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Institute of Biotechnology
(Visiting address: Viikinkaari 9)
00014 University of Helsinki
Tel +358 2941 59358
Fax +358 2941 59366
University of Helsinki Business
Identity Code: FI-03134717
Hope for antivirals against parechoviruses
The Butcher and Wolthers labs as part of the AIROPico consortium have recently published an article providing an atomic model of human parechovirus 1. The atomic model was then used to define the epitopes and modes of neutralization for two potential therapeutic antibodies against human parechovirus 1.
Parechoviruses are medically-relevant human pathogens causing mild to severe infections. Currently there are no vaccines or antivirals against them. The Butcher and Wolthers labs as part of the AIROPico consortium in collaboration with the company AIMM Therapeutics, have recently published an article in the Journal of Virology providing an atomic model of human parechovirus 1.
The atomic model was then used to define the epitopes and modes of neutralization for two potential therapeutic antibodies against human parechovirus 1. These human monoclonal antibodies show cross-neutralization against other human parechoviruses as well.
The AM18 antibody recognizes arginine-glycine-aspartic acid motif present on viral capsid protein 1 and neutralizes the virus by competing with the cellular receptor which also recognizes the same motif. The AM28 antibody neutralizes by binding to a conformational epitope and blocking the viral RNA release site.
"This is a first step towards developing therapies against parechoviruses which is one of the long term goals of AIROPico," says Research Director Sarah Butcher.
The study was supported by the Seventh Framework Programme of the European Union AIPP under contract PIAPP-GA-2013-612308 (AIROPico), the Academy of Finland, the Sigrid Juselius Foundation, the Netherlands Organisation for Health Research and Development, The AMC Research Council, the European Molecular Biology Organization and the European Society of Clinical Virology.
Image: Pasi Laurinmäki (the model of antibody binding to human parechovirus 1.)
Cytoskeletons shaking hands
Cytoskeletal systems collaborate with each other in animal cells. Post-doctoral researcher Yaming Jiu has revealed that cytoplasmic intermediate filaments interact with arcs, specific contractile actin filament structures which transport intermediate filaments from cell periphery toward the nucleus.
Animal cells harbor three types of cytoskeletal elements: actin filaments, intermediate filaments and microtubules. Despite their name, cytoskeletons are very dynamic structures, which undergo rapid reorganization in cells and thus contribute to numerous cellular processes, such as morphogenesis, motility, intracellular transport, and cell division. Consequently, defects in cytoskeletal structures lead to various diseases, including cancer and neurological disorders.
Different cytoskeletal systems do not function in isolation, but collaborate with each other in cells. Post-doctoral researcher Yaming Jiu working at the Institute of Biotechnology, University of Helsinki has now revealed that cytoplasmic intermediate filaments interact with specific contractile actin filament structures called arcs.
"Actin arcs transport intermediate filaments from cell periphery toward the nucleus. Consequently, disruption of actin arcs led to an abnormal spreading of the intermediate filament network toward the cell periphery and associated defects in cell morphogenesis. Intermediate filaments resist the movement of arcs, and their depletion led to abnormalities in the shape of the arc-rich leading edge of motile cells," describes research director Pekka Lappalainen.
This study provides the first example of specific actin filament structures functionally interacting with intermediate filaments, and proposes that interplay between different cytoskeletal systems is crucial for diverse cellular and physiological processes.
The work was carried out in collaboration between the groups of Pekka Lappalainen and Markku Varjosalo at the Institute of Biotechnology, and John Eriksson’s group at the Turku Centre for Biotechnology.
Jiu Y, Lehtimäki J, Tojkander S, Cheng F, Jäälinoja H, Liu X, Varjosalo M, Eriksson JE, Lappalainen P. Bidirectional Interplay between Vimentin Intermediate Filaments and Contractile Actin Stress Fibers. Cell Press 28 May 2015. (PubMed)
New Academy Research Fellowships to BI
Andrii Domanskyi, Ville Paavilainen, Laura Ahtiainen, Markku Varjosalo and Sari Tojkander have been awarded the Academy Research Fellowships.
Anddrii Domanskyi works as a postdoctoral researcher in Mart Saarma’s group. In his research project “Neuroprotective microRNAs, trophic factors and stress in adult dopaminergic neurons: significance for Parkinson’s disease” Domanskyi aims to identify specific neurotrophic factor induced microRNAs that are essential for neuronal survival and are able to prevent the degeneration of dopaminergic neurons. The work may lead to the development of novel therapies to treat Parkinson's disease.
In project “Translocational regulation of protein biogenesis” Group Leader Ville Paavilainen proposes to reveal the mechanism by which a unique small-molecule Sec61 inhibitor achieves its substrate-selectivity. Additionally, the project aims to identify the cellular roles of a conserved translocon component whose inhibition can be utilized for therapeutic purposes.
Laura Ahtiainen is from Irma Thesleff’s group. Her project “Imaging cellular mechanisms of epithelial morphogenesis in development and disease” focuses on the cellular events that lie between the genetic signaling networks and observed phenotypes in transgenic mouse models.
In Group Leader Markku Varjosalo’s project “Human Kinome and Cancer” his team will identify the phosphorylation mediated informational flow and map the architecture and dynamics of molecular networks that have important clinical implications for cancer.
Sari Tojkander has been working in Pekka Lappalainen lab. She will start her own group in the Faculty of Veterinary Medicine and continue her research project “Cellular forces in breast cancer” there. In this project she is in understanding how tumor stroma influences the major force-producing actomyosin structures in breast cancer cells and how the consequent changes in intracellular force-production affects the ability of these cancer cells to scatter and invade.
The funding for Academy Research Fellows is granted for five years and the funding period is set to start in September.
Director Howy Jacobs congratulating Andrii Domanskyi
Photo: Tinde Päivärinta
Tommi Kajander’s team received 0.47M€ funding for structural studies of membrane proteins of the synapse
Grant from Jane and Aatos Erkko Foundation allows the group to expand on the studies of the synaptic integral membrane proteins.
Team leader Tommi Kajander received 470 k€ from Jane and Aatos Erkko foundation to study the structural biology of neuronal synaptic adhesion proteins and integral membrane proteins.
"The aim is to continue the structural and functional studies of synaptic adhesion molecules and their ligands. We have already recently crystallized some of them and solved some of their structures," Tommi Kajander says.
The most important goal of the Erkko funding according to Kajander is to expand on the studies of the synaptic integral membrane proteins. For most of these only structures of bacterial homologs are known.
"Our aim is to develop protein engineering and expression techniques towards solving structures of vertebrate synaptic proteins such as the voltage gated Ca2+ channel and other synaptic and neuronal membrane protein targets. "
The group also wishes to use imaging techniques of synaptic adhesion with fluorescence and electron microscopy to look at larger scale structures induced by the adhesion protein expression at the neuronal synapses.
All of the proteins studied are involved in neurological diseases and disorders, such cognitive disorders and epilepsy, stroke and pain and migraine. Therefore the structural and functional results will have important impact on understanding these diseases and the maintenance of synaptic functions overall.
Looking to fossils to predict tooth evolution in rodents
Fifty million years ago, all rodents had short, stubby molars – teeth similar to those found in the back of the human mouth, used for grinding food. Over time, rodent teeth progressively evolved to become taller, and some rodent species even evolved continuously growing molar teeth. A new study published in the journal Cell Reports predicts that most rodent species will have ever-growing molars in the far distant future
“Our analyses and simulations point towards a gradual evolution of taller teeth, and in our future studies we will explore whether tinkering with the genetic mechanisms of tooth formation in lab mice—which have short molar teeth—will replicate the evolution of taller teeth,” says co-senior author Ophir Klein, an associate professor at the University of California San Francisco School of Dentistry.
For their research, Dr. Klein and his colleagues used fossil data from thousands of extinct rodent species to study the evolution of dental stem cells, which are required for continuous tooth growth. They found evidence that most of the species possess the potential for acquiring dental stem cells, and that the final developmental step on the path toward continuously growing teeth may be quite small. "Just studying how molars become taller should tell us about the first steps in the arrival of stem cells," Klein says
The team’s computer simulations predict that rodents with continuously growing teeth and active stem cell reserves will eventually outcompete all other rodent species, whose teeth have a finite length. This won’t likely apply to people, however.
“As we humans have short teeth, evolutionarily speaking we would have to go through multiple steps that would take millions of years before we could acquire continuously growing teeth. Obviously, this is not something that would happen as long as we cook our food and don’t wear down our teeth,” says co-senior author Jukka Jernvall, an evolutionary biologist at the University of Helsinki, in Finland. “However, regarding rodents, it will be interesting to resolve the regional and taxonomic details of the 50 million year trend.”
Tapaltsyan V, EronenJT, Lawing AM,Sharir A, Janis C, Jernvall J, and Ophir, Klein OD. Continuously growing rodent molars result from a predictable quantitative evolutionary change over 50 million years. Cell Reports 2015; 11: 1–8.
Image: Vagan Tapaltsyan and Ophir Klein
Connecting industry and academia
Dr Toomas Neuman spent two months in Finland creating wider networks and planning new business enterprises. This was made possible by AIROPico, a Marie Curie Industry – Academia Partnership and Pathways Grant within the EU’s Seventh Framework Programme, promoting staff exchanges between industry and academia in the picornavirus field.
CSO Toomas Neuman of an Estonian company Protobios has had a busy two month period in Finland. Since January, he has been taking part of all kinds of activities within AIROPico, a project generating more knowledge on infections caused by human picornaviruses. The project is also a part of another project creating contacts between enterprises and academia.
"Actually, this collaboration came in a good time. I am a molecular cell biologist and as such not familiar with analysing techniques for viruses," says Toomas Neuman, who has been doing business in the biotechnology field both in the U.S. and in Estonia since 1999.
Dr Neuman's time in Finland has been divided between contacts in Helsinki, Turku and Tampere. In the University of Helsinki he has been collaborating with Sarah Butcher's research group in the Institute of Biotechnology, attending seminars, giving lectures, taking part in workshops and generally getting to know people.
"Connections are important. My main target here is community building. That works better in Europe than in the U.S. as the grant system here forces you to find partners. In the U.S. you are more on your own."
In Helsinki Dr Neuman put together a group of students interested in starting a business of their own.
"We went through all the procedures step by step, so now the students know what it takes to build up a company. It is essential to realise that you need partners in creating a successful company. As a researcher, you can start one, but you cannot bring it much further without any money. And most researchers don't have all the business knowledge even if they have the best knowledge of their own field of science. So you will need connections."
Dr Neuman has for years had connections in Finland. He has collaborated with for example Professor Mart Saarma and Professor emeritus Antti Vaheri.
"Professor Vaheri and others have found out that a small number of vaccinated people – using one particular type of flu vaccine – develop narcolepsy. Collaborative research has identified that vaccinated people who develop narcolepsy developed antibodies that target sleep center in the brain and can be related to development of narcolepsy", Dr Neuman says.
Dr Neuman with his Finnish collaborators is planning to establish a new company in Finland to explore further the possibilities of this find. He also wants to encourage the researchers to start thinking about new possibilities. "Often the big things in science happen somewhere else than in small countries like Finland, Estonia and Sweden. We have to try to get those things happen here, too! But that needs work, and you can get nowhere without collaboration," Dr Neuman says.
Text and photo: Elina Raukko
Stem cells age-discriminate organelles to maintain stemness
Study suggests that asymmetric apportioning of old cellular components during cell division may represent an anti-aging mechanism by stem cells.
Tissue stem cells, that continuously renew our tissues, can divide asymmetrically to produce two types of daughter cells. One will be the new stem cell, where as the other will give rise to the differentiating cells of the tissue.
A study jointly lead by laboratories in the Institute of Biotechnology and Massachusetts Institute of Technology (MIT) investigated whether stem cells may also use asymmetric cell division to reduce accumulation of cellular damage. Damage buildup can cause stem cell exhaustion that results in reduced tissue renewal and aging.
Researchers developed a novel approach to follow cellular components, such as organelles, age-selectively during cell division.
“We found that stem cells segregate their old mitochondria to the daughter cell that will differentiate, whereas the new stem cell will receive only young mitochondria” says Pekka Katajisto, a Group leader and Academy research fellow at BI.
Mitochondria appear to be particularly important for stem cells, as other analyzed organelles were not similarly age-discriminated, and since inhibition of normal mitochondrial quality control pathways stopped their age-selective segregation.
“There is a fitness advantage to renewing your mitochondria,” says David Sabatini, Professor at MIT and Whitehead Institute. “Stem cells know this and have figured out a way to discard their older components.”
While the mechanism used by stem cells to recognize the age of their mitochondria remains unknown, forced symmetric apportioning of aged mitochondria resulted in loss of stemness in all of the daughter cells. “This suggests that the age-selective apportioning of old and potentially damaged organelles may be a way to fight stem cell exhaustion and aging,” says Katajisto.
Katajisto laboratory is now exploring how old mitochondria differ from old, and whether this phenomenon occurs in other cell types beyond the human mammary stem-like cells examined here as well as in in vivo.
Human mammary stem-like cell apportions aged mitochondria asymmetrically between daughter cells. Mitochondria were labeled age-selectively red 51 hours prior to imaging, leaving mitochondria that are younger unlabelled. The daughter cell that will become the new stem cell (bottom left) receives only few old mitochondria.
Katajisto P, Döhla J, Chaffer C, Pentinmikko N, Marjanovic N, Iqbal S, Zoncu R, Chen W, Weinberg RA, Sabatini DM. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science. 2015 Apr 2. pii: 1260384. [Epub ahead of print]
Picture: Julia Döhla
€ 0,9 M as grants from the Sigrid Juselius Foundation
According to the decision made on 18 March, Sigrid Juselius Foundation is financing 17 researchers in the Institute of Biotechnology with grants worth almost € 900,000. About € 200,000 of the total is directed to young research group leaders.
The researchers of the Institute of Biotechnology (BI) have been given almost € 0.7 M as established researchers' grants by the Sigrid Juselius Foundation. The established researchers' share in the BI is about 7.6 % of the total amount of the grants of their category.
The new and continued grants given by the SJF for new group leaders were worth € 1.16 M. The Institute's share of those grants – almost € 0.2 M – was about 16.5 per cent of the total.
Grants for young research group leaders
Grants for established researchers
SPPS Early Career Award to Ari Pekka Mähönen
SPPS Early Career Award is a monetary award to an early career scientist based in Scandinavia. The award is granted to a young, highly talented scientist, who has shown good progress and made significant, independent contributions to Scandinavian plant biology.
This time the Award was decided to give to two equally qualified young scientists, Dr. Ari Pekka Mähönen from the Institute of Biotechnology and Dr. Nathaniel Street, from Umeå University.
Societas Physiologiae Plantarum Scandinavica (SPPS) is an international society based in Scandinavia promoting experimental plant physiology from molecular biology to ecophysiology.
More information in the SPPS Newsletter
Recognition to several leading researchers and staff of the Institute
University rector Jukka Kola has recognized the outstanding contributions of 37 UH employees, including Group Leader Petri Auvinen, Research Technicians Merja Mäkinen, Riikka Santalahti, Technician Anna-Liisa Nyfors and Academician Irma Thesleff from BI, by the award of a special medal of honour.
In his speech Kola mentioned that the recipients have, as a members of the scientific community, met researchers, students and a wide range of customers for many years and made a significant contribution to University and society.
Golden scientific community medal may be granted at least 30 years in the service of the scientific community. It is granted by the Federation of Finnish Learned Societies.
New collaborative effort among Nicolas Di-Poi’s Laboratory and Finnish herpetologists for researching craniofacial patterning and evolution in snakes
In collaboration with the tropical zoo “Tropicario” in Helsinki, Dr Nicolas Di-Poi’s Laboratory obtained about 25 large eggs of about 100 mm from African rock python (Python sebae), the Africa's largest snake and one of the five largest snake species in the world (specimens may approach or exceed 6 m). The female snake incubates them for about 3 months and aggressively defends her eggs.
Di-Poi’s Laboratory is using non-classical model organisms at key phylogenetic positions and showing high levels of morphological variation/innovation for studying the Evo-Devo of craniofacial tissues. Developing python embryos from those eggs will be used for understanding how the developmental genetic program has evolved to generate the impressive morphological diversity of skull bones in snakes.
Picture: Jarmo Lanki
New information on Parkinson’s disease: neural growth factor GDNF not needed by the midbrain dopamine system
Recent Finnish study overturns results from seven years ago.
A key factor in the motor symptoms associated with Parkinson’s disease is the gradual degeneration and death of dopamine neurons. The glial cell-derived neurotrophic factor, or GDNF, has been proven to protect dopamine neurons in test tube conditions and in animal models for Parkinson’s disease. GDNF and its close relative, neurturin, have also been used in experimental treatments of patients with severe Parkinson’s disease. The results have been promising, but vary widely in terms of efficacy. At the moment, two companies are conducting tests to determine the clinical effects of GDNF on Parkinson’s sufferers.
According to an article published in Nature Neuroscience in 2008, removing GDNF from adult mice through gene technology causes significant damage to the midbrain dopamine system as well as triggers motor disorders. The article concluded that GDNF is vital to the maintenance and function of dopamine neurons in adult animals.
At the same time, Academy of Finland Research Fellow Jaan-Olle Andressoo, from Professor Mart Saarma’s research group at the Institute of Biotechnology, had developed a mouse model that was equivalent to the model used in the other study, with minor technical differences. In Andressoo’s model, GDNF was removed from the central nervous system towards the end of the fetal period through gene deletion, and the mice remained healthy until high age. They studied the brains of the GDNF knockout mice together with the research group of University Lecturer Petteri Piepponen, based in the Faculty of Pharmacy.
“We decided to confirm the previous result using the mouse model Andressoo developed, and noticed that the complete absence of GDNF did not cause significant changes to the number or function of dopamine neurons. Since the result surprised us, we wanted to verify it using two alternative methods, one of which was identical to the method in the previously published article,” explains Dr Jaan-Olle Andressoo.
In addition, some of the experiments were conducted in parallel at Professor Anders Björklund’s laboratory at Lund University. The Lund tests similarly indicated no changes to the dopamine systems or the behaviour of the mice. This clearly established that GDNF is not a necessary component of the maintenance of midbrain dopamine system.
The manuscript including the new research results was approved for publication in the same series as the previous study – in a respected Nature Neuroscience journal. However, the study was subjected to even closer scrutiny than is associated with the normal publication procedure.
“The editors considered the manuscript to be a correction, so in addition to the normal peer review, they sent it to the researchers who published the previous results for comments. Ultimately, our results were deemed indisputable.”
Kopra J, Vilenius C, Grealish S, Härma MA, Varendi K, Lindholm J, Castrén E, Võikar V, Björklund A, Piepponen TP, Saarma M, Andressoo JO. GDNF is not required for catecholaminergic neuron survival in vivo. Nat Neurosci. 2015 Feb 24;18(3):319-22
Mart Saarma has been appointed Vice President of the European Research Council
Professor Mart Saarma has been appointed Vice President of the European Research Council. He will take over the Life Sciences domain. He was already serving as ERC Scientific Council member since 2011.
The ERC Scientific Council represents the European scientific community, and decides the ERC strategy and distribution of funding.
Prof. Saarma has studied the structure, biology and therapeutic potential neurotrophic factors and their receptors. His recent studies are focused on the role of neurotrophic factors in development and neurodegenerative diseases. His group has characterised several new GDNF family receptors and demonstrated that RET receptor tyrosine kinase is the signalling receptor for GDNF. Recently his group has discovered a new neurotrophic factor CDNF and shown that it very efficiently protects and repairs dopamine neurons in animal models of Parkinson’s disease. He has received several domestic and international science prizes, including the Nordic Science Prize by Lundbeck Foundation in 2009. He is the member of several academies and EMBO. Currently he is the member of EMBO Council and Vice President of the European Research Council.
A novel role for mRNA export factor Ddx19/Dbp5 in nuclear import of MKL1 identified
RNA export factor Ddx19 is required for nuclear import of the SRF coactivator MKL1
Controlled transport of macromolecules between the cytoplasm and nucleus is essential for homeostatic regulation of cellular functions. For instance, gene expression entails coordinated nuclear import of transcriptional regulators to activate transcription and nuclear export of the resulting mRNAs for cytoplasmic translation.
Kaisa Rajakylä from the research group of Dr. Maria Vartiainen has now linked these two processes by reporting a novel role for Ddx19/Dbp5, an established mRNA export factor and translation regulator, in nuclear import of MKL1, the signal-responsive transcriptional activator of SRF.
They show that Ddx19 is not a general nuclear import factor, and that its specific effect on MKL1 nuclear import is separate from its role in mRNA export. Mechanistically, Ddx19 operates by modulating the conformation of MKL1, which affects its interaction with Importin-b for efficient nuclear import. They thus propose that Ddx19 plays an important role in coordinating the key nucleo-cytoplasmic shuttling events in gene expression by linking transcriptional activation, mRNA export and translation.
In serum stimulated MCF7 cells MKL1-GFP (green) is nuclear (left), but becomes more cytoplasmic in cells depleted with Ddx19 (right). Nucleus is stained with dapi (blue).
Rajakylä EK, Viita T, Kyheröinen S, Huet G, Treisman R, Vartiainen MK. RNA export factor Ddx19 is required for nuclear import of the SRF coactivator MKL1. Nat. Commun. 6:5978 doi: 10.1038/ncomms6978 (2015).
Text and picture: Maria Vartiainen and Kaisa Rajakylä
- Auvinen lab / DNAGEN
- Bamford lab
- Butcher lab
- Di-Poi lab
- Frilander lab
- Helariutta lab
- Hietakangas lab
- Holm lab
- Iwai lab / NMR
- Jacobs lab
- Jernvall lab
- Jokitalo lab / EM
- Katajisto lab
- Lappalainen lab
- Löytynoja lab
- Mähönen lab
- Ojala lab
- Paavilainen lab
- Permi lab
- Saarma lab
- Schulman lab
- Shimmi lab
- Thesleff lab
- Varjosalo lab / Proteomics unit
- Vartiainen lab
- Airavaara Mikko
- Andressoo Jaan-Olle
- Fagerholm Susanna
- Kajander Tommi
- Kuure Satu
- Michon Frederic
- Mikkola Marja
- Nyman Tuula
- Salazar-Ciudad Isaac
- Zhao Hongxia
- Wikström lab
- CoE in Metapopulation Research (2012-2017)
- Coe in Bio membrane Research (2014-2019)
- CoE in Experimental and Computational Developmental Biology (2014-2019)
- CoE of Molecular Biology of Primary Producers (2014-2019)
- CoE in Translational Cancer Biology (2014-2019)
Academy of Finland Centres of Excellence operating in the Institute