The Svedberg Prize
The Svedberg Prize is a scientific award, handed out by SFBBM and the Swedish National Committee for Molecular Biosciences to a young and successful, Swedish or foreign, biochemist, working in Sweden. the nomination period is open.
The Svedbergpriset är en vetenskaplig utmärkelse om cirka 35 000 kronor som årligen delas ut av svenska föreningen för biokemi, biofysik och molekylärbiologi tillsammans med den Svenska nationalkommittén för molkekylära biovetenskaper. Fonden upprättades med medel från den 9:e internationella biokemikongressen och syftar till att ge en årlig prissumma för vetenskaplig forskning inom biokemifältet i Sverige. Fonden instiftades av Svenska nationalkommittén för biokemi och administreras av Kungliga vetenskapsakademin.
Mottagaren av Svedbergpriset ska vara en svensk, eller utländsk, i Sverige verksam biokemist eller molekylärbiolog som ej fyllt eller fyller 40 år det år priset delas ut.
- 2001 - Mikael Oliveberg
- 2002 - Stefan Björklund
- 2003 - Johan Ericsson
- 2004 - Claes Gustafsson
- 2005 - Ruth Palmer
- 2006 - Piergiorgio Percipalle
- 2007 - Nico Dantuma
- 2008 - Thomas Helleday
- 2009 - Per Hammarström
- 2010 - Per Jemth
- 2011 - Karin Lindkvist
- 2012 - Martin Högbom
- 2013 - Martin Ott
- 2014 - David Drew
- 2015 - Ingemar André
The Svedberg Award 2003
Johan Ericson Department of Cell and Molecular Biology, Karolinska Institute
Specification of Cell Fate in the Developing CNS
Background After undergraduate studies in molecular biology at Umeå University, I began my graduate training in 1990 in Thomas Edlund’s laboratory at the Department of Microbiology, Umeå University. In his laboratory, I became exposed to general questions related to how cells can acquire their unique functional properties during embryonic development, and in January 1995 I presented a thesis examining the establishment of cell diversity in the developing anterior pituitary and in the ventral CNS. I thereafter pursued post-doctoral studies in Thomas M. Jessell’s laboratory at Columbia University in New York. In Tom’s lab, I became interested into mechanisms that control the patterned generation of neuronal subtypes along the dorsal-to-ventral (DV) axis of the developing spinal cord, and I have continued to work along this line of research also after establishing my own laboratory at the Karolinska Institute in 1999.
Research The functional basis of the central nervous system (CNS) depends on the precise spatial and temporal generation of distinct functional types of neurons during embryonic development. Neurons acquire their identity in response to local signals that provide positional information to dividing neural progenitor cells along the DV and anterior-to-posterior (AP) axes of the neural tube. Our research has been directed at understanding the cellular and molecular mechanisms that control the formation of neuronal cell diversity in the developing spinal cord and brainstem. These axial levels are the simplest and most well characterised subdivisions of the CNS, and thus represent a suitable model system to approach basic principles of neural development.
We have shown that the secreted protein Sonic hedgehog (Shh) have a central role in the induction of most neurons generated in the ventral half of the CNS, and further that Shh act as a gradient morphogen which induce different types of neurons at different concentration thresholds. This observation raised the issue how neural progenitors can perceive, and respond differently, to small changes in the ambient concentration of Shh. We found that a key role for Shh in this process is to control the spatial expression of a set of homeodomain (HD) transcription factors in responding progenitor cells, establishing a combinatorial code of homeodomain protein expression that control the specification of distinct neuronal subtypes at defined positions. Unexpectedly, the ability of these HD proteins to induce specific neuronal subtypes depend their ability to act as transcriptional repressors. In contrast to conventional activator models of cell fate specification, this finding places derepression strategies at the heart of neuronal differentiation in the developing CNS.
In addition to these studies of cell patterning along the DV axis, we have begun to investigate how DV patterning may be integrated with patterning mechanisms that operates along the AP axis and also over time. By examining the generation of motor neurons and serotonergic neurons in the brainstem, we have recently shown that close interactions between DV and AP patterning genes not only control spatial, but also temporal, aspects of neuronal fate specification. These data suggest that mechanisms that underlie the generation of different neurons in space and over time are tightly interconnected.
Selected references: Pattyn, A., Vallstedt, A., Dias, J., Sander, M., and Ericson, J. (2003). Complementary roles for Nkx6 and Nkx2 class proteins in the establishment of motoneuron identity in the hindbrain.Development 130, 4149-59. Pattyn, A., Vallstedt, A., Dias, J., Abdel Samad, O., Krumlauf, R., Rijli, F.M., Brunet, J-F., and Ericson, J. (2003). Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev 17, 729-737. Persson, M., Stamataki, D., te Welscher, P., Andersson, E., Rüther, U., Ericson, J., and Briscoe, J. (2002). Dorsal-Ventral Patterning of the Spinal Cord Requires Gli3 Transcriptional Repressor Activity. Genes Dev 16, 2865-78. Vallstedt, A., Muhr, J., Pattyn, A., Andersson, E., Pierani, A., Mendelsohn, M., Sander, M., Jessell, T.M., and Ericson, J. (2001). Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron 31, 743-55. Muhr, J., Andersson, E., Persson, M., Jessell, T.M., and Ericson, J. (2001). Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 104, 861-873. Briscoe, J., Pierani, A., Jessell, T. M., and Ericson, J. (2000). A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435-445. Briscoe, J., Sussel, L., Serup, P., D.Hartigan-O´Connor, D., Jessell, T.M., Rubenstein, J.L.R., Ericson, J. (1999). Homeobox gene Nkx2.2 and specification of neural identity by graded Sonic hedgehog signalling. Nature 398, 622-627.
The Svedberg Award 2004
Claes Gustafsson Karolinska Institutet
Transcription in eukaryotic cells
Research Summary We want to elucidate the molecular basis of regulated gene expression. Of special interest to us is to understand how activators and repressors can influence the rate by which individual genes are transcribed. Most of our work concerns the nuclear RNA polymerase II transcription machinery, but we also have an interest in the mechanisms of mitochondrial transcription in human cells.
The Mediator complex acts as a bridge, conveying regulatory information from enhancers and other control elements to the general transcription machinery. The Mediator was originally identified in Saccharomyces cerevisiae and is required for the basal and regulated expression of nearly all RNA pol II dependent genes. Mediator complexes were later also identified in metazoans, confirming a role for Mediator in transcription regulation in higher eukaryotes as well. Mediator is needed for the function of a large number, if not a majority, of human specific transcription factors. Medically important transcription factors, which operate via the Mediator include the nuclear hormone receptors, the vitamin D receptor, Sp1, p53 etc. In spite of its general significance for transcription control, the exact mechanisms of Mediator function remain unclear. In our project, we aim to elucidate the molecular basis of Mediator dependent tran-scriptional regulation. A second line of research in the lab concerns the molecular basis for regulated transcription in the human mitochondrion. The compact mito-chondrial genome encodes for 13 key components in the respiratory chain and the levels of mitochondrial transcription correlates with the overall energy requirement of the eukaryotic cell. Surprisingly little is known about the mechanistic and regulatory aspects of mitochondrial transcription. We have recently identified two novel transcription factors and for the first time reconstituted mammalian transcription in vitro. Building on our unique in vitro system, we now work to elucidate the biochemical basis for basal and regulated transcription in the mammalian mitochondrion.
The Svedberg Award 2005
Umeå Center for Molecular Pathogenesis, Umeå University Background I was born in Kilmarnock, Scotland in 1970, and carried out my undergraduate studies in Biochemistry at the University of Dundee, Scotland. During this time I became interested in signal transduction, and was lucky enough to join the laboratory of Peter Parker at the Cancer Research UK (then called the Imperial Cancer Research Fund) where I worked on a then novel family of PKC related protein kinase and the signal transduction pathways they were involved in. I defended my PhD thesis in January 1996, after which I moved to San Diego, California to take up a post-doctoral position at the Salk Institute, in the laboratory of Tony Hunter. At this time I was still interested in signal transduction, but realized I wanted to learn more about genetics and how to use genetic model systems to address the complex problems we face in the field of signal transduction. During this time I began working with the small banana-fly Drosophila melanogaster, and utilizing the fly to tackle signal transduction via tyrosine kinases. In 1996 I moved to Umeå University in Sweden and have continued with this line of research. My group is based at the Umeå Center for Molecular Pathogenesis and focuses on addressing signal transduction in developmental processes using the banana-fly as our main tool.
Research A wide range of processes are mediated by receptor tyrosine kinases (RTKs) and their signalling pathways. The growing list of processes regulated by these receptors across the phylogenetic tree is extremely broad, and includes induction of cell fates, guidance of cell and axon migration, and cell proliferation. Ligand binding to the extracellular domain induces activation of the kinase on the cytoplasmic side, which initiates the intracellular signalling. The activated RTKs phosphorylate themselves and cytoplasmic substrates, leading to activation of a number of downstream signalling molecules, and ultimately induce changes in gene expression and the phenotypic state of the cell. RTKs thus play important roles in cellular proliferation and differentiation. In addition, RTKs reveal oncogenic potential when their kinase activities are constitutively enhanced by point mutation, amplification, or rearrangement of the corresponding genes. Mammalian Anaplastic Lymphoma Kinase (Alk) was originally identified as a member of the insulin receptor subfamily of RTKs that acquires transforming capability when truncated and fused to nucleophosmin (NPM) in the t(2;5) chromosomal rearrangement associated with a specific type of aggressive non-Hodgkin’s lymphoma. To date, many chromosomal rearrangements leading to an activated Alk RTK have been described. However, when we began working on Alk in the Drosophila system, there were few insights into the normal structure of Alk and information on the function of this novel RTK was lacking.
Using Drosophila as our model system we were able to show that Alk-mediated signalling drives muscle fusion in the developing embryonic gut. As a result of this work we have been able to show that the Drosophila Alk RTK is the receptor, or part of a receptor complex, responsible for binding the recently identified Jeb protein. Jeb is a novel extracellular signalling molecule which is not transcribed in the visceral mesoderm itself, but in the neighboring somatic mesoderm, and is then specifically taken up by the visceral mesoderm cells. Jeb has been shown to be required for visceral mesoderm migration and differentiation. Analysis of Jeb and Alk localization reveals a complex interplay between Jeb and the Alk positive visceral mesoderm. In wild-type embryos Jeb is expressed in cells ventral to the Alk positive visceral mesoderm clusters, and at the sites of contact between these cells a clear co-localisation of Jeb and Alk can be observed. The Alk positive visceral mesoderm cells, which contact the Jeb secreting mesoderm, respond to Jeb by differentiating. Together Jeb and Alk signal through an ERK mediated signalling pathway to drive specification of a particular cell type (founder cells) and subsequent fusion of the visceral mesoderm muscle cells. In the absence of either the Jeb ligand or Alk receptor tyrosine kinase function there is a critical failure in the fusion process within the visceral mesoderm. The targets of Jeb induced Alk-mediated signalling include the fusion determinant Duf/Kirre, together with the T-box transcription factor org-1, which explain the muscle fusion defects found Alk mutant animals [2-4]. Presently we continue to work on the signal transduction pathways regulated by Alk, and on understanding how these molecules function during developmental processes such as muscle development. Our goal is to map these basic mechanisms in Drosophila, which is less complex than mouse or human, and therefore aid n laying the basic groundwork for understanding these fundamental processes in higher organisms such as ourselves.
References: 1. Freeman M: Developmental biology: partners united. Nature 2003, 425:468-469. 2. Stute C, Schimmelpfeng K, Renkawitz-Pohl R, Palmer RH, Holz A: Myoblast determination in the somatic and visceral mesoderm depends on Notch signalling as well as on milliways(mili(Alk)) as receptor for Jeb signalling. Development 2004, 131:743-754. 3. Lee HH, Norris A, Weiss JB, Frasch M: Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers. Nature 2003, 425:507-512. 4. Englund C, Lorén CE, Grabbe C, Varshney GK, Deleuil F, Hallberg B, Palmer RH: Jeb signals via the DAlk receptor tyrosine kinase to drive visceral muscle fusion. Nature 2003, 425:512-516.
The Svedberg Award 2006
Piergiorgio Percipalle Department of Cell and Molecular Biology, Karolinska Institutet
Background After graduating in Chemistry, I started my PhD at the International Centre for Genetic Engineering and Biotechnology, Trieste, where I worked on the molecular mechanisms of protein-DNA recognition using chemical, biochemical and biophysical assays. I obtained my PhD in molecular genetics at the International School for Advanced Studies with a thesis entitled “Engineering DNA-binding proteins based on the helix-turn-helix motif”. I then moved to the MRC Laboratory of Molecular Biology, Cambridge, where I did a postdoc in the laboratory of Daniela Rhodes. In Daniela’s lab I mapped some of the protein-protein interactions that take place during protein import into the cell nucleus. That period was very creative for me since I started thinking about why actin is imported into the cell nucleus where it is such an abundant protein (about 15% of cellular actin is present in the cell nucleus). I then moved to the Karolinska Institutet in the laboratory of Bertil Daneholt where I became acquainted with the polytene chromosomes of the dipteran insect Chironomus tentans, ideal to study gene expression in situ. In that period, the polytene chromosomes turned out to be instrumental to establish that actin is in active transcription sites and it is a genuine component of nascent pre-messenger-ribonucleoprotein (pre-mRNP) particles. In January 2004, I became a principal investigator in the Department of Cell and Molecular Biology (CMB) at the Karolinska Institutet. Since then, we have shown that actin is an essential transcription factor in both RNA polymerase I (pol I) and RNA polymerase II (pol II)-mediated transcription.
Research The research in my group focuses on the mechanisms of transcriptional and post-transcriptional control of gene expression. We are studying both normal cells and cancer cells where these mechanisms are profoundly affected and deregulated, leading to disruption of controlled gene activity and malignant cell transformation. One of our main interests is to understand the crosstalk between transcription apparatus and dynamic alterations of chromatin structure which are mediated by chromatin remodelling complexes and histone modifying enzymes. These factors are recruited on active genes through complex relay mechanisms which are not yet fully understood. Several independent studies have shown that nuclear actin may perform a pivotal role in this dynamic recruitment since it is present in certain ATP-dependent chromatin remodelling complexes, in pre-mRNP particles and it is associated with all three eukaryotic RNA polymerases. Some mechanistic insights came from the discovery of nuclear actin-binding proteins. In ribosomal gene transcription, the interaction between actin and nuclear myosin 1 (NM1) is required to recruit the novel chromatin remodelling complex B-WICH, an activator of pol I transcription elongation. On the other hand, pol II transcription requires the interaction between actin and the heterogeneous ribonucleoprotein hnRNP U. This mechanism appears to be conserved from humans to insects and is likely to be required for the recruitment of specific histone acetyl transferases to maintain a productive pol II transcription elongation phase. Based on the above observations, we have proposed that actin functions in molecular switches as an allosteric regulator of RNA polymerase-mediated transcription. Molecular switches may represent a means of recruiting co-factors on active genes, with the help of specific adaptors, NM1 in pol I transcription and hnRNP U in pol II transcription. This model raises many intriguing questions. We are currently focusing on two of them, namely “what is the polymerization state of actin during its function along actively transcribed genes?” and “are actin-based molecular switches required only for transcription or they are also utilized down-stream for post-transcriptional control of gene expression?
Selected references Percipalle P * (2007) Genetic connections of the actin cytoskeleton and beyond. BioEssays, in press Percipalle P *, Östlund Farrants A-K (2006) Chromatin remodelling and transcription: Be-WICHed by nuclear myosin 1. Current Opinion Cell Biology, 18: 267-274 Percipalle P *, Visa N (2006) Molecular functions of nuclear actin. J Cell Biol, 172: 967-971 Percipalle P *, Fomproix N, Cavellan E, Voit R, Reimer G, Krüger T, Thyberg J, Scheer U, Grummt I, Östlund Farrants A-K (2006) The chromatin remodelling complex WSTF-SNF2h interacts with nuclear myosin 1and serves a role in RNA polymerase I transcription. EMBO Reports 7: 525-530 Kukalev A, Nord Y, Palmberg C, Bergman T, Percipalle P * (2005) Actin and hnRNP U cooperate for productive transcription by RNA polymerase II. 2004. Nature Struct Mol Biol 12: 238-244 Percipalle P, Fomproix N, Kylberg K, Miralles M, Björkroth B, Daneholt B, Visa N (2003) An actin-ribonucleoprotein interaction is involved in transcription by RNA polymerase II. Proc. Natl Acad Sci USA 100: 6475-6480
The Svedberg Award 2007
Nico Dantuma Department of Cell and Molecular Biology (CBM), Karolinska Institutet
Background In 1992, I graduated in Biology and Medical Biology at the Free University in Amsterdam. As part of my undergraduate training, I had spent already more than one year at the bench being involved in two research projects dealing with enteropathogenic bacteria and estrogen-dependent growth of breast tumors at the Free University and the Netherlands Cancer Institute, respectively. It was during this time at the bench that I became really fascinated with science and in particular with doing research. Directly after my graduation, I started my PhD project at the Utrecht University where I studied how the African migratory locust (Locusta migratoria) mobilizes and transports lipids during their long distance flights resulting in the identification of a novel endocytotic lipoprotein receptor. In 1997, I defended my thesis and moved to Stockholm to join the laboratory of Maria Masucci, who was then at Microbiology and Tumor Biology center (MTC) of the Karolinska Institute. It was in the Masucci lab that I started to work on the ubiquitin/proteasome system, which is still the major focus of our research. As a postdoctoral fellow I studied how the Epstein Barr virus, which causes infectious mononucleosis and is linked to several forms of cancer, manipulates the ubiquitin/proteasome system. After my postdoctoral period, I established my own research group with a major focus on the ubiquitin/proteasome system in neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease. In 2003, I spent a sabbatical year in the group of Jacques Neefjes at the Netherlands Cancer Institute during which I became acquainted with various live cell imaging techniques. Shortly after my return to Stockholm, I moved my group to the department of Cell and Molecular Biology (CMB) also at the Karolinska Institute, where we continued our work on the ubiquitin/proteasome system in neurodegeneration as well as the development of new tools for following the ubiquitin/proteasome system in living cells. More recently, we started to study the role of the ubiquitin/proteasome system in DNA repair, a process that is highly relevant for our understanding of cancer.
Research The ubiquitin/proteasome system is involved in many cellular processes. It is for example important for the cell cycle, programmed cell death, transcription, DNA repair, intracellular transport and, last but not least, for the destruction of misfolded or otherwise abnormal proteins. Best known is the role of the ubiquitin/proteasome system in regulated degradation of proteins but it also has less well understood non-proteolytic functions. Degradation is accomplished in a two step process. First, proteins that are destined for degradation are poly-ubiquitylated, which means that a long chain of a small protein called ubiquitin is being attached to the protein that will be degraded. Second, proteins with poly-ubiquitin chains bind to the proteasome, which is a large proteolytic complex that subsequently cuts the poly-ubiquitylated protein in small fragments. Regulated degradation of proteins is the perfect means to irreversibly inactivate regulatory proteins or to destroy abnormal and potentially dangerous proteins. It has become increasingly clear that there are different forms of ubiquitylation and many of those do not target proteins for degradation. For example, in transcription and DNA repair mono-ubiquitylation (attachment of a single ubiquitin) plays an important regulatory role without targeting proteins for degradation.
We have developed a number of tools that allows to analyse the functionality of the ubiquitin/proteasome system and to follow the dynamics of certain components of the system. Many neurodegenerative diseases are characterized by the presence of deposits of aggregated misfolded proteins in the affected brain regions. Since the ubiquitin/proteasome system is the primary pathway responsible for clearance of misfolded proteins, it has been proposed that problems with the ubiquitin/proteasome system may be a common nominator in neurodegenerative disorders. With our tools we have, for example, shown that protein aggregation causes a major problem for the system. We also found that an abnormal ubiquitin which has been found in Alzheimer’s disease interferes with the household functions of the ubiquitin/proteasome system. Finally, we demonstrated that cellular stress conditions, which are commonly found in neurodegenerative diseases, affects the functionality of the ubiquitin/proteasome system.
We have been trying to elucidate why the ubiquitin/proteasome system works less efficient during stress conditions. To our surprise, we found that probably the protein ubiquitin itself is the bottleneck. Despite the fact that high levels of ubiquitin are present in all cells, the levels are still rate limiting which is probably due to the fact that ubiquitylation is involved in so many cellular processes. As a consequence different ubiquitin-dependent processes are competing for a limited pool of ubiquitin and especially during stress when much more ubiquitin is required for degradation the system runs havoc. Based on this finding we postulated the ‘ubiquitin equilibrium hypothesis’ according to which the limited amount of ubiquitin enables crosstalk between various ubiquitin-dependent processes. We indeed found that blocking ubiquitin-dependent degradation directly affects ubiquitin-dependent transcription by competing ubiquitin from histones which dictate transcriptional activity. At the moment, we are also looking at other ubiquitin-dependent processes to get a better idea of the level of crosstalk and the relevance if this crosstalk in diseases.
Inspired by our earlier work in which we studied how certain proteins resist proteasomal degradation, we started to work on Rad23, a protein involved in nucleotide excision repair which protects our genome from UV-induced DNA damage. Interestingly, Rad23 has to interact with the proteasome when the DNA is being repaired but somehow it escapes from degradation. We identified the domain (stabilization signal) that is responsible for protecting Rad23 and showed that the stabilization signal of Rad23 is important for DNA repair. Thus, our research shows that some proteins protect themselves from degradation by the proteasome, a situation that we had only observed previously for pathologic proteins such as a viral protein and proteins causing neurodegenerative diseases. We also found that UV light causes mono-ubiquitylation of histones and that this is ubiquitylation is part of the DNA repair response, which is another example of the direct link between DNA repair and the ubiquitin/proteasome system. The functional significance of this DNA damage-induced histone modification remains unclear.
In our ongoing research, we focus on these fascinating aspects of the ubiquitin/proteasome system and are ready for new surprises.
Please visit our website for more information: Dantuma lab..
About our research:
Key references from the Dantuma lab:
Bergink, S., F.A. Salomons, D. Hoogstraten, T.A.M. Groothuis, , H. de Waard, J. Wu, L. Yuan, E. Citterio, A. Houtsmuller, J. Neefjes, J.H.J. Hoeijmakers, W. Vermeulen and N.P. Dantuma. 2006.DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A.Genes Dev. 20:1343-1352.
The Svedberg Award 2008
Thomas Helleday Professor at Molecular Genetics at Stockholm University and Cancer Therapeutics at the University of Oxford (UK).
A committee consisting of members from the SFBM and Swedish National Committee for Molecular Biosciences boards has decided to propose Thomas Helleday, to the The Svedberg award 2008 for his “Outstanding contributions to the understanding of the molecular mechanisms of homologous recombination in mammalian cells and their use for cancer treatment”. Helleday is affiliated at the Department of Genetics, Microbiology and Toxicology, Stockholm University and at the University of Oxford, UK. The award of SEK 35 000 together with the medal and diploma was presented at the annual meeting of SFBM 22-23 September 2008 in Göteborg.
Presentation of Helleday’s research My interest for cancer research was born when I, aged 16, work extra as nurse’s assistant at a hematology unit at Danderyd’s hospital in Sweden. Patients died like flies and were suffering from horrendous side effects of the cancer drugs. This was my first encounter with death and I couldn’t bear it – I decided to find a cure for cancer. I started my Ph.D. project on genetic recombination in mammalian cells in spring 1996, following my undergraduate degrees in Molecular Biology and Business Administration and Economics (civilekonom), both from the Stockholm University. One of the main findings in my thesis was that commonly used brominated flame retardands induced gene rearrangements similar to those found in cancer. This and other reports showing for instance that brominated flame retardants accumulate in human breast milk resulted in a ban of brominated flame retardants in Sweden. Following my dissertation in 1999, I received my own grants that allowed me to start up a small group in Stockholm. Realizing I needed to do a postdoc, I joined the lab of Mark Meuth at the Institute for Cancer Studies, University of Sheffield (UK). As I refused to listen or take orders as a postdoc, Mark Meuth kindly offered me a lectureship in 2000 to develop my own ideas as a group leader. From this time, I have split my time between my groups at the Stockholm University and England. The focus has been to understand how homologous recombination is used to repair lesions that occur at stalled replication forks in mammalian cells. A breakthrough came in 2005, when the group showed that PARP inhibitors selectively kill BRCA2 defective tumours. The patent was licensed to KuDOS Ltd (Cambridge) and today, PARP inhibitors are used world wide in clinical trials for breast and ovarian cancers. I have previously been awarded several prizes including, European Association for Cancer Research Young Cancer Researchers Award 2007, The Royal Swedish Academy of Sciences Hilda and Alfred Eriksson’s Prize 2007, British Association for Cancer Research – AstraZeneca Young Scientist Frank Rose Award 2006, The Eppendorf Young European Investigator Award 2005, European Environmental Mutagen Society Young Scientist Award 2005. Currently, I am a professor in Molecular Genetics at Stockholm University and a professor in Cancer Therapeutics at the University of Oxford (UK). The lab in Stockholm has 15 members and the Oxford lab 7 members.
Current Research The primary goal of the Helleday labs is to exploit tumour defects for targeted treatment of cancer. Virtually all cancers have a defect the DNA damage response, by mutations in tumour suppressor genes. The defect in DNA damage signalling or repair weakens the ability of the cancer cell to properly replicate DNA, resulting in genetic instability that drives cancer progression. In this project we uncover cancer specific signalling and repair pathways that are targeted for novel anti-cancer treatments. The project involves identification of DNA lesions formed during replication and characterisation of DNA damage signalling and repair pathways activated by these lesions. The group is engaged in understanding basic concepts of DNA damage signalling and repair as well as conducting pre-clinical trials, to translate our basic discoveries to the clinic.
Selected recent references: Gottipati, P., Cassel,. T.N., Savolainen, L., Helleday, T. (2008) Transcription-associated recombination is dependent on replication in mammalian cells. Molecular and Cellular Biology, 28(1):154-64.
Bartkova, J., et al. (2006) Oncogene-induced senescence is an integral part of the tumorigenesis barrier imposed by DNA damage checkpoints, Nature, 444(7119), 633-7.
Renglin Lindh, A., Rafii, S., Schultz, N., Cox, A., Helleday, T. (2006) Mitotic defects in XRCC3 variants T241M and D213N and their relation to cancer susceptibility, Human Molecular Genetics, 15(7), 1217-1224.
Bryant, H.E., Schultz, N, Thomas, H.D., Parker, K.M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N.J., Helleday, T. (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymerase Nature, 434, 913-7.
El-Khamisy, S.F., Saifi, G.M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J.R., Caldecott, K.W. (2005) Defective DNA Single-Strand Break Repair in Spinocerebellar Ataxia with Axonal Neuropathy-1, Nature, 434, 108-13.
Sørensen, C.S., Hansen, L.T., Dziegielewski, J., Syljuåsen, R.G., Lundin, C., Bartek, J., Helleday, T. (2005) The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair, Nature Cell Biology, 7(2), 195-201.
Saleh-Gohari, N., Bryant, H.E., Schultz, N., Parker, K.M., Cassel, T.N., Helleday, T. (2005) Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks, Molecular and Cellular Biology, 25(16), 7158–7169
The Svedberg Award 2009
Per Hammarström Assistant professor and group leader at the Department of Physics, Chemistry and Biology at Linköping University.
A committee consisting of members from the SFBM and Swedish National Committee for Molecular Biosciences boards has decided to propose Per Hammarström to the Svedberg Award 2009 for his ”Innovative contributions to the understanding of protein misfolding at a molecular level. His research contributes to understanding diseases caused by aberrant protein folding and protein aggregation.” Hammarström is affiliated at the Department of Physics, Chemistry and Biology at Linköping University. The award of SEK 35 000 together with the medal and diploma will be presented at the FEBS congress in Göteborg on 26 June-1 July 2010.
Presentation of Hammarström’s research
Background I received my MSc in Biochemistry at Linköping University in 1995 and joined thereafter Uno Carlsson´s research group as a PhD student. During my PhD studies I worked on protein folding studies of the protein carbonic anhydrase. Carbonic anhydrase was considered a monster in protein folding studies. 259 residues long, dominated by beta-sheet structure and filled with seventeen proline residues. CA did not follow simple kinetics and populated several folding intermediates. The notion at the time was that model proteins for folding studies should be fast folders i.e. small proteins (>130 residues was deemed large) preferably with alpha-helical structure stabilized by local contacts and to make circular dichroism studies easier. Preferably model proteins should be 2-state folders (only populating the native and unfolded conformation at equilibrium) since intermediates were considered off-pathway species and merely complicated the folding reaction. Anyway we worked diligently with CA and made some intriguing findings. We were interested in studying two specific aspects of protein folding: i) The interaction with folding assistants, i.e. molecular chaperones, that prevented protein aggregation, and ii) How residual structure in the unfolded protein guided folding towards the native state. We used new labeling methods to study residual structure of the unfolded state and interactions with the molecular chaperone GroEL.
After my PhD defense I received a Wenner-Gren fellow stipend and I joined Jeff Kelly at The Scripps Research Institute 2000-2002, where I studied the serum protein transthyretin, a protein linked to several amyloid diseases in humans, both sporadic and inherited. On transthyretin we were used biophysical measurements to reveal mechanistic insight into how the native protein was stabilized/destabilized by mutations and small molecule ligands. Ligands that we showed raised the kinetic threshold for TTR dissociation have recently entered clinical studies (now at phase II) for treatment of familial amyloidotic polyneuropathy, showing that biophysical protein folding studies are highly relevant for drug development. After my post-doc I returned to LiU on to a recruitment grant from SSF, and backed by the Wenner-Gren repatriation grant I started my group. I have since then been very fortunate to receive a junior research fellow position from VR and a FFL-2 grant from SSF, and most recently a KVA research fellow position. I was appointed Professor of Protein Chemistry in 2008.
Protein folding is an amazing example of molecular self-organization. With an astronomical number of possible conformations for the unfolded polypeptide the protein will fold spontaneously within fractions of a second (for small proteins) to minutes (for larger proteins).
Protein aggregation was for decades regarded as a mere nuisance in protein research. This process often occurred after a tedious isolation procedure for functional studies and in concentrated protein solutions used for setting up crystallization screens. Just as frustrating were the early days of protein folding when protein samples turned opalescent during rapid dilution of a chemically denatured protein in the stopped flow machine or during thermal denaturation. Few researchers at the time realized that the misfolded states of proteins would hold the key to some of the most severely debilitating diseases known to man.
With the discovery of molecular chaperones in the 1980s and their essentiality in cellular homeostasis things started to change. In the medical community, the discovery of insoluble protein deposits as pathognomonic hallmarks in various human diseases made researchers and pathologists alike realize that there was more to this than mere coincidence. The most amazing quality of protein folding is that it actually works at all, rendering functional proteins from the nascent chain protruding from the ribosome, despite the complex crowded environment of the cell and that the protein can undergo dramatic conformational conversions (folded to unfolded and back) in the surrounding hostile environment of the extracellular space.
Current research It is today recognized that impaired protein folding plays a key role in a wide variety of diseases. The misfolding diseases can for simplicity be divided into three main categories:
1) Loss-of-function diseases (e.g. Marble brain disease)
2) Gain-of-toxic-function diseases (e.g. Alzheimer’s disease)
3) Infectious protein misfolding (e.g. Creutzfeldt-Jakob disease)
There are substantial overlaps between these disease categories and for many diseases it is still not clear which of these mechanisms that are dominant for disease pathology. In several instances it is likely a combination of 1 and 2, which will further drive a vicious cycle of cell stress and organ impairment.
In my research group we are especially interested in how the conformational spaces of misfolded proteins are dictated and which folds/assembly forms that are pathogenic and which are not. We also investigate the effect of molecular chaperones, natural protectors against misfolded proteins, and small molecule ligands on the misfolding processes. In collaboration with others we model amyloid disease in transgenic Drosophila melanogaster and study functional response in vitro (cell culture or human fluids such as plasma).
One of the most intriguing aspects of these diseases is the templated conformational conversion that is believed to be the basis for prion infection. We investigate if this is a common molecular denominator for the amyloidoses, which could render the notion of prion-like infections a possibility in a vast array of more widespread diseases including Alzheimer´s disease. We study the human prion protein, the amyloid beta peptide and transthyretin which are all linked to protein deposition in the form of amyloid in vivo. There is ample evidence that different point mutations in these proteins dictate the disease phenotype. For the human prion protein around 20 different point mutations and two SNPs (rendering single residue substitutions) have been described which all present different disease phenotypes. The same phenomenon holds true for transthyretin (>100 mutations have been identified) and for amyloid beta which also extensively varies in peptide chain length, depending on processing. Our goal is to understand theprerequisites for amyloid fibril formation and conformational stability of both the native structure and the misfolded conformations. We have found that several aggregated forms of proteins can interconvert emphasizing that these are dynamic structures with rather shallow barriers between them. As spin-off effects, our findings could potentially be used for diagnostic and therapeutic intervention in these diseases.
Examples of publications on different proteins linked to misfolding diseases “Amyloid Fibrils of Human Prion Protein are Spun and Woven from Morphologically Disordered Aggregates”. Almstedt K, Nyström S, Nilsson KPR, Hammarström P. Prion (2009), 3 (4), in press.
“Modeling familial amyloidotic polyneuropathy (Transthyretin V30M) in Drosophila
Melanogaster”. Berg I, Thor, S, Hammarström P. Neurodegener Dis. (2009) 6(3):127-38.
“Small-molecule suppression of misfolding of mutated human carbonic anhydrase II
linked to marble brain disease”. Almstedt K, Rafstedt T, Supuran CT, Carlsson U, Hammarström P. Biochemistry (2009), 48(23):5358-64.
“Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer’s
disease using novel luminescent probes”. Nilsson KP, Aslund A, Berg I, Nyström S, Konradsson P, Herland A, Inganäs O, Stabo-Eeg F, Lindgren M, Westermark GT, Lannfelt L, Nilsson LN, Hammarström P. ACS Chem Biol. (2007) 2(8):553-60.
“Lysozyme amyloidogenesis is accelerated by specific nicking and fragmentation but
decelerated by intact protein binding and conversion”. Mishra R, Sörgjerd K, Nyström S, Nordigården A, Yu YC, Hammarström P. J Mol Biol. (2007) 23;366(3):1029-44.
The Svedberg Award 2010
Per Jemth Associate professor and group leader at the Department of Medical Biochemistry and Microbiology, Uppsala University.
A committee consisting of members from the SFBM and Swedish National Committee for Molecular Biosciences boards has decided to propose Per Jemth to the Svedberg Award 2010 for his ”Important contributions to the understanding of the interplay between protein folding and peptide-protein interactions in cell membrane protein organization.” The award of SEK 35 000 together with the medal and diploma was presented at the FEBS congress in Göteborg on 26 June-1 July 2010.
Presentation of Jemth’s research Background When I started my chemistry studies in Uppsala, I was favouring inorganic chemistry, possibly because of reading popular physics. But, I realized after a while how exciting the chemistry of life is and by the time I received my MSc in 1994, I knew biochemistry was what I wanted to do. I joined Bengt Mannervik’s group at Uppsala University for my PhD studies. Here, I worked on three different types of enzymes, mainly on glutathione transferases but also on glyoxalase I and glyoxalase II. Enzyme kinetics was my main tool and I used it to dissect enzyme mechanisms and the role of conformational changes in catalysis. I also ventured into enzyme evolution, which is a major area of research in Bengt’s group.
In my first postdoc (2000-2002) I changed scientific field to start working on glycobiology with Ulf Lindahl at the medical faculty at Uppsala University. It was widely believed in the glycobiology field that the glycosaminoglycan heparan sulfate contained a “code”, much like DNA. This view emerged from the very specific antithrombin-“heparin pentasaccharide” interaction, which Ulf and his coworkers successfully developed into the drug Fragmin. In my work I designed heparan sulfate oligosaccharide libraries and purified and sequenced a large number of saccharides and used these to assess ligand and substrate specificities for enzymes involved in biosynthesis of heparan sulfate as well as proteins known to interact with heparan sulfate. I did not find any evidence for specific interactions and from these experiments a new view emerged that most heparan sulfate-protein interactions are non-specific and mainly related to the overall charge of the molecule. The specificity of heparan sulfate-protein interactions is still a vexing issue in the field.
After this postdoc I looked for a new challenge and found it in protein folding. Up to then my knowledge about this absolutely fundamental aspect of protein science was close to zero and I was therefore happy to go to Cambridge, UK, on a long-term EMBO fellowship for two years to learn about protein folding in Alan Fersht’s lab. Here, I contributed to another controversial issue, the role of intermediates in protein folding. We found evidence for a productive intermediate in a small protein domain and also characterized the structure of the transition state for the folding reaction of this protein. Except for a solid knowledge in protein folding I found a long-term collaborator in Stefano Gianni, another postdoc in Alan’s group.
With this background, I came back to Sweden and the Department of Medical Biochemistry and Microbiology, Uppsala University, in 2004 with the aim of combining the different aspects of biochemistry I have worked on, into novel projects and ideas. My current position is a “forskarassistenttjänst” funded by the Swedish Research Council.
Current research There are two main projects in the lab. (1) folding, binding and allostery in protein-ligand interactions, and (2) oncogenic proteins from human papillomavirus.
(1) Folding, binding and allostery in protein-ligand interactions
One main aim is to address and answer the question: What is the relation between protein dynamics and function? The role of dynamics in protein function is currently a very hot topic in protein science. I here use the word “dynamics” in its widest sense, that is, it could be combined folding and binding of intrinsically disordered proteins to tiny and even transient rearrengements of the folded polypeptide. Yet, there is still a paucity of experimental data regarding many aspects of how dynamics actually influence the function of proteins. In my lab, we want to test current hypotheses regarding protein dynamics and address unanswered questions with experimental data. We also want to understand the most flexible functional polypeptides: intrinsically disordered proteins.
(2) Oncogenic proteins from human papillomavirus.
Cervical cancer is very common in the world with half a million new cases per year resulting in the deaths of more than 200,000 women. Infection by high-risk strains of human papillomavirus (HPV) is the cause of cervical cancer. A salient feature of HPV induced cancer is the continued expression of the two major viral oncoproteins, E6 and E7. We want to understand the molecular details of the interactions between these E6 and E7 proteins and their cellular targets. The final goal of this project is to find a drug lead/hit, which binds tightly to and incapacitates the oncogenic HPV proteins but which do not interact with other cellular proteins.
While the main expertise of my lab is protein engineering and kinetics we also use NMR, X-ray crystallography, single molecule spectroscopy and other techniques, via collaborations with a number of great scientists to whom I am much grateful.
Haq, S. R., Jürgens, M. C., Chi, C. N., Elfström, L., Koh, C. S., Selmer, M., Gianni, S., and Jemth, P. (2010) The plastic energy landscape of protein folding: A triangular folding mechanism with an equilibrium intermediate for a small protein domain. J. Biol. Chem. 285, 18051-18059.
Bach, A., Chi, C. N., Pang, G. F., Olsen, L., Kristensen, A. S., Jemth, P., and Strømgaard, K. (2009) Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95/NMDA receptor interaction. Angew. Chem. Int. Ed. 48, 9685-9689.
Chi, C. N., Bach, A., Engström, Å., Wang, H., Strømgaard, K., Gianni, S., and Jemth, P. (2009) A sequential binding mechanism in a PDZ domain. Biochemistry 48, 7089-7097.
Calosci, N., Chi, C. N., Richter, B., Camilloni, C. Engström, Å., Eklund, L., Travaglini-Allocatelli, C., Gianni, S., Vendruscolo, M. and Jemth, P. (2008) A comparison of the successive transition states for folding reveals alternative early folding pathways. Proc. Natl Acad. Sci. USA. 105, 19241-19246.
The Svedbergpriset 2011 tilldelas lundaforskare
Karin Lindkvist, forskare vid medicinska fakulteten på Lunds universitet, tilldelas The Svedberg-priset om 35 000 kronor för sina studier av aquaporiners struktur och dess reglering, och även för sin forskning kring T-cellsaktivering av superantigener. Karin Lindkvist läste sin grundutbildning i kemi vid Lunds universitet och fortsatte med att doktorera inom molekylär biofysik vid samma lärosäte. Karin disputerade 2003 och har därefter genomfört ett mycket framgångsrikt post-docprogram på Stanford University – School of Medicine i Kalifornien. Med ett Ingvar Carlsson-anslag från Stiftelsen för Strategisk Forskning etablerade Karin sig vid Göteborgs universitet och kunde bygga upp en självständig forskargrupp. Hon är i dagsläget verksam som forskare inom medicinsk strukturbiologi vid Lunds universitet.
Superantigener kan utsöndras från vissa bakterier och får man sådana bakterier i kroppen kan immunförsvaret reagera så starkt att man blir sjuk. Karin har nyligen med hjälp av röntgenkristallografi lyckats bestämma strukturen för ett superantigenkomplex med T-cellsreceptornoch majorhistokompabilitetskomplex (MHC) vilket publicerades i Nature Communications 2010. Superantigener är kända för att orsaka förgiftningssymtom, till exempel så kallad tampongsjuka. Det finns även teorier om att superantigeners inblandning i olika autoimmuna sjukdomar, exempelvis reumatism. Förhoppningen är att strukturstudien är ett led på vägen mot ett framtida vaccin mot superantigener.
Kristallografistudier av membranproteiner
Under tiden som forskarassistent i Göteborg blev Karin intresserad av membranproteiner. Hennes forskarlag lyckades bland annat med att kristallisera ett membranprotein med den hittills högsta upplösningen som någonsinrapporterats för membranproteiner. Strukturen visade att dessa proteintunnlarreglerar vattenbalansen i cellen, och kallas därmed för aquaporiner. Tunnlarna är trånga, endast en vattenmolekyl i taget
kan passera dem. Kunskapen om aquaporiners struktur kan vara oerhört värdefull för kommande läkemedelsutveckling.
The Svedbergpriset 2012 tilldelas Martin Högbom
Martin Högbom, forskare vid naturvetenskapliga fakulteten på Stockholms universitet, tilldelas The Svedberg-priset om 35 000 kronor för sina studier av ADP-ribosylhydrolasers struktur och funktion. Priset delades ut i samband med öppnandet av Svenska föreningen för biokemi, biofysik och molekylärbiologis årliga symposium i Tällberg, den 9 september.
Martin Högbom doktorerade inom biokemi vid Stockholms universitet och arbetade under tiden även vid Technische Universität Berlin och University of Toronto. Efter att ha disputerat 2003, var han postdoc vid Uppsala universitet och Karolinska Institutet. Martin erhöll därefter en forskarassistent-tjänst från vetenskapsrådet och etablerade en självständig forskargrupp. Han är idag docent och forskningsgruppsledare vid ”Stockholm Center for Biomembrane Research”, Institutionen för Biokemi och Biofysik, Stockholms universitet. Martin har erhållit ett flertal nationella och internationella utmärkelser för sin forskning och är även ledamot av Sveriges unga akademi.
Martin har bidragit med viktiga upptäckter inom flera forskningsområden med metalloproteiner som centralt tema, och visat på en mycket hög forskningsaktivitet. En viktig upptäckt i Högboms laboratorium rör ADP-ribosylering, en viktig posttranslationell modifiering av proteiner. ADP-ribos adderas på ett kontrollerat sätt till målproteiner och reglerar flera centrala cellulära processer, t.ex. DNA reparation och apoptos. ADP-ribosylering har också en viktig roll vid cellsignalering. Hur proteiner ADP-ribosyleras har undersökts i detalj av flera olika laboratorier, men det är självklart också av central betydelse att förstå hur ADP-ribos tas bort från målproteiner. Denna reaktion katalyseras av ADP-ribosylhydrolaser och Högboms laboratorium lyckades för några år sedan kristallisera ett sådant protein (DraG) i flera olika konformationer och i molekylär detalj förklara hur detta enzym kan ta bort ADP-ribos från målproteiner. Detta genombrott är inte bara av grundvetenskaplig betydelse, men har också betydelse för våra möjligheter att utveckla nya typer av läkemedel, som kan påverka nivåerna av ADP-ribosylering och styra centrala cellulära processer inblandade i t.ex. tumörutveckling.
Martin Ott disputerade hos Walter Neupert i München 2005, på en avhandling om membranproteinbiogenes i mitokondrier. Efter en framgångsrik postdoc hos Sten Orrenius på Karolinska Institutet där han studerade apoptos återvände han till Tyskland och universitetet i Kaiserlautern, där han först blev gruppledare och sedan erhöll en prestigefylld Juniorprofessortjänst. Martin är idag verksam som forskarassistent på Stockholms universitet.
Martin studerar proteinsyntes i mitokondrier, en process som har många unika drag. Translation, membranintegration och assemblering av mitokondriellt translaterade proteiner verkar styras av för varje mitokondriellt protein mycket specifika faktorer. Det har tidigare varit förhållandevis okänt hur produkterna från de få, ca. 30-40, gener som finns i mitokondriernas egen arvsmassa kan samverka med de flera hundra proteiner som återfinns i mitokondrierna men som kodats av cellkärnans arvsmassa. Det är molekylära detaljer i denna samverkan som Martin studerar, med fokus på hur cellens energifabrik – den mitokondriella elektrontransportkedjan – tillverkas. Denna fabrik består av ett antal membranbundna proteinkomplex som tillverkas i ett flertal intrikata steg inne i mitokondrien som kopplar samman mitokondriernas proteinsyntes med den i cellkärnan, och kräver ett komplicerat infogande och ihopsättning av fabrikens olika delar i mitokondriemembranet.
Med en kombination av klassisk biokemi och modern genetik har Martin Ott och hans forskargrupp i stor detalj lyckats kartlägga flera av de första stegen i detta syntesmaskineri, vilket har mycket stor grundläggande betydelse för vår förståelse av reglering och syntes av den ”fabrik” som ger upphov till den energi som mitokondrierna förser cellerna med, vilket i sin tur är nödvändigt för att vi alla ska kunna andas, leva och utföra våra arbeten. Martins forskarinsatser är därmed en god illustration på hur grundläggande biokemiska studier ger en ökad förståelse av livets kemi.
The Svedbergs pris i biokemi The Svedberg (1884-1971) var professor i fysikalisk kemi vid Uppsala universitet och forskningen fokuserade på kolloider och makromolekylära föreningar. Theorell fick Nobelpriset i kemi 1926 för de upptäckter han gjort med den av honom utvecklade analytiska ultracentrifugen. The Svedbergpriset är en vetenskaplig utmärkelse som årligen delas ut av svenska föreningen för biokemi, biofysik och molekylärbiologi tillsammans med den Svenska Nationalkommittén för molekylära biovetenskaper. Fonden upprättades med medel från den 9:e internationella biokemikongressen och syftar till att ge en årlig prissumma för vetenskaplig forskning inom biokemifältet i Sverige.
The Svedberg Prize of 2014 has been awarded to David Drew, Stockholm University.
David Drew, a scientist at the Natural Sciences faculty of Stockholm university has been awarded the Svedberg Prize for his structural and functional studies of membrane proteins. The prize award ceremony will take place on the 24th of September at Marstrand’s Havshotell at the 2014 annual meeting of the Swedish Society for Biochemistry, Biophysics and Molecular Biology (SFBBM). David Drew obtained his Masters degree from the University of Auckland, New Zeeland. In 2000 David started his PhD studies at the Department of Biochemistry and Biophysics, Stockholm University. He graduated in 2005 with a thesis describing novel methodology for overexpression and purification of membrane proteins. In 2006 he was awarded EMBO post-doctoral fellowship to join the group of Professor So Iwata at the Imperial College in London. There, he further developed his purification method and its application in membrane protein crystallography projects. Between 2009-2013 David was a Royal Society Fellow at the Imperial College in London where he supervised several PhD students. In 2013 he was recruited to Stockholm and started to create his research group at Stockholm University as a Wallenberg Academy Fellow. At Stockholm University David has established a research group with a focus on functional and structural studies of membrane transporters. David has received several national and international awards for his studies of membrane proteins.
All biological cells need to exchange various chemical entities with their surroundings. Proteins inserted into cell membranes control this process – in a typical cell about 30% of all genes are responsible for the expression of membrane proteins. It is estimated that about 50% of these proteins may play a role as drug targets and can be used in the development of new drugs against a broad range of diseases. The three-dimensional structure of these proteins is of crucial importance in the study of their function as well as in the design of new compounds of pharmaceutical interest. However, their expression, purification and crystallisation have always been a bottleneck in these studies.
David Drew’s research is focused on the general aspects of membrane proteins and particularly on a class called secondary transporters. In humans these transporters play essential role in many biological processes, among which are absorption of peptides, transport of cholesterol and sugars, transport of signal substances within synaptic vesicles and of pharmaceutical compounds. Understanding the fundamental mechanisms of these processes is of extreme importance, for example in the design of new pharmaceuticals. David has made substantial contribution to the development of novel methods for expression and purification of membrane proteins. Among these is protein stabilisation by detergent optimisation, which is required for more efficient and reproducible crystallisation of membrane proteins, and GFP-based optimisation of overexpression and purification of eukaryotic membrane proteins in yeast-based expression system. Using these methods, David and his group determined the three-dimensional structures of several membrane proteins: Na+/H+- antiporter, Na-dependent bile acid transporter, oligopeptide-proton transporter, and recently a mammalian glucose transporter. These works are not only of fundamental scientific interest, but may also play a central role in the development of new drugs for the treatment of, for example, hypertension, epilepsy, heart and blood vessel diseases, etc.
Ingemar André, Lunds universitet, tilldelas 2015 års Svedbergs pris för sina innovativa bidrag inom proteindesign. Genom att utveckla beräkningstekniska metoder har André visat att det är möjligt att designa proteiner som spontant bildar större aggregat med simultan kontroll över geometrier och gränsytor. Ingemar Andre har med sin forskning öppnat ett nytt område inom proteindesign och etablerat sig som forskningsledare i Sverige.
Årets Svedbergsstipendiat är Ingemar André som är lektor verksam vid kemiska institutionen vid Lunds Universitet. Ingemar disputerade 2005 vid Lunds Universitet och gjorde en postdoktor period mellan 2006-2009 hos David Baker vid University of Washington. Det var också vid University of Washington som Ingemar påbörjade sin profil inom proteindesign.
Proteindesign kan beskrivas som ett omvänt protein-folding problem, där man istället för att försöka förutsäga en struktur från ett proteins primärsekvens istället definierar en tredimensionell struktur och letar efter primärsekvenser som kan stabilisera denna struktur. Att hitta lämpliga primärsekvenser med denna ansats är mycket svårt och kräver innovativa beräkningsmetoder. Proteindesign har potentiella tillämpningsområden inom utveckling av enzymer som kan katalysera nya reaktioner. En konkret och viktig tillämpning är till exempel enzymatisk spjälkning av cellulosa till värdefulla småmolekyler. Ingemar André har tagit en unik riktnig inom proteindesign och utvecklar metodik för att designa större komplex av proteiner med samtidig kontroll över gränsytor och geometrier.
Ingemar André visade nyligen att ansatsen fungerar i en artikel i den ansedda tidsskriften PNAS (extern länk http://www.pnas.org/content/111/50/17875.long).
Ingemar André kommer ge en föreläsning om sin forskning under Svenska föreningen för biokemi, biofysik och molekylärbiologis årliga symposium som anordnas i Stockholm 21-22 September.
The Svedbergpriset är en vetenskaplig utmärkelse om cirka 40 000 kronor som årligen delas ut av svenska föreningen för biokemi, biofysik och molekylärbiologi tillsammans med den Svenska nationalkommittén för molkekylära biovetenskaper till en ung biokemist verksam i Sverige. Priset utgörs även av en silvermedalj samt ett handskrivet diplom. Fonden instiftades av Svenska nationalkommittén för biokemi och administreras av Kungliga vetenskapsakademin och syftar till att ge en årlig prissumma för vetenskaplig forskning inom biokemifältet i Sverige.