Procedings of the Natinal Academy og Sciences (PNAS).
- Dahlgaard K, Jung A, Qvortrup K, Clausen H, Kjaerulff O, Wandall HH (2012): Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension. Proceedings of the National Academy of Sciences (PNAS).
- Cao R, Ji H, Feng N, Zhang Y, Yang X, Andersson P, Sun Y, Tritsaris K, Hansen AJ, Dissing S, Cao Y (2012): Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proceeding of the National Academy of Sciences (PNAS).
Changing all types of blood to 0
The difference between blood groups A, B and 0 is a particular carbohydrate, contained in red blood cells. Prior to a blood transfusion or organ transplant, it is important to ascertain that donor and recipient share the same blood group. Otherwise people may die. Group 0 lacks a sugar, A has one type of sugar, B another and ABs have both kinds. If a particular sugar is missing, antibodies are present. Researchers at the Copenhagen Center for Glycomics have identified the genes that determine people's blood group, and have developed enzymes that remove these sugars. It is therefore now possible to transform all types of blood into group 0, and use it in transfusions for everybody.
- Liu QP, Sulzenbacher G, Huaiping Yuan, Bennett EP, Pietz G, Saunders K, Spence J, Nudelman E, Levery SB, White T, Neveu JM, Lane WS, Bourne Y, Olsson ML, Henrissat B, Henrik Clausen (2007): Bacterial glycosidases for the production of universal red blood cells. Nature Biotechnology.
Dopamine, reward and cocaine
Dopamine is one of the brain's most important neurotransmitters and controls our motivation to obtain a reward. The amount of dopamine in the brain's synapses is controlled by a particular protein, the dopamine transporter, which conveys dopamine back into the nerve cell. Drugs like cocaine and amphetamines work by blocking the dopamine transporter. Detailed insight into how cocaine blocks the dopamine transporter at the molecular level has provided new ideas about how it might be possible to treat cocaine abuse. New research has also shown that a particular family of 'scaffold proteins' (PDZ domain proteins) plays a surprisingly important role in the presence of the dopamine transporter in the synapse. This insight can be used, for example, to better understand diseases in which changes in the dopamine balance play an important role, e.g. schizophrenia, ADHD and Parkinson's disease.
- Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, Kopajtic T, Shi L, Katz JL, Tanda G, Newman AH (2012): R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biological Psychiatry.
- Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, Loland CJ (2008): The binding sites for dopamine and cocaine in the dopamine transporter overlap. Nature Neuroscience.
Vitamins for the immune system
Both vitamin A and D are important to a properly functioning immune system. New research shows how these vitamins affect the immune system.
- Agace WW, Persson EK (2012): How vitamin A metabolizing dendritic cells are generated in the gut mucosa. Trends Immunology.
- von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C (2010): Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunology.
One vaccine against the influenza virus
Approximately every two years, an influenza epidemic breaks out, mortality rates increase, especially in the elderly population, and it costs society money in lost working days. It is possible to vaccinate against influenza, but the vaccines need to be adapted almost every year because the virus changes. Certain properties of the influenza virus are, however, very stable and, by targeting a vaccine on these antigens, it will probably be possible to develop a vaccine that will work for many years.
- Andersson A-M C, Håkansson KO, Jensen BAHJ, Christensen D, Andersen P, Thomsen AR, Christensen JP (2012): Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein. PLOS One.
New culture systems for the production of the hepatitis C virus
Approximately 170 million people have hepatitis C, and at least 350,000 die of complications every year. It is crucial for the development of medicines that attack the virus directly, as well as for the development of vaccines, to be able to cultivate hepatitis C variants in cells in the laboratory.
- Li Y-P, Ramirez S, Gottwein JM, Scheel TKH, Mikkelsen L, Purcell RH, Bukh J (2012): Robust full-length hepatitis C virus genotype 2a and 2b infectious cultures using mutations identified by a systematic approach applicable to patient strains. Proceedings of the National Academy of Sciences (PNAS).
Chronic infections and biofilms
The formation of bacterial biofilms is a frequent cause of chronic infections and is extremely difficult to treat with ordinary antibiotics. Biofilms are responsible for infections in artificial heart valves, knee and hip replacements and medical devices such as catheters, etc. New types of 'antibiotics' – such as ajoene from garlic – have been found to inhibit bacterial communication systems (quorum sensing) so that the host's defence systems can eliminate the bacterial biofilm.
- Jakobsen TH, van Gennip M, Phipps RK, Shanmugham MS, Christensen LD, Skindersoe ME, Rasmussen TB, Friedrich K, Uthe F, Jensen PØ, Moser C, Nielsen KF, Eberl L, Larsen TO, Tanner D, Høiby N, Bjarnsholt T, Givskov M, Alhede M (2012): Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing. Antimicrobial Agents and Chemotherapy.
- Givskov M. (2012): Beyond nutrition: health-promoting foods by quorum-sensing inhibition. Future Microbiology.
Every year, approximately one million children die from malaria and about 20 million suffer severe bouts of the disease. Several hundred million cases of malaria are recorded every year, so far from every case is life-threatening. Researchers have now identified the proteins that are responsible for some cases of malaria becoming serious.
- Lavstsen T, Turner L, Saguti F, Magistrado P, Rask TS, Jespersen JS, Wang CW, Berger SS, Baraka V, Marquard AM, Seguin-Orlando A, Willerslev E, Gilbert MTP, Lusingu J, Theander TG (2012): Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proceedings of the National Academy of Sciences (PNAS).