Junior Investigator in the Spotlight
With this page, we recognize and appreciate junior investigators who have demonstrated exceptional achievements. Each month one will be in the spotlight where her/his outstanding accomplishments will be highlighted.
In The Spotlight: Andreas Due Ørskov, Grønbæk group. Shared first author of the study: Ohtani, H., Ørskov, A. D., Helbo, A. S., Gillberg, L., Liu, M., Zhou, W., Ungerstedt, J., Hellström-Lindberg, E., Sun, W., Liang, G., Jones, P. A., and Grønbæk, K. (2020) Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity are Linked to Clinical Responses to 5-Azacytidine. Cancer Research. doi: 10.1158/0008-5472.CAN-19-1696.
The study concerns patients with a higher-risk variant of the blood cell cancer, myelodysplastic syndrome (MDS). Besides allogeneic hematopoietic stem cell transplantation, which is potentially curative, the treatment of these patients consists mainly of epigenetic therapy (DNA demethylating therapy). However, the mechanisms by which this treatment exerts its effects in patients with MDS have not yet been fully elucidated. We therefore analyzed at a whole-transcriptomic level the genes specifically upregulated in those patients responding to DNA demethylating therapy. As has also been shown in cell cultures, we found that DNA demethylating therapy upregulates intracellular viral defense pathways in the responding patients and that this effect could be caused by a selective induction of evolutionarily younger transposable elements, including human endogenous retroviruses (ERVs). This provides new insights on how DNA demethylating therapy may modulate the immune system in MDS. Furthermore, the study contributes to the scientific basis of the potentially advantageous effect of combining DNA demethylating therapy and immunotherapy in MDS and in cancers in general.
I have been part of the Grønbæk Group at BRIC and Department of Hematology, Rigshospitalet, the last couple of years as a PhD student and finished my PhD in April 2020. The defense took place digitally during the Corona shutdown. My educational background is as a trained medical doctor, and I am currently back in the clinic as a resident at a department of internal medicine at Amager Hospital. The future plan is to specialize specifically within hematology – and hopefully in a combination with translational hematological research.
In The Spotlight: Simon Husby, Grønbæk group. First author of the study: Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study. Leukemia, 1-13. doi: 10.1038/s41375-020-0795-z
And shared first author of the study: Clonal hematopoiesis evolves from pre-treatment clones and stabilizes after end of chemotherapy in patients with MCL. Blood. doi: 10.1182/blood.2019003539
The first study investigated defects in blood stem cells in a national cohort of patients with lymphoid cancer. We found that approximately a quarter of these patients had stem cell mutations, primarily in genes with a function as either epigenetic regulators or with role in the DNA repair pathway. Approximately 10% of patients with stem cell defects in the DNA repair pathway had very poor survival after receiving high-dose chemotherapy. This implies that these patients (cell's) are unfit for further chemotherapy and should, if possible, receive targeted novel therapies.
The second study investigated the development of blood stem cells defects over time in patients. We investigated >350 samples from 50 patients with lymphoma and found that virtually all stem cell mutations were present before any chemotherapy was administered. Furthermore we found that clones with mutations in DNA repair pathway genes expanded dramatically in patients after the first administration of chemotherapy.
I finished my ph.d. in September 2019 and I am now working as a full-time doctor at the Department of Hematology, Rigshospitalet, Copenhagen. From this autumn I will return to BRIC as a postdoc, focusing on the translational use of DNA repair pathway status in the treatment of patients with blood cancers.
In The Spotlight: Aditya Sankar, Helin group. First author of Nature Cell Biology paper: Sankar, A., Lerdrup, M., Manaf, A. et al. KDM4A regulates the maternal-to-zygotic transition by protecting broad H3K4me3 domains from H3K9me3 invasion in oocytes. Nat Cell Biol (2020). https://doi.org/10.1038/s41556-020-0494-z
In this study, we have highlighted that a maternal factor called KDM4A is critically required in mouse oocytes (also likely human oocytes), to ensure that the oocyte chromatin/epigenome stays quite relaxed and open. Using a knockout mouse model for KDM4A, we applied low input chromatin immunoprecipitation and single cell transcriptomics in oocytes and early mouse embryos to demonstrate that inheritance of abnormally organized chromatin from the mother through the unfertilized oocyte prevents proper transcriptional activation of the fertilized embryo leading to developmental failure. As a general takeaway, we were able to demonstrate that histone modifications guide transcriptional activation in a direct manner be it at genes or at transposons. Remarkably, we could reverse the embryo death to near-normal survival rates only by supplementation of catalytically active Kdm4a mRNA injection in the oocyte just before its fertilization. Since abundance of KDM4A is found to be highly variable in all the human oocytes we investigated, it is highly likely that in human oocytes expressing lower amounts of KDM4A are potentially pre-disposed to insufficient embryonic transcriptional activation after fertilization – a common phenomenon seen in IVF clinics.
The field of reproductive health in the context of safeguarding fertility outcomes will (or already is) in my opinion, be a major global health challenge for the planet along with infectious diseases and metabolism disorders. And there is much to do. I believe that this study could achieve its full potential due to the excellent collaboration of expertise on display between the Hoffmann (human germline; ICMM-CCS), Helin (epigenetics and chromatin; Danstem/BRIC/MSKCC), Dahl (low-input chromatin mapping; Oslo) laboratories and Mads Lerdrup (BRIC/ICMM-CCS). I am in particular thankful for the immensely rewarding opportunity to lead and drive such a study from start to finish.
Before taking on my PhD with Prof. Kristian Helin on chromatin epigenetics, I was lucky to have trained under some fantastic mentors at great institutions such as Petra Hajkova (MRC-LIMS, London), Donal O’Carroll (EMBL, Rome) and Julius Brennecke (IMBA, Vienna) who have pioneered the field of germline epigenetics. I firmly believe that good mentors are key to keeping your intellectual hunger intact and great collaborators can open up your potential to tackle ambitious questions. As I have a goal to set up my own laboratory in the future, my time is spent on wrapping up some other research stories in the pipeline and developing my own research program on gene regulation mechanisms in development and homeostasis.
In The Spotlight: Philip (Phil) Seymour is one of three first authors (alongside former Serup Group Ph.D. students Anuska la Rosa Egeskov-Madsen and Caitlin Collin) of the Developmental Cell paper: “Jag1 Modulates an Oscillatory Dll1-Notch-Hes1 Signaling Module to Coordinate Growth and Fate of Pancreatic Progenitors”
During development, acinar, duct and endocrine cells in the pancreas arise from multipotent progenitors via their segregation into acinar-fated “tip” cells at the periphery of the growing organ and duct-/endocrine-bipotent “trunk” cells in the core. While Notch signaling is known to regulate growth of multipotent progenitors and tip vs. trunk fate choice, which Notch ligands are involved is unclear. In this paper, we demonstrate oscillations in expression of both the ligand Dll1 and the Notch downstream target Hes1 which are crucial for multipotent progenitor expansion and tip vs. trunk fate choice. In contrast, a second ligand - Jag1 - restrains growth of multipotent progenitors by attenuating Notch activity cell-autonomously. Later, when restricted to tip cells, Jag1 signals to neighboring progenitors to assign them to a trunk fate: without Jag1, 95% of trunk cells are lost. Additional loss of Dll1 completely obliterates trunk progenitors and, so, duct and endocrine cells, revealing partial redundancy with Jag1.
Phil’s research has, from his Ph.D. (University of Bath, UK) focused upon understanding the mechanisms regulating pancreatic development and regeneration. During his initial postdoc (UC Irvine and UC San Diego), Phil characterized the roles of Sox9 in the developing pancreas. Following a brief but enjoyable stint in industry (Novo Nordisk), Phil joined the lab of Palle Serup at DanStem, unravelling how Notch signaling governs fate choice in the embryonic pancreas. Following a fun year working with pancreatic organoids in the lab of Anne Grapin-Botton (DanStem), Phil has joined the newly-established lab of Luis Arnes (DanStem/BRIC) focused upon dissecting the roles of lncRNAs in pancreatic development and cancer.
In The Spotlight: Meral Ilcim Thestrup, The Ober group, First author of Nature Communications paper: Thestrup, M.I., Caviglia, S., Cayuso, J., Heyne, R. L. S., Ahmad, R., Hofmeister, W., Satriano, L., Wilkinson, D. G., Andersen, J. B., and Ober, E. A. (2019) A morphogenetic EphB/EphrinB code controls hepatopancreatic duct formation. Nature Communications 10, 5220. doi: 10.1038/s41467-019-13149-7
Significant progress has been made in understanding the mechanisms driving the development and functional differentiation of digestive organs such as the liver and pancreas for the past decades. However, hepatopanreatic ducts (HPDs) connecting the liver and pancreas to the intestine and facilitating the f
low of the bile from the liver and enzymes from the pancreas to enable digestion have received little attention. A recent study from the Ober group published in Nature Communications provided a description of the steps of HPD formation using zebrafish as a model showing that HPD forms through
a dynamic cell hollowing mechanism. Furthermore, they showed that Eph/Ephrin proteins, which are well-known in the nervous system as cues for neuronal axon guidance, also act in a different context and direct HPD tube formation through cell intercalation. Interestingly, like in the brain, different Eph receptors and Ephrin ligands appear to be expressed in different domains and signal across these boundaries, creating a morphogenetic code throughout the HPD and its surroundings. These findings provide first comprehensive insights in HPD formation at molecular and cellular level, thus, paving the road for the future research in HPD development and congenital diseases like biliary atresia. This project represents the PhD work of first author Ilcim Thestrup, including fruitful collaborations other team members and groups at the BRIC and the Francis Crick Institute, London.
Ilcim Thestrup studied the development of the central nervous system and neural circuitry in zebrafish at the Max Plank Institute of Neuroscience (Germany) and rodents at Duke University (USA). Then, she joined the Ober group as a PhD student to investigate the relationship of progenitor movement and cell fate decisions. Now, Ilcim is pursuing her research career in the field of disease modelling and cardiac genetics at the Biomedical Institute, University of Copenhagen.
In The Spotlight: Assistant Professor William (Billy) Hamilton, The Brickman group, First author of Nature paper: Hamilton, W.B., Mosesson, Y., Monteiro, R.S., Emdal, K.B., Knudsen, T.E., Francavilla, C., Barkai, N., Olsen, J.V. and Brickman, J.M. (2019). Dynamic lineage priming is driven via direct enhancer regulation by ERK.Nature, doi: 10.1038/s41586-019-1732-z.
How are distinct cellular identities established in development? How are time and space measured? These are some of the most fundamental questions in developmental biology. My work aims to understand how external signals are interpreted by cells and how they convert these signals into precisely timed responses, in what can be a very noisy environment. Billy has been studying this process at DanStem for approximately 7 years and has uncovered that the framework to choose between self-renewal and differentiation, i.e. the gene-regulatory networks that underpin these choices, are hardwired into stem cells. These regulatory networks are interdependent and rely on extracellular signalling for dominance to be shifted from one to the other. However, this process is complex and is undoubtedly dependent on a host of intrinsic factors. He now hope to expand his research into the field of protein translation to understand how signalling, cell size and shape, as well as cellular fitness impact on cell identity. This new direction will be interdisciplinary, facilitated by the strong theoretical and experimental interactions he gained as a member of StemPhys.
Billy obtained his PhD at the Edinburgh University in the labs of Tilo Kunath and Mike Tyers, where he worked on defining factors that regulate MAPK signalling in mouse embryonic stem cells. He then joined the Brickman lab in Copenhagen where he expanded upon this to uncover how MAPK signalling regulates transcription and plasticity during early stem cell differentiation.
In The Spotlight: Postdoctoral Fellow Martti Maimets was awarded first place poster at the conference 'Intestinal Organoids - from stem cells to metabolism and microbiome interactions', September 29 -October 2, 2019.
The conference brought together world-leading scientists across several research fields to discuss how new technologies including the versatile organoid culture system can provide important knowledge about epithelial cell fate decisions, function and interplay with the microbiota.
The intestine plays essential roles in controlling our metabolism by nutrient uptake, hormone secretion and facilitation of symbiosis with the commensal microbiota. Understanding the complex roles of the epithelium in these processes has proven a great challenge – but a challenge that will provide insights into disease mechanisms and potentially new and improved treatment options.
Martti has been immersed with the biology of organoids since 2010 when he joined the laboratory of professor Rob Coppes in Groningen, the Netherlands as a PhD candidate with the aim of investigating the potential use of salivary gland stem cells in regenerative medicine. By developing conditions for the growth of salivary gland organoids, he identified Wnt/β-catenin signalling pathway as a key driver for adult salivary gland stem cells and demonstrated that the activation of this pathway allows extensive in vitro expansion of these cells. Conducting these studies sparked his interest in the driving force of microenvironment in stem cell biology. To further pursue this topic, he joined the lab of Associate Professor Kim Jensen, (BRIC/DanStem) in Copenhagen, Denmark. During his three years as a postdoc they have collected evidence on how intestinal mesenchymal cells guide epithelial regionalisation during development.
In The Spotlight: PhD student Iris Unterweger, Ober group, was awarded a Boehringer Ingelheim Travel Grant for participation in the “Embryology: Concepts and Techniques in Modern Developmental Biology” summer course at the Marine Biological Laboratory (Woods Hole, USA).
This summer, Iris had the opportunity to attend the six-week laboratory and lecture Embryology course at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, USA. Beside the BIT grant, Iris received a “John & Madleine Trinkaus Endowed Scholarship” and a “Company of Biologists Ltd Scholarship” via the MBL. She applied to this course with the goal of getting in depth knowledge of fundamental principles and mechanisms within the field of embryonic development. “Now looking back, it was so much more than I had expected” says Iris. Besides the daily lectures and the opportunity to get hands-on experience with a wide variety of embryos, encompassing both classic and emerging model organisms, such as butterflies, the atmosphere is very inspiring. Late night experiments, thinking outside the box and informal discussions with both students and faculty, for instance about terminology or the future use of CRISPR made this course absolutely unique.
Iris is educated as a molecular biologist, and completed her Master thesis at the Max-Delbrueck Center for Molecular Medicine (Berlin) before joining DanStem in 2017 as a PhD student in the Ober group. She is interested in how organs form, and currently, her research focuses on understanding the potential of hepatic progenitor cells and their individual contributions to a functional organ.
In The Spotlight: Postdoctoral Fellow, Rita Soares Monteiro, The Brickman group, awarded Lundbeck Foundation Postdoctoral Fellowship. Project title: Cell cycle dynamics and regulation by ERK signalling in mouse embryonic stem cells
In this project Rita is aiming to understand how differentiation is linked to proliferation during early embryonic development. 'We will investigate this question, focusing on how the ERK pathway is coupled to the cell cycle in embryonic stem cell (ESC) differentiation' says Rita. A major goal of this project is to monitor both ERK signalling and cell cycle progression alongside mathematical modeling to decipher how signals dynamically regulate lineage choice and cell cycle phase. The outcomes of this project will provide new insights into the relationship between cell cycle regulation and differentiation while revealing the importance of interdisciplinary studies to achieve an integrative understanding of development.
Rita did her bachelors and masters in Evolutionary and Developmental Biology at the Faculty of Sciences of the University of Lisbon and obtained her Ph.D. degree at the University College London working at the lab of Professor Jim Smith, the Francis Crick Institute. During her Ph.D., she studied the regulation of early cell fate determination in amphibian embryos and the role of tissue-specific transcription factors during this process.
In The Spotlight: Postdoctoral Fellow, Jordi Guiu, The Jensen group, First author of Nature paper: Guiu, J., Hannezo, E., Yui, S., Demharter, S., Ulyanchenko, S., Maimets, M., Jørgensen, A., Perlman, S., Lundvall, L., Mamsen, L.S., Larsen, A., Olesen, R.H., Andersen, C.Y., Thuesen, L.L., Hare, K.J., Pers, T.H., Khodosevich, K., Simons, B.D., Jensen, K.B. (2019). Tracing the origin of adult intestinal stem cells. Nature, doi: 10.1038/s41586-019-1212-5.
Cells in tissues are organised hierarchically with a stem cell on top producing their progeny. Importantly during colorectal cancer and intestinal injury this hierarchical behaviour is broken and seemingly differentiated cells might behave as stem cells. Recent work from Jordi Guiu as part of Kim B. Jensen group published in Nature shows that cells in fetal intestine are organised in a flat unhierarchical fashion, thus there is not a designated destiny for cells. Instead all them are equal and have the same probability to become adult intestinal stem cells in vivo. These findings provide a direct link between the observed plasticity and cellular reprogramming of differentiating cells in adult tissue following damage, revealing that stem cell identity is an induced rather than a hardwired property.
Jordi Guiu did his PhD in Anna Bigas laboratory (Barcelona) were he focused on the genetic circuitry that controls the establishment of hematopoietic stem cells during development. Then he joined Kim Jensen lab as a postdoc, were he obtained a Marie Curie fellowship to study the specification of intestinal stem cells during development.
In The Spotlight: Assistant Professor Pia Nyeng, First Author of Developmental Cell paper: Nyeng, P., Heilmann, S., Löf-Öhlin, Z.M., Pettersson, N.F., Hermann, F.M., Reynolds, A.B., Semb, H.(2019).p120ctn-Mediated Organ Patterning Precedes and Determines Pancreatic Progenitor Fate.Developmental Cell, 49, 1-17, doi: 10.1016/j.devcel.2019.02.005.
Pia Nyeng studied biology at the University of Copenhagen (Denmark). She did her PhD in Jan Jensen’s group at University of Colorado in Denver (USA) studying FGF-regulation of endodermal organ development. After a short postdoc at Cleveland Clinic in Ohio (USA) she joined Henrik Semb’s group at Lund University (Sweden) as a postdoc. Here she generated new methods for live imaging of pancreatic organotypic cultures and initiated her studies on regulation of pancreas morphogenesis and cell differentiation.
Since the start of Danstem in 2011, Pia has been part of the Semb research group as a postdoctoral researcher and later as an Assistant Professor. Pia’s work at Danstem was supported by a 3-year postdoctoral fellowship from JDRF. Pia is now looking forward to pursue an independent career at the Department of Science and Environment at Roskilde University.
An interview with Pia
In The Spotlight: Postdoctoral Fellow, Patrick Anders Aldrin Kirk, The Kirkeby group, awarded Lundbeck Foundation Postdoctoral Fellowship. Project title: Elucidating the role of lncRNAs in human neural subtype specification using paired CRISPR knockout libraries and single cell RNAseq
Patrick's project aims at uncovering the functional role of long non-coding RNAs (lncRNA) in neural subtype specification during embryonic development. This will be done by developing a comprehensive paired CRISPR library for knockout of lncRNA that are found within the CNS during early development. Elucidation of the fictional role of these lncRNAs by CRISPR knockout on neural cell specification will then be assessed in a microfluidics based In vitro model of the developing human brain.
Patrick obtained his PhD in neurobiology from Lund University in Sweden. His research focuses on combining gene and cell therapy approaches for neurodegenerative disorders, which also included development of novel viral vectors. Another part of his research is also focuses on understanding neuronal function and connectivity in both the healthy and diseased brain, using chemogenetics. His current research interests focus mainly on understanding developmental cues necessary for neuronal subtype specification during development. Patrick hopes to use this knowledge to further investigate future cell therapy approaches within the brain.
In The Spotlight: Postdoctoral Fellow, Paul Riccio, The Semb group, awarded Marie Sklodowska-Curie Actions Postdoctoral Fellowship. Project title: Using the precision mouse genetic tool MADM to elucidate the role of EGFR in directing beta cell differentiation and pancreatic morphogenesis
Succesfull clinical trials of islet transplantation have invigorated the diabetes research community to pursue cell replacement therapies as an eventual cure. These trials relied upon rare human donor tissue. If we can reliably manufacture insulin-producing beta cells from stem cells, many more patients will be able to achieve insulin independence. The Semb group recently showed the EGFR signaling pathway modulates apical polarity in early endocrine progenitors, committing them to beta differentiation. Paul will use his expertise in the cutting edge genetic tool, Mosaic Analysis with Double Markers to determine why only a portion of these progenitors execute beta differentiation, knowledge key to replicating this process with human stem cells.
Paul has a long-standing interest in how organs like the pancreas form tubes. During his predoctoral training at Columbia University in New York he showed that Ret-expressing tip cells in the kidney undergo competitive cell rearrangements to sculpt the renal collecting system. He will continue to study the dynamics of progenitor cells during tube formation in the pancreas, but also hopes to understand how these morphogenetic events are coordinated with and influence the differentiation processes he will examine during the Marie-Sklodowska Curie Actions Fellowship.
In the Spotlight: Assistant Professor and Translational Scientist Anant Mamidi, First author of Nature paper: Mamidi, A., Prawiro, C., Seymour, P.A., de Lichtenberg, K.H., Jackson, A., Serup, P., and Semb, H. (2018). Mechanosignalling via integrins directs fate decisions of pancreatic progenitors. Nature, doi: 10.1038/s41586-018-0762-2
Incredible progress has been made since the discovery of Insulin almost 100 years ago in terms of disease mechanisms and alternative treatment approaches. This is the stem cell era and significant progress has been made in implementing cell therapies for treating various chronic diseases including diabetes. It is crucial to understand the basic molecular mechanisms behind organ development, In order to achieve a robust and efficient cell differentiation to obtain the right cells in vitro for cell therapy.
Recent work by Anant Mamidi as part of Semb research group uncovered the cascade of molecular events that occur within and around the pancreatic progenitor cells and are responsible for dictating cell fate decisions towards endocrine lineage including insulin expressing beta cells. This work is very important in creating a road map that can be eventually useful in making islet like insulin producing cells in vitro for future cell therapies.
Anant Mamidi obtained his Masters in Microbiology from India and PhD in developmental biology from University of Padova, Italy. He worked as a post-doc and now as Assistant Professor at DanStem since its start in 2011. Anant is continuing to pursue his interest in translational aspects of stem cell research and hopes to contribute in advancement of cell therapy for diabetes patients.
An interview with Anant