- Latest publications
- Research database Tuhat (browse public data)
- Research database Tuhat (manage data, log-in)
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
Boosting the body’s own production of neurothrophic factors could help Parkinson’s sufferers
A recent study indicates that GDNF clearly regulates the function of the dopaminergic neurons in the midbrain. With the help of a new research method, the amount of GDNF was topically increased specifically in the areas of the brain associated with GDNF production, such as the areas which are central to the development of Parkinson's disease.
The motor symptoms of Parkinson’s result from the gradual loss of function and subsequent destruction of dopaminergic neurons in the midbrain. GDNF-based therapy has been one of the most promising treatments for Parkinson’s. In animal models, GDNF injected directly into the head has effectively protected dopaminergic neurons from experimental damage, and even repaired existing damage.
The efficacy of GDNF has also been tested on Parkinson’s sufferers, but despite initial promising results, extensive benefit was not conclusively established in the two second-stage clinical studies so far conducted.
“The modest results are likely at least partially attributable to problems with dosage and delivery. GDNF is a large protein, so introducing it directly into brain tissue is difficult, and can result in uncontrolled neurite outgrowth at the injection site. Further information is also needed on the mechanisms through which GDNF influences the dopaminergic neurons, particularly in the ageing brain,” states Jaan-Olle Andressoo, principal investigator at the University of Helsinki’s Institute of Biotechnology.
Controlled release of GDNF possible
Jaan-Olle Andressoo has developed a new microRNA-based method for increasing the amount of GDNF in the brain.
“The benefit of the resulting mouse model is that the amount of GDNF is increased in a controlled manner and only in the cells that normally express it. In the part of the brain most crucial for Parkinson's disease, the striatum, the expression of GDNF was doubled. In addition, the expression remains susceptible to normal gene regulation. This means we can gain information on the physiological effects of GDNF, which was not possible with previous methods,” Jaan-Olle Andressoo explains.
In follow-up studies conducted at the University of Helsinki's Faculty of Pharmacy, the overexpression of GDNF was found to slightly increase the number of dopaminergic neurons as well as the amount of dopamine in the striatum. The overexpression also enhanced the release of dopamine and protected the neurons from damage.
The impact on Parkinson’s disease was studied together with Professor Mart Saarma. Researchers from Umeå University and the University of Tartu also participated in studying GDNF’s mechanisms of action.
Based on the research results, principal investigator Jaan-Olle Andressoo is now developing methods which would enable the increase bodies own GDNF levels inside the brain.
“If we succeed, we will probably be able to restore neural connections that have already been weakened using specific elevation of bodies own neurotrophic factors, first among Parkinson’s sufferers, and later among patients with other degenerative neural illnesses. Our preliminary results are highly promising,” suggests Andressoo.
Kumar A, Kopra J, Varendi K, Porokuokka LL, Panhelainen A, Kuure S, Marshall P, Karalija N, Härma MA, Vilenius C, Lilleväli K, Tekko T, Mijatovic J, Pulkkinen N, Jakobson M, Jakobson M, Ola R, Palm E, Lindahl M, Strömberg I, Võikar V, Piepponen TP, Saarma M, Andressoo JO. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. PLoS Genet. 2015;11(12):e1005710
Article in Plos Genetics
A new open access software for processing and quantification microscopy datasets
Multidimensional light (LM) and electron (EM) microscopy imaging is among the key methods in biosciences nowadays. The knowledge of complex 3-D structures of cells and cell organelles in their natural context is important for understanding the structure-function relationship. As the amount of collected data is exponentially increasing, the effectiveness of processing raw data into analyzed results has key importance.
To address the challenges of processing of large microscopy datasets, over the last four years the research team of Eija Jokitalo at the Electron Microscopy Unit of the Institute of Biotechnology, has been developing their own software solution: Microscopy Image Browser (MIB). MIB is an open source software aimed for efficient processing and image segmentation of multidimensional datasets obtained by both LM and EM. Use of MIB improves and eases the full utilization of the acquired data and allows quantitatively analyze morphological features. The effectiveness of using MIB in research has been already proved in more than 10 different scientific projects, ranging from cellular level to whole organisms. MIB is a flexible package that is easily extended with a custom plugins to address specific questions of any research project.
Concomitant to publishing a paper describing its features, MIB was officially released under the terms of the GNU General Public License v2 and is now freely available from a dedicated website: http://mib.helsinki.fi. In addition to the program itself, the website contains a collection of test cases and video tutorials.
Belevich I, Joensuu M, Kumar D, Vihinen H, Jokitalo E. (2015) Microscopy Image Browser: A Platform for Segmentation and Analysis of Multidimensional Datasets. PLoS Biol.14(1):e1002340.
A collage image of a graphical user interface of Microscopy Image Browser (MIB) and a 3D model of Trypanosoma brucei. The dataset was obtained with Serial Block Face Scanning Electron Microscopy and processed and segmented using MIB. Image by Ilya Belevich, Institute of Biotechnology, University of Helsinki.
Article in PLoS Biology.
Picture: EM unit
At the roots of mammals – specification of mammary cells
Mammary glands, or breasts, are the class defining features of mammals and successful development and function of the mammary glands is vital for the survival of offspring. Mammary gland development commences during embryogenesis with the establishment of a species typical number of mammary primordia, 5 pairs in mice, on each flank of the embryo. It is thought that mammary cell fate can only be induced along the mammary line, a narrow region of the ventro-lateral skin running from the axilla to the groin, but the molecular mechanisms of mammary cell fate specification are still poorly understood.
In a recent study, published in PLoS Genetics, Marja Mikkola’s research team at the Institute of Biotechnology, University of Helsinki, has addressed this question by analysing loss- and gain-of-function mice of the Ectodysplasin (Eda)/Edar/NF-κB pathway. Eda is a signaling molecule that regulates the formation of organs that develop as appendages of the skin (hair and several glands) in all vertebrates studied so far. In humans, mutations in the EDA pathway genes cause a congenital disorder characterized by sparse hair, missing teeth, and defects in exocrine glands including the breast. It was previously shown that even though Eda is dispensable for induction of mammary primordia, excess Eda induces formation of supernumerary mammary glands in mice.
The new study revealed that overexpression of Eda (in transgenic K14-Eda mice) led to formation of extra mammary glands also in the neck, a region previously not thought to harbor capacity to support mammary development. Further, the effects of Eda were shown to be mediated by transcription factor NF-κB. Genome-wide transcriptional profiling identified several downstream mediators of Eda/ NF-κB including many members of the Wnt signaling pathway. With the aid of an ex vivo culture system, Maria Voutilainen, the first author of the study showed that suppression of canonical Wnt signaling dose-dependent inhibited formation of supernumerary mammary primordia in K14-Eda tissue explants.
The presence of extra nipples is a fairly common developmental abnormality in humans, and it is tempting to speculate that misregulation of Eda or its effectors might account for some of these cases. Moreover, tinkering with the Eda pathway activity could provide an evolutionary means to modulate the number and location of mammary glands known to vary greatly between mammals, similar to its confirmed involvement in regulating the number of sweat glands in humans and armor plates in threespine sticklebacks.
Developing mammary glands in control and K14-Eda mouse embryos. Positions of mammary buds 1 to 5 are indicated; black arrows highlight the incipient supernumerary mammary primordia along the milk line and red arrow a supernumerary mammary bud in the neck.
Voutilainen M, Lindfors PH, Trela E, Lönnblad D, Shirokova V, Elo T, Rysti E, Schmidt-Ullrich R, Schneider P, Mikkola ML (2015). Ectodysplasin/NF-κB promotes mammary cell fate via Wnt/β-catenin pathway. PLoS Genet 11:e1005676.
Article in Plos Genetics
Picture: Maria Voutilainen
How do cells sense their mechanical environment?
Studies from the past few years have revealed that, in addition to guidance by biochemical signals such as growth factors, also the mechanical properties of extracellular matrix and neighboring cells have a fundamental role in cell morphogenesis, differentiation and migration. Furthermore, it has become evident that defects in reading the mechanical properties of the extracellular environment are associated with cancer progression.
Contractile actin filament bundles, called stress fibers, are the major mechanosensitive structures in many animal cells. These actomyosin bundles form only in rigid environment, and their assembly and alignment can be controlled by external forces applied to the cell. However, the principles underlying the mechanosensitive formation of stress fibers have remained elusive.
In a new study, the laboratory of Pekka Lappalainen at Institute of Biotechnology, University of Helsinki, discovered that both assembly and disassembly of actin filaments in stress fibers are precisely regulated by tension. In this paper, published in eLife, they also identified a signaling pathway that controls mechanosensitive actin filament assembly in focal adhesions located at the tips of stress fibers.
-These findings uncover the principles by which mechanosensitive actin structures form in cells. Interestingly, many components in this pathway are de-regulated in various cancers. Thus, in the future it will be important to examine how disruption or re-activation of this newly identified mechanosensitive pathway affects cancer progression, says Sari Tojkander, the first author of this study.
'Actin stress fibers (left panel) can apply strong forces to their substrate as measured by traction force microscopy (right panel)
Tojkander S, Gateva G, Husain A, Krishnan R, Lappalainen P (2015): Generation of contractile actomyosin bundles depends on mechanosensitive actin filament assembly and disassembly. eLife
Picture: Lappalainen group
Pekka Katajisto receives 1,5M€ from ERC to investigate the mechanisms of asymmetric cell division in relation to aging
Our tissues are constantly renewed by stem cells. Over time, stem cells accumulate cellular damage that will compromise renewal and results in aging. As stem cells can divide asymmetrically, segregation of harmful factors to the differentiating daughter cell could be one possible mechanism for slowing damage accumulation in the stem cell. Earlier this year the laboratory of Pekka Katajisto discovered that some stem cells apportion chronologically old cellular components asymmetrically in cell division. Katajisto, a Group Leader at the Institute of Biotechnology, has now received ERC Starting Grant (1 500 000€) to investigate the mechanisms underlying this novel phenomenon and its relevance for aging.
- First we aim to identify how old and young cellular compartments differ, and how stem cells recognize them to facilitate the asymmetric segregation, says Katajisto.
The mechanistic studies will allow Katajisto’s lab to determine if age-selective segregation of organelles is necessary for stem cell maintenance and tissue regeneration. Results may also open new possibilities to target aging associated functional decline and the multitude of aging associated diseases.
- We are very excited for the ERC grant. The best results are yet to come, Katajisto continues.
Picture: Veikko Somerpuro
Mart Saarma has been elected as a member of Academia Europaea
Professor Mart Saarma has been elected as a member of Academia Europaea - The Academy of Europe, which brings together leading scientists and scholars to collectively promote learning, education and research. Founded in 1988, with about 3000 members which includes leading experts from the physical sciences and technology, biological sciences and medicine, mathematics, the letters and humanities, social and cognitive sciences, economics and the law. Membership is by invitation.
Prof. Mart 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. 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 Saarma is the member of EMBO Council and Vice President of the European Research Council.
Picture: Linda Tammisto
High-risk research, part 2:
Research in kidney development can provide solutions for many renal insufficiency patients
Supported by the Academy of Finland’s high-risk funding, Satu Kuure is studying the development of the kidneys and lower urinary tract.The research could help patients with congenital kidney disorders, cancer and diabetes.
Functional renal defects have a profound impact on our national economy. In addition to cleft lip/palate and heart disease, congenital kidney malformations are amongst the most common congenital defects. A reduced number of nephrons due to a developmental defect also renders the person susceptible to high blood pressure. As well, chemotherapy and diabetes can severely disrupt the function of the kidneys especially in the patients with already reduced nephron number.
“As many as one in three hundred children has a congenital kidney disorder, and there is currently no cure as such. Dialysis is extremely expensive and inconvenient, and approximately 60% of transplanted kidneys ultimately cease to function,” explains team leader Satu Kuure, who received high-risk funding from the Academy of Finland in September to support her research in the development of the kidneys and lower urinary tract.
The initial funding period is 16 months, and at the end of 2016 the Academy will evaluate the progress of the projects to select the ones eligible for extended funding.
Kuure, a biochemist who received her Master’s degree from the Faculty of Science at the University of Oulu and her doctorate from the Faculty of Medicine at the University of Helsinki, became interested in the development of the kidneys and cellular communication at an early stage. While working at Columbia University after completing her dissertation, she heard that there was a new mouse model with abnormally developing kidneys generated in Professor Mart Saarma’s lab at the Institute of Biotechnology.
“It turned out that overproduction of a protein that is instrumental in the proper growth and shape of kidneys, leads to smaller kidneys and problems with the differentiation of several other tissue types.”
Kuure team has since then worked with two other mouse models which are expected to be helpful in unlocking the secrets of kidney development. Research with these mouse models is not easy to carry out, as it involves simultaneous modification of three different genes.
“We are at the core of real medical problems: through basic research, we are ensuring the generation of new applications, which in turn may lead to new forms of treatment," remarks Kuure, who has worked as team leader for just over a year.
At the moment, Satu Kuure’s group employs four people.
Darshan Kumar represents University of Helsinki at international doctoral candidate meeting
Each capital university nominated just one representative for the UNICA and COIMBRA training in Dubrovnik in October
Darshan Kumar is a PhD student in the research group led by Eija Jokitalo at the Institute of Biotechnology, and an active member of the BiotechClub in the Integrative Life Science Doctoral Programme ILS. He was nominated by Vice Rector Keijo Hämäläinen to represent the University of Helsinki at the joint training for doctoral candidates in Dubrovnik, Croatia. The UNICA and COIMBRA training brought together students from each European capital university, one from each.
“The sole purpose of this training was to make all the PhD students from interdisciplinary fields realise the strengths of doing a PhD, and to learn to channel the skills acquired during a PhD to navigate your future career,” Kumar explains. “Not only did we get to understand various fields of disciplines where PhD holders could find jobs, we also got a feeling of what it is like being in those respective sectors. It was great to have made many connections and to have networked with junior to senior participants in the workshop representing various universities throughout Europe."
Darshan Kumar's participation was supported by the ILS doctoral programme.
"We encourage PhD students to open their eyes to international career options in both industry and academia," says ILS director, associate professor Ville Hietakangas from the Department of Biosciences and the Institute of Biotechnology.
Darshan Kumar brings back insight on the topics learned in the training and is sharing the knowledge with his fellow PhD students. The regular ILS networking events and the BiotechClub provide excellent platforms for such sharing.
"The group project work was challenging and made us realise not only how to execute various tasks under time constraints but also how to manage group dynamics,” continues Kumar. “Our sub-group of five doctoral students was awarded the best idea for a Horizon 2020 proposal on sciences-based business education. Overall it was an unforgettable event, with lots of fun and unmatched professional teaching.”
Plant regulatory network simulations reveal a mystery in cytokinin patterning
Researchers at the University of Helsinki have discovered that cytokinin patterning, an important process in plant development, cannot happen via diffusion alone. While investigating a regulatory network in plant roots, they identified unexpected physical constraints on how cytokinin patterns form.
Interactions between the hormones auxin and cytokinin are central in plant development. In the growing root, cytokinin activates molecular exporters which pump auxin out of cells and auxin activates a gene which blocks cytokinin activity. This mutual inhibition is believed to form an exclusive domain for each hormone. The cells where auxin accumulates become xylem cells, which make up wood.
Sedeer el-Showk, a PhD student at the Ari Pekka Mähönen’s group, Institute of Biotechnology, used computational simulations to test the auxin-cytokinin network in a root cross section. The simulations showed that the network is enough to form the observed patterns, but also identified unexpected limits on cytokinin movement and patterning.
Molecular transporters are known to regulate the movement of auxin, but similar transporters have not been found for cytokinin. Nevertheless, a gradient in the distribution of cytokinin is thought to be important in several plant developmental processes, from patterning in the early embryo to continuous growth of the shoot.
However, the simulations showed that cytokinin diffusion cannot form a pattern on a scale small enough for these tissues. “It's easy to propose a cytokinin gradient when you're doing an experiment, but it turns out that physical constraints make it very unlikely that diffusing cytokinin forms a pattern on these scales,” explains lead author Sedeer el-Showk. “The pattern has to be created in another way. It could be a pattern in the cytokinin receptors or it might be that there are cytokinin transporters waiting to be discovered. Either way, there's a mystery to solve.”
The work was carried out in collaboration with the groups of Verônica Grieneisen and Stan Marée at the John Innes Centre in the UK. “Our computational work started with experimental data. We've confirmed our simulations with new experiments, and then our computational model has also indicated new lines for experimental work,” says group leader Ari Pekka Mähönen. “The back-and-forth between experiments and computational work means the two approaches reinforce and double-check each other.”
Unrealistic physical parameters were used to simulate the cytokinin gradient shown here.
el-Showk S, Help-Rinta-Rahko H, Blomster T, Siligato R, Marée AFM, Mähönen AP, Grieneisen VA. Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out. PLOS Computational Biology
Image: Mähönen group
The BI SAB site visit 15-16 October, 2015
The BI Scientific Advisory Board visited the Institute on 15-16 October to evaluate the progress of nine BI Group Leaders, and also Institute as a whole. The Chair of the BI Board Jari Niemelä opened the evaluation and its first session on Thursday morning. Director Howy Jacobs give an overview of BI’s activities in 2013-2015, and presented a vision for coming years. Research Directors introduced the highlights, challenges and future plans of each research program. After the opening session the SAB site visit continued with closed meetings and group leader interviews.
On Friday afternoon SAB chair Joan Steitz chaired a Q&A session for the whole institute staff. Discussion was lively – e.g. position of team leaders, challenges in postdoctoral careers and many other issues were discussed. Program ended with the poster session where all evaluated groups presented their research. The visit will be followed by an evaluation report.
Picture: Elina Raukko
Genetic mechanisms of dietary sugar sensing revealed by Drosophila research
The conserved sugar-sensing transcription factor complex Mondo-Mlx controls the majority of sugar-activated genes.
Sugars are an important source of nutritional energy for many animals, but also contribute to metabolic diseases in human such as type 2 diabetes, metabolic syndrome and cancer.
Dietary sugars are sensed within the cell by Mondo-Mlx, a transcription factor that is functionally conserved among animals and controls expression of many key metabolic genes in response to sugar intake. The group of Ville Hietakangas has been studying the role of Mondo-Mlx in Drosophila and has earlier found that loss of Mondo-Mlx function results in Drosophila larvae that are unable to survive on a diet that contains sugar (Havula et al. 2013 PLoS Genetics).
Most recently the Hietakangas group has adopted a genome-wide approach to study the function of Mondo-Mlx in sugar-induced gene transcription. “We wanted to identify the role of Mondo-Mlx in fast genetic response to dietary sugars in the whole organism. Drosophila is a great model to study nutritional responses, not only due to the ease of genetic manipulation and conserved metabolic pathways, but also because the larvae are eating continuously,” explains Essi Havula, co-first author of the study.
RNAseq analysis of sugar-fed mlx-mutant animals provided new insight into the control of sugar-regulated transcription. In an organism-wide setting, Mondo-Mlx controls the majority of sugar-regulated genes, implying that it has a much wider regulatory role than previously anticipated. In addition to the well-established roles in activating glycolysis and fatty acid synthesis, the study uncovered a number of new functions, such as regulation of digestive enzymes in the gut.
In addition to metabolic target genes, Mondo-Mlx also controls the expression of other regulatory genes, including transcription factors and secreted hormones. One of the new targets of Mondo-Mlx, the GLI-similar transcription factor, Sugarbabe, was found to promote the activation of lipid and serine biosynthesis but also to repress gut amylase expression. The finding that Mondo-Mlx serves as a master-regulator of a sugar sensing regulatory network explains its ability to coordinate such a wide spectrum of metabolic genes.
A collaboration with Dr. Samuli Ripatti’s group (Institute for Molecular Medicine Finland, FIMM) revealed that the study may also help to understand the molecular mechanisms underlying human metabolic disorders and conditions. The ENCAGE Consortium has recently identified several gene variants associated with circulating triglyceride levels (Surakka et al. 2015 Nature). Interestingly human homologs of Mondo-Mlx targets were enriched among triglyceride-associated genes. Thus Mondo-Mlx targets can be used to predict putative causal genes related to the triglyceride-associated genomic variants in humans.
Above: Loss of mlx leads to developmental delay and lethality at larval stage when the animals fed with high sugar diet. Below: Most of the sugar upregulated processes, such as glycolysis and pentose phosphate pathway, are regulated by Mondo-Mlx.
Jaakko Mattila, Essi Havula, Erja Suominen, Mari Teesalu, Ida Surakka, Riikka Hynynen, Helena Kilpinen, Juho Väänänen, Iiris Hovatta, Reijo Käkelä, Samuli Ripatti, Thomas Sandmann and Ville Hietakangas: Mondo-Mlx mediates organismal sugar sensing through Gli-similar transcription factor Sugarbabe. Cell Reports 13, 1–15, October 13, 2015
Picture: Essi Havula and Erja Suominen
Risk-taking research, part 1: Growing whole teeth
Bad or missing teeth are not only an aesthetic matter, but they also contribute to the person's total health. MD and PhD Anamaria Balic aims at finding a way to grow tooth enamel and eventually whole teeth both in vitro and in vivo. She is one of the three recipients of the Academy of Finland special risk-taking funding in the Institute of Biotechnology for 2015–2016.
Anamaria Balic, MD, PhD, has been working in the Institute for two years in Professor Irma Thesleff's group. With a background of both dental development and cancer research, she has taken on the major task of discovering how whole teeth could be grown first in vitro and, eventually, in the mouth.
– The dentin part of the tooth, which is made by the stem cells within the dental pulp, the core of the tooth, has been grown in vitro before. No one has so far been able to grow enamel.
The enamel in humans thins out with age due to physical and chemical erosion. And once it is gone, it is gone for good, since we lose the stem cells that generate enamel already during childhood. Many rodents have a huge advantage over people as their dental stem cells keep on producing new dental tissues for their continuously growing teeth.
Accordingly, Anamaria Balic started with a mouse model to discover how tooth epithelial stem cells could be programmed into enamel-producing cells, ameloblasts. The road might be long, but if her efforts succeed, the results will be ground-breaking. At this stage she is very happy that the Academy of Finland has noticed the importance of her research.
– It is a good token that I am one of those who are considered to have a chance to succeed in what we are doing. This gives me a lot of self-confidence.
The Academy of Finland risk-taking funding system is transparent. The recipients need to report on their work by the end of the next year, and then it is estimated whether their funding will continue for the rest of the funding period.
– This absolutely motivates you - you work faster and more efficiently. Transparency means also transparency for the public, which is very important. You need to be close to the public and communicate!
Text and picture: Elina Raukko
The other two recipients of the AoF risk-taking funding at the Institute of Biotechnology, Jaan-Olle Andressoo and Satu Kuure, will be presented later.
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
- Ahtiainen Laura
- Airavaara Mikko
- Andressoo Jaan-Olle
- Auvinen Petri / DNAGEN
- Bamford Dennis
- Butcher Sarah
- Di-Poi Nicolas
- Domanskyi Andrii
- Fagerholm Susanna
- Frilander Mikko
- Helariutta Ykä
- Hietakangas Ville
- Holm Liisa
- Iwai Hideo / NMR
- Jacobs Howy
- Jernvall Jukka
- Jokitalo Eija / EM
- Kajander Tommi
- Katajisto Pekka
- Kuure Satu
- Laiho Marikki
- Lappalainen Pekka
- Löytynoja Ari
- Michon Frederic
- Mikkola Marja
- Mähönen Ari pekka
- Paavilainen Ville
- Saarma Mart
- Salazar-Ciudad Isaac
- Schulman Alan
- Shimmi Osamu
- Thesleff Irma
- Varjosalo Markku / Proteomics unit
- Vartiainen Maria
- Zhao Hongxia
- 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