Biomedicum Helsinki Foundation Grantees 2023

The board of the Biomedicum Helsinki Foundation has granted a total of 204 000 euros of research grants in the year 2023. Assigned grants have been awarded from the following specific funds within the Foundation: Borrelia Fund, Timo Lehtonen Urology fund, Brain Cancer FundMarketta Helenius Fund for Health Sciences,Cardiovascular Fund, Neurological and Cerebrovascular Disorder Fund or from the Cancer and Cell Based Cancer Research Fund

Clinical Investigator Post-doctoral grant

NameTitleAbstract of research proposalFund
Olli DufvaDeciphering genomic determinants of immunity in tumour organoid models at single-cell resolutionRecent successes in cancer immunotherapy demonstrate the power of therapeutic targeting of the cellular interactions within cancer ecosystems. However, it is not known why many patients do not respond to immunotherapy and how to overcome the resistance. How the different cell types and states in a tumour dynamically respond to immune challenge, and how variation in the responses is defined by tissue type and genetic variation remains currently unexplored. Here, I aim to develop organoid-immune models that recapitulate the complexity of human tumours and coupled with recently developed single-cell multi-omic measurements enable large-scale screens to discover genes controlling immune responsiveness at a previously unattainable resolution. In a cohort of over 250 cancer organoids representing a spectrum of solid tumours, we will examine the transcriptomic and epigenetic responses of the tumour cells to immune cell co-cultures using a single-cell multi-omic readout of gene expression and chromatin accessibility. Integration of these responses with the tumour genetic alterations will reveal genomic determinants of variation in immune reactivity. We will experimentally test the discovered associations at scale using CRISPR screens with a single-cell genomic readout in the organoid models. As a result, we aim to identify predictors of response to existing immunotherapies and discover new immunotherapeutic targets in patients with cancers resistant to existing therapies.Cancer and Cell Based Cancer Research50000€

Young Investigators’ Grant

NameTitleAbstract of research proposalFund
Autio MatiasCharacterizing the Tumor Microenvironment in Diffuse Large B-cell LymphomaDiffuse Large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Today, most patients are cured using immunochemotherapy. However, about 30% of patients still experience a relapse with a dismal prognosis. In addition to malignant B-cells, DLBCL tumors also consist of a tumor microenvironment (TME) consisting of blood vessels, extracellular matrix, and immune cells, such as T-lymphocytes, macrophages, and NK-cells. The impact of the TME on DLBCL pathogenesis and patient survival is still largely unknown. The aim of this study is to characterize the immune TME and to correlate its composition with biological and clinical factors, as well as with patient outcome. We will perform multiplex immunohistochemistry to identify T-lymphocytes, B lymphocytes, macrophages, and other immune cells, as well as immune checkpoint molecules expressed on the surface of these cells. We will also study the spatial relationship between these cells. We intend to identify different cellular neighborhoods in the tumor and correlate the presence or absence of these with clinical factors and survival. The aim of this project is to get a deeper understanding of the organization of the different immune cells in the TME. The knowledge gained from this study increases our understanding of the heterogeneity of DLBCL and helps us to identify the patients benefitting from novel TME targeted and checkpoint blockade therapies. Cancer and Cell Based Cancer ResearchCancer and Cell Based Cancer Research6000€
Borchers JoonatanPrimary adrenal insufficiency: Epidemiological aspects and associating features in APECEDPrimary adrenal insufficiency (PAI) is a rare disease leading to deficient concentration of adrenal steroid hormones. Causes and incidence of PAI are varying in different populations and ages. Epidemiology and causes of PAI have been studied in adults but the reports on children are scarce. One of the common causes of PAI in children is autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Increased mortality has been suggested for APECED, PAI being one of the most common causes of death. Another clinical feature of APECED that is not studied is tendency for hypokalemia that is suggested to be due to several different etiologies.

This study aim to determine the epidemiology and spectrum of causes for PAI in Finnish children. These factors are studied by identifying all Finnish children with PAI born and diagnosed during 1996-2016 from the Finnish National Care Register for Health Care. We also aim to determine the role of PAI and other causes for hypokalemic tendency related to APECED as well as the mortality and causes of death of APECED patients by studying the large Finnish APECED cohort that contains almost all Finnish patients with APECED. For studying the hypokalemic tendency 68 healthy control subjects have attended study visits to cross-sectionally analyze electrolyte and adrenal steroid concentrations. For mortality rates the general Finnish population, obtained from registry maintained by Statistics Finland, is used as the reference population.
Elomaa PinjaSimple devices for single cell trapping and droplet digital PCRDroplets are widely used in biomedicine for creating reaction chambers for different applications such as high throughput single cell capture and digital droplet PCR (ddPCR) for absolute quantification and high sensitivity. For creating monodisperse emulsion, there is a need to use precisely controlled pumping system and special microfluidic chip. Such systems rely on multiple machines and several hour hands-on times. Furthermore, these systems typically cost thousands of euros in addition to the expensive reagents. These techniques are therefore restricted from those who cannot afford such investment or those how would need a disposable, rapid system.
First new idea to correct this urgent problem was to use hydrophilic spots on hydrophobic black silicon surface. System was used to capture single cells and results were compatible with existing methods. Another approach to the problem was to create a manually pressurized microfluidic all-in-one chip. The pump-free system has been successfully tested using isothermal ddPCR SARS-CoV-2 SIBA assay (Aidian). Similar results were also achieved using spot chip. These novel innovations are easy to use, small and rapid, giving reliable results under 30 minutes. All these functions make both of the chips ideal for different laboratory environments and as well for point-of-care applications in clinic or home. Home-testing will be the future´s healthcare and our chip is showing a glimpse of what the POC testing might someday be.
Gigliotta AdrienMyelin plasticity in resilience and susceptibility to psychosocial stress-induced anxietyAnxiety disorders are the most prevalent mental disorders, with both genetic and environmental risk factors, such as chronic psychosocial stress. In a mouse model of chronic psychosocial stress (CPS), our group showed that remodelling of myelin sheaths, a newly identified form of brain plasticity, is a major response to stress-induced anxiety. The effects varied based on the mice’s genetic background and whether they developed social avoidance after CPS (indicating susceptibility) or not (resilience). We hypothesize that CPS-induced myelin plasticity is regulated by how oligodendrocytes (OLs), the myelinating cells in the central nervous system, respond to stress hormones.  Our overall goal is to define the cellular mechanisms of stress-induced myelin plasticity. My specific aims are 1) To assess the role of glucocorticoid on OLs cultured from C57BL/6NCrl (mostly stress resilient) and DBA/2NCrl (mostly stress susceptible) mouse strains. 2) To establish the role of the communication between microglia, the resident brain macrophages, and oligodendrocyte precursor cells (OPCs) in stress-susceptibility and resilience. I showed that glucocorticoids differently impact OPC proliferation, maturation, and myelin production in B6 and D2 mouse OPC cultures. Regarding aim 2, we found differences between B6 and D2 defeated mice in microglial activation and morphology and their distance to OPCs compared to control animals. These findings could suggest new treatments for anxiety disorders.6000€
Gondane AishwaryaO-GlcNAc transferase epistatically regulates gene expression in response to transcriptional stressThe aim of my PhD work is to establish the spatiotemporal roles of the transcriptional kinases and glycosylation in transcription. Transcriptional machinery is analogous to a jigsaw puzzle; hence it is critical to place the right pieces (regulators) at the right place to complete the picture.

Transcription is regulated by dynamic phosphorylation catalyzed by CDK7, CDK9 or CDK12 and re- / de-glycosylation catalyzed by OGT / OGA, respectively. Current model proposes that all kinases act on all genes. Our preliminary data shows that co-targeting any of the transcriptional kinases and OGT selectively kills prostate cancer cells.

I use chemistry-based metabolic labelling of RNA coupled to sequencing (SLAM-seq) to describe, how each of the transcriptional kinases together with OGT and OGA coordinate to sustain the pro-proliferative transcriptional program. My SLAM-seq data revealed that each of these kinases regulate a distinct set of genes, contradicting the existing dogma. To instill confidence in these distinct roles, I performed ChIP-seq against the transcriptional kinases and show that each kinase is enriched at the different target genes.

My PhD project represents a comprehensive attempt to solve the jigsaw puzzle of transcription. To place the activities of the transcriptional kinases, OGT and OGA across the gene body, I propose to track the RNA Pol II behavior using ChIP-seq in the presence and absence of the selective inhibitors using the Young Investigator’s grant.
Urological research4000€
Hautakangas HeidiLarge-scale genome-wide studies of migraineMigraine is a common brain disorder characterized by severe headache, nausea, and sensitivity to light and sound. It has two major subtypes: migraine without aura and migraine with aura. Its prevalence is around 15% globally, with an estimated 40% heritability. The molecular mechanisms are still poorly understood. Migraine was ranked as the second most disabling condition in terms of years lived with disability (Global Burden of Diseases 2019), showing its importance as a global public-health problem.
In my first first-author publication we conducted the largest genetic study of migraine to date with 102,084 cases and 771,257 controls by expanding the earlier International Headache Genetics Consortium data by 71% more cases. We identified 123 risk loci, including 86 new and some subtype-specific risk alleles, that are enriched for genes highly expressed in vascular and central nervous system tissues.
My first and completed goal was to identify new genetic risk loci and tissues specific for migraine, and to stratify migraine risk loci by subtypes. My second goal is to fine-map the risk loci to pinpoint the putative causal variants, which is crucial for designing targets for new therapeutics. My third goal is to further stratify the risk loci by different migraine symptoms and drug usage.
The unparalleled statistical power of our large sample size provides an unprecedented view to investigate the biology behind migraine and its subtypes through an unbiased genome-wide approach.
Neurological and Cerebrovascular Disorder6000€
Huuhtanen JaniFUNCTIONAL AND ANTIGEN-SPECIFIC CHARACTERIZATION OF IMMUNE CELLS AT THE SINGLE-CELL LEVEL REVEALS CONVERGENCE OF ADAPTIVE AND INNATE IMMUNITYImmune aplastic anemia (AA) is a rare bone marrow failure (BMF) disorder characterized by an autoimmune response against hematopoietic stem and progenitor cells (HSPCs), but the exact mechanisms that break self-tolerance and sustain inflammation are incompletely understood. In this study, we aim to characterize and functionally validate immune cell phenotypes and T cell receptor (TCR) targets in AA, and associate them with clinical variables.

We have used scRNA+TCRαβ-seq to profile AA (n=13) from bone marrow (BM) and peripheral blood (PB), and compared these samples to healthy controls (HC) (n=35) and hematological malignancies (n=36). TCRβ-seq was used to profile AA (n=144) and have been used compare to other BMFs (n=137), autoimmune disorders (n=45), malignancies (n=39), and HC (n=866). Findings were validated in co-cultures of HSPCs with immune cells (AA n=7, HC n=4).

Our preliminary results show convergent shift of both innate and adaptive immune cells in AA, where NK cells gain T cell-like memory properties and T cells gain NK-like TCR-independent killing abilities to maintain autoinflammation in AA. We were able to find an AA associated TCR fingerprint, which was validated in two different cohorts and were linked to clinical variables.

Our findings have the potential to inform the development of new targeted therapies for AA, by identifying novel immune cell targets and TCR motifs.
Huuska NoraAivovaltimonpullistuman puhkemiseen vaikuttavat tulehdukselliset tekijät: seerumin amyloidi A, imusuonet ja lymfosyytit tulehdusvasteen säätelyssä.Aivovaltimoaneurysma (AA) on aivovaltimon pullistuma, jonka kantajia arvioidaan olevan noin 2-3% väestöstä. AA:n puhkeaminen aiheuttaa aivoverenvuodon, johon sairastuneista n. 30-40 % kuolee. AA:n seinämälle ominaista on sen rakenteellinen rappeutuminen sekä krooninen tulehdusreaktio, jotka edetessään johtavat lopulta AA:n puhkeamiseen. AA:n seinämään kertyy runsaasti kuonapartikkeleita, kuten rasvaa, apolipoproteiineja ja punasolujen hajoamistuotteita, joilla on tulehdusta lisäävä ja AA-seinämää rappeuttava vaikutus. Imusuonten ajatellaan toimivan yhtenä verisuonen seinämään kertyneiden kuonapartikkelien poistojärjestelmänä ja ateroskleroottisessa valtimoseinämässä tulehdusvastetta säätelevänä tekijänä, mutta niiden esiintymistä ei ole aiemmin tutkittu AA:n seinämässä. Lisäksi AA:n seinämään tiedetään hakeutuvan runsaasti makrofageja ja neutrofiilejä, jotka ylläpitävät kroonista tulehdusta, mutta lymfosyyttien merkitys AA:n muodostumiselle on tuntemattomampi.
Tämän väitöstutkimuksen tavoitteena on selvittää amyloidi A:n (SAA:n) merkitystä, imusuonten esiintymistä sekä lymfosyyttien roolia AA:n seinämässä. Tutkimus pohjautuu immunovärjäyksiin yhteensä 36:ssa puhjenneessa ja puhkeamattomassa seinämärappeuma-asteiltaan erilaisessa AA-näytteessä, jotka on kerätty leikkausten yhteydessä HUS neurokirugian klinikassa. Potilailta kerätyt AA-näytteet ovat ainutlaatuisia, sillä AA:n endovaskulaarisen hoidon yleistyessä AA-kudosta saadaan tutkimuskäyttöön yhä harvemmin.
Neurological and Cerebrovascular Disorder4000€
Lähdeoja TuomasEvidence Synthesis in Orthopaedics – Guiding Clinical Practice in Shoulder SurgeryAims: 1) To synthesise the comparative evidence on two common shoulder problems: Posttraumatic instability and surgery for subacromial pain syndrome (SAPS). 2) To create a clinical practice guideline on surgery for SAPS. 3) To provide evidence on knowledge gaps on minimal important differences (MID) and patient acceptable symptom states (PASS) of common shoulder outcomes.

Methods: Established methods of systematic reviews and meta-analysis were used, guided by the PRISMA statement and Cochrane methodology. The GRADE approach was used for certainty of evidence. The clinical practice guideline was a BMJ Rapid Recommendation. For the MID and PASS work, we used multiple established methods: the receiver operating characteristic, the mean difference of change and the mean change and the 75th percentile methods as appropriate.

Results: Main findings were: Moderate certainty evidence that labrum repair after primary dislocation reduces risk of future dislocations. High certainty evidence that subacromial decompression surgery provides no patient-important benefit compared to placebo surgery or non-sugical care. The Rapid Recommendation was strong against surgery. Different methods yielded different estimates for MID and PASS, the context of use determines the most appropriate value.

Conclusion: Surgery for subacromial pain syndrome should be avoided. Shoulder dislocation patients can benefit from surgery.
Lahtinen AtteGermline variants in severe hematological diseases and their effect on hematopoietic stem cell transplantation outcomes and comorbiditiesHematopoieettinen kantasolusiirto on ainoa parantava hoitovaihtoehto pahanlaatuisia verisairauksissa. Hoitojen kehityksestä huolimatta niiden vaikutusta ei voida rajoittaa verisoluihin ja ne vaikuttavat myös muihin kudoksiin. Hoitojen sivuvaikutukset vaikuttavat potilaan ennusteeseen ja huonontavat elämänlaatua. Perinnöllisten tekijöiden on tunnistettu lisäävän riskiä haittavaikutuksille, mutta näiden merkitys on suurelta osin vielä tuntematon. Tunnistamalla näitä ennen hoitoa voimme parantaa kalliiden ja kuormittavien hoitojen tuloksia yksilöllistämällä hoitoa ja seurantaa hoitojen jälkeen.

Tutkimuksessa hyödynnetään eksomisekvensointidataa, jota analysoidaan yhdessä potilaista kerättyjen kliinisten tietojen kanssa. Potilasaineisto koostuu n. 700 hematologisesta potilaasta ja näistä on kuhunkin osatyöhön valittu soveltuvat. Ensimmäisessä (akuutti lymfaattinen leukemia -potilaat) ja toisessa (kantasolusiirtopotilaat) tutkittiin hematologisia sairauksia sekä muita syöpäsairauksia aiheuttavien varianttien esiintymistä potilailla. Näiden tulokset on julkaistu v. 2022.

Kolmannessa osatyössä tutkitaan ituratavarianttien vaikutusta kantasolusiirtoon useiden muuttujien osalta. Neljännessä osatyössä tutkitaan kantasolusiirtopotilaiden siittiöiden tuotantoa tavoitteena turvata lisääntymiskyky kuormittavien hoitojen jälkeen. Potilaiden sukusolunäytteiden tiedot yhdistetään muihin tietoihin ja analysoidaan ituratavarianttien, sairauden ja annettujen hoitojen vaikutusta näihin.
Cancer and Cell Based Cancer Research6000€
Laivuori MirjamiPrognostic factors of lower extremity artery disease – from diagnostic strategies and medication to histologic plaque characteristics.The aim of the thesis is to provide a deeper understanding of the factors that lead to severe lower limb ischeamia and increased risk of adverse cardiovascular events in patients with lower extremity artery disease (LEAD). The individual studies of the thesis analyse 1) the association of ankle brachial index and toe pressure to survival of LEAD patients, 2) the effect of statin medication on overall and amputation free survival in patients with varying severity of LEAD as depicted by ABI, 3) osteoid metaplasia in femoral artery plaques and associations to clinical factors and 4) bone marrow -like tissue in femoral artery plaques, its characterisation and association to clinical characteristics.

Studies 1-3 have been published. For the fourth study, femoral artery plaques have been sectioned and stained with immunofluorescence staining following a multiplex protocol containing four rounds of immunofluorescence staining with signal detection and bleaching in between. Bone marrow areas from the stained sections have been analysed using machine learning tools for quantification of cells expressing CD45, CD34, CD3, CD117, CD56, CD20, CD68, CD11b and CD11c. The data is combined with clinical data from patient records. The data is analysed and submission of article is expected during early autumn 2023. The thesis book is being written with expected dissertation during winter 2023-24. The grant will be used for salary of the researcher for the finalisation the thesis.
Lampainen KaisaRannekanavaoireyhtymä: ilmaantuvuus, riskitekijät sekä taloudelliset vaikutukset suomalaisessa väestössäTämän väitöskirjatutkimuksen tavoitteena on selvittää hermopinteiden ilmaantuvuutta suomalaisessa väestössä, selventää tupakoinnin, ylipainon ja työperäisten altisteiden merkitystä rannekanavaoireyhtymän riskitekijänä sekä määrittää hermopinteiden aiheuttamia terveydenhuollon kustannuksia. Jotta yläraajan hermopinteitä voitaisiin ehkäistä, niiden riskitekijät tulisi voida paremmin tunnistaa. Työperäisten riskitekijöiden tunnistaminen mahdollistaa paremman työhygienian, ja vähentää työperäistä sairastavuutta. Kustannusvaikuttavuuden ja yhdenvertaisuuden edistäminen ovat sosiaali-ja terveydenhuollon päätavoitteet. Tutkimuksen tavoitteena on tuottaa eväitä kustannusvaikuttavuuden lisäämiseen.

Tutkimuksen aineistona on käytössä koko Suomen kattava aineisto THL:n HILMO-rekisteritiedoista vuosilta 1998-2016 sekä näihin yhdistettynä Kelan tiedot sairauslomista sekä tilastokeskuksen tiedot eri ammattiryhmistä. Näiden lisäksi käytössä on Pohjois-Suomen syntymäkohortti 1966-aineisto. Tutkimusaineistot ovat suurelta osin hyödyntämättä. Tutkimuksen ohjaajat ovat oman alansa huippuosaajia. Tutkimuksen jäseninä ovat ohjaajien lisäksi Jaro Karppinen (fysiatrian professori, Oulun yliopisto), Juha Auvinen (yleislääketieteen professori, Oulun yliopisto), Jouko Miettunen ( kliinisen epidemiologian professori, Oulun yliopisto) ja Shiri Rahman (johtava tutkija, TTL). Neljännessä osatyössä mukana ohjaamassa on Helsingin yliopisto terveydenhuollon tuotantotalouden apulaisprofessori Paulus Torkki.
Marketta Helenius Fund for Health Sciences4000€
Launonen Inga-MariaOxidative stress influencing the tumor-immune interplay in triple-negative breast cancerBreast cancer represents the most common cancer in women, with over 2 300 000 new cases worldwide each year. Triple negative breast cancer (TNBC) constitutes 20% of all cases, is the most aggressive subtype, and patients with BRCA1 mutations are more likely to harbor this subtype than others. The tumor-immune microenvironment is an important player in the initiation, progression, and treatment response in cancers: tumor-infiltrating lymphocytes are an important prognostic factor in triple negative breast cancer and can be routinely scored in clinical practice. However, oxidative stress has been found to hamper the efficacy of immune checkpoint therapies activating cytotoxic T-cells through T-regulatory cells.

Importantly, the complex interplay between the tumor-immune microenvironment and oxidative stress is still unknown. We explore this using cutting edge tissue cyclic immunofluorescence (t-CycIF) single-cell imaging from tissue microarrays consisting of 365 patient samples. The ultimate goal is to decipher the immune suppressive mechanisms induced by the oxidative stress in the tumor in order to develop new immunotherapeutic and combinatorial treatment strategies as well as new biomarkers for patient stratification.
Lavikka KariAccelerating Cancer Research through Interactive Visualization TechniquesMy Ph.D. thesis focuses on developing interactive data visualization techniques to unravel drug resistance in cancer, specifically targeting ovarian high-grade serous cancer (HGSC). The project builds upon GenomeSpy, a powerful tool I have developed to analyze genomic data. The objective is to expedite research, enhance data exploration, and gain insights into the mechanisms underlying drug resistance. By creating user-friendly visualizations, integrating diverse data sources for comprehensive analysis, and implementing interactive and easily accessible tools for statistical analysis, the project aims to improve outcomes for HGSC patients and contribute to advancements in various biological sciences beyond disease research. GenomeSpy’s adaptability and versatility make it a valuable tool for advancing our understanding of diverse biological phenomena.6000€
Maldonado Sartori RocioA genetic engineering strategy to control cell proliferationRobust proliferation is a key feature of most cell lines used for research. Some of them, like induced pluripotent stem cells (iPSC), additionally hold a lot of promise for regenerative medicine and cell/gene therapies, as they differentiate into functional, potentially therapeutic tissues. In this context, cells that do not exit the cell cycle during the differentiation bring about a fundamental biological risk of unlimited or unwanted growth that hampers the extensive use of these cells beyond the clinical trial stage. Here, we describe a novel metabolic safety system to control cell proliferation without the addition of exogenous genetic elements.
Using CRISPR/Cas9, we inactivated the enzyme in charge of the de novo thymidylate synthesis (TYMS) in several cell lines. This resulted in cells that proliferate when supplemented with exogenous dTMP but fail to grow in its absence. As thymidine is needed for DNA, but not RNA synthesis, this approach targets only dividing, proliferative cells, without affecting postmitotic tissue. Thus, the method allows robust cell culture and manufacture while diminishing the risk of uncontrolled growth of transplanted cells.
Under dTMP supplementation, TYMS-/- iPSCs produce mature teratomas in vivo and differentiate normally into potentially therapeutic cell types, e.g. pancreatic beta cells. After terminal differentiation, the cells no longer require dTMP to remain functional, as seen by prolonged in vivo production of human insulin in mice.
Markkinen SallaMunuaissiirron luovuttajan ja potilaan geneettisen vaihtelevuuden, sekä siirtoparien välisten geneettisten erojen vaikutus siirteen komplikaatioihin suomalaisilla munuaissiirtopareilla.Tarve munuaissiirroille kasvaa jatkuvasti ikääntyvän väestön sekä lisääntyvien, länsimaille tyypillisten, elintapasairauksien seurauksena. Kudossopivuustestauksista huolimatta emme tällä hetkellä pysty ennustamaan siirron komplikaatioita riittävästi. Tutkimme retrospektiivisesti aikuisten munuaissiirtoaineistosta munuaisen saajan ja luovuttajan välistä perinnöllistä vaihtelua koko genomin tasolla. Hypoteesina on, että mikä tahansa geneettinen ero potilaan ja luovuttajan välillä voi johtaa potilaan immuunivasteen aktivoitumiseen, kun siirteen mukana tuleva proteiini tunnistetaan potilaan elimistössä vieraaksi. Lisäksi tutkimme koko genomin assosiaatioanalyysillä ja geeniekspressiometa-analyysillä kaikkea geneettistä vaihtelevuutta sekä potilaan että luovuttajan genomissa erikseen. Tutkimuksen tavoite on genomitiedon avulla luoda nykyistä parempia ennustetyökaluja siirtojen komplikaatioille sekä pitkäaikaiselle onnistumiselle kliiniseen käyttöön.4000€
Pajanoja CerenUnderstanding neural crest stemness in development and diseaseDuring early embryonic development, gastrulation transforms pluripotent stem cells into restricted cells specific to each germ layer. However, neural crest cells, originating from the ectoderm, exhibit a unique ability to generate cell types associated with ectoderm, mesoderm, and endoderm. Despite their significance, the mechanisms underlying neural crest formation and the acquisition of its exceptional stemness potential remain poorly understood. Unraveling these molecular processes is crucial for comprehending neural crest-related disorders like lethal pediatric cancer neuroblastoma and advancing potential therapeutic interventions. In my PhD project, I employ cutting-edge techniques such as single-cell-Multiplex-Spatial-Transcriptomics (scMST) in conjunction with RNA-sequencing to track transcriptional changes from gastrulation to neurulation. This research describes how the neural crest sustains its pluripotency-like potential throughout the ectoderm after gastrulation, while also aim to explore the transcriptional details governing fate determination during ectodermal patterning. My current findings challenge prevailing knowledge by revealing a gradual process of ectodermal patterning and shedding light on the remarkable acquisition of stemness potential in neural crest development.Cancer and Cell Based Cancer Research4000€
Parviainen AnnaNovel Epidemiological Aspects of Type 1 Diabetes in ChildrenAim: To report recent changes in the incidence rate (IR) of type 1 diabetes (T1D) in Finnish children, and to explore factors affecting these changes.
Methods: The research is based on register data from the Finnish Pediatric Diabetes Register, the Diabetes in Finland database and the National Infectious Diseases Register. IRs of T1D were assessed per 100000 person years and IR ratios (IRR) were calculated using Poisson regression.
Results: Before the Covid-19 pandemic, in 2015–2018, the IR of T1D in children aged <15 years had decreased compared with 2003–2006 (IRR 0.90), with the greatest decrease in children aged <5 years (IRR 0.77). After introduction of the rotavirus vaccine to the vaccination program in 2009, exposure to rotavirus infections and the IR of T1D decreased in parallel, and at population level, a reduction of one percentage point in the proportion of rotavirus exposed children was associated with a decrease of 8% in the IR of T1D in those aged <5 years. However, during the first 18 months of the pandemic, compared to a reference period in 2014-2019, the IR of T1D once again increased (IRR 1.16), but few of those diagnosed during the pandemic tested positive for SARS-CoV-2 antibodies. There were significant age-related differences in phenotype and genotype of children diagnosed with T1D.
Conclusions: T1D is a heterogeneous disease with a fluctuating incidence influenced by environmental factors affecting onset and progression of islet autoimmunity.
Perez FernandoTumoral microenvironment and genomic biomarkers for precision oncology in ovarian cancerAround 50% of ovarian cancers harbor genomic alterations related to a specific DNA-repair system deficiency [1]*. This DNA-repair system is called homologous recombinations and is highly relevant in the clinics for the treatment of ovarian cancer. 1) In recent clinical trials it was shown that only the patients with ovarian cancers that exhibit an homologous recombination DNA-repair deficiency (HRD) get unprecedented clinical benefit, such as way longer survival times, when treated with novel drugs that inhibit a DNA polymerase (PARP) [2]. 2) Additionally, it has been shown that HRD can shape the tumor microenvironment of ovarian cancer in a way that patients could tentatively get benefits from immunotherapy [3].

This dissertation’s first general objective is to develop biomarkers to detect HRD to be used in the clinics for ovarian cancer and further in endometrial cancer. A second general objective is to study the effect of HRD in the tumor microenvironment in a large cohort.

For the development of the HRD biomarker, this project takes advantage of the large multi-omics datasets publicly available, like The Cancer Genome Atlas (TCGA), additionally with the current machine learning techniques available. For the study of the tumor microenvironment, we performed high multiplex fluorescence microscopy that allows us to spot 31 different relevant proteins to detect different types of cells and its spatial organization.
Qadri SamiGeneettiset tekijät ei-alkoholiperäisen rasvamaksataudin patogeneesissä—vaikutukset maksan lipidimetaboliaan ja histopatologiaanSuomalaisista neljäsosalla on ei-alkoholiperäinen rasvamaksatauti (NAFLD), joka on merkittävä maksakirroosin aiheuttaja. NAFLD:n tautimekanismit ovat heterogeenisiä. ”Metabolinen NAFLD” liittyy metaboliseen oireyhtymään ja lisää voimakkaasti tyypin 2 diabeteksen sekä valtimotaudin ilmaantumista. Väestössä yleiset geenivariantit, sekä altistavat (erityisesti PNPLA3) että suojaavat (HSD17B13), säätelevät yksilökohtaista NAFLD:n ja oheissairauksien riskiä. PNPLA3-riskivariantin kantajilla on rasvamaksasta huolimatta paradoksaalisesti alentunut valtimotaudin riski, mutta syytä tälle ei tiedetä. Suojaava HSD17B13-variantti vähentää NAFLD-potilailla maksan sidekudoslisää ja tulehdusta vielä tuntemattomalla mekanismilla. Hiljattain kuvattu GPAM-variantti altistaa NAFLD:lle ja kirroosille, mutta variantin aineenvaihdunnallisia vaikutuksia ei ole tutkittu. Geenivarianttien vaikutukset maksan kudospatologiaan ovat myös tuntemattomia. Selvitämme näitä kysymyksiä ihmisissä käyttämällä genotyyppiin perustuvaa rekrytointia ja hyödyntämällä kudosnäytteiden omiikka-analyyseja, stabiili-isotooppimerkkiaineita, maksan magneettitutkimuksia, sekä koneoppimiseen perustuvaa kudosanalytiikkaa. Tutkimukset ovat oleellisia tulkittaessa geeniaktiivisuutta muokkaavien NAFLD-täsmälääkkeiden vaikutuksia ihmisissä ja NAFLD:n patogeneesin kannalta.4000€
Rönkkö JuliusDevelopment of hiPSC-Derived Models for the Study of Charcot-Marie-Tooth DiseaseIn my doctoral research, I investigate the role of IP3Rs in motor neuron function and Charcot-Marie-Tooth  disease (CMT) pathogenesis using patient-specific induced pluripotent stem cell (iPSC)-derived models. 

Charcot-Marie-Tooth disease (CMT) is an incurable progressive neurodegenerative disease of the peripheral nervous system. We have recently identified mutations in the ITPR3 gene, which encodes inositol 1,4,5 trisphosphate receptors (IP3Rs), as a new cause of CMT. IP3Rs are central signaling hubs for the cell, releasing Ca2+ from the endoplasmic reticulum upon binding of IP3. However, the roles of IP3Rs in peripheral nervous system cells (PNS) have not been studied previously.

To study how IP3Rs contribute to neuronal functions and human disease, I have created new hiPSC lines with CRISPR/Cas9 gene editing by knocking out the ITPR1-3 genes. Additionally, I have generated three  patient specific knockin hiPSC lines with CMT-causing ITPR3 mutations, which have not been studied before. To study the role of the IP3Rs in PNS cells and the role of mutations in CMT, I will differentiate the generated hiPSC models into spinal motor neurons and Schwann cells and characterize them using various unbiased methods such as electrophysiology, electron microscopy, functional Ca2+ imaging and LC-MS metabolomic profiling.
Neurological and Cerebrovascular Disorder6000€
Sarasjärvi KiiraPsychometric Validation of (Short) Warwick-Edinburgh Mental Well-Being Scale in Finnish Context – Mental Well-Being before, during and after COVID-19People are still mistakenly using the terms “mental health” and “mental health illness” interchangeably, when in fact mental health is more than just a lack of mental illness. One reason for this is that the current mental health field is very symptom-centered, with most used mental health scales are measuring mental health symptoms rather than mental well-being. The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) measures mental well-being in population level, and therefore investigating and using this scale can help us to expand the ways and advocate of how we determine mental health in the future.

In the present project, the psychometric properties of WEMWBS and its shorter version (S)WEMWBS are tested by using confirmatory factor analysis and measurement invariance in Finnish context. Thereafter, the scale will be used to assess the population’s mental well-being before, during, and after COVID-19 whilst exploring plausible risk and protective factors in both youth and adult populations. Large and well-representative population samples of School Health Promotion Study 2017-2023 and longitudial FinnHealth Study are used.

Once, the validation of the scales is completed, the results can be directly implemented in research and clinical work. The cut-offs of (S)WEMWBS can be used as an early-prevention screening tool, whilst establishing the protective and risk factors, we can create more effective treatments and health promotion strategies to improve people’s health.
Marketta Helenius Fund for Health Sciences4000€
Sultan IbrahimMolecular mechanisms of coronary vasculature development and relationship to physiological and pathological hypertrophyCardiovascular diseases (CVDs) are the leading cause of death worldwide. In healthy individuals, the heart pumps to maintain perfusion of peripheral organs. As a consequence of increased cardiac demand, cardiomyocytes (CMCs) undergo enlargement to upscale the pumping capacity, resulting in cardiac hypertrophy. The progression of cardiac hypertrophy can be physiological and beneficial, when triggered by demanding exercise or pregnancy, or it can be pathological and detrimental when triggered by cardiac ischemia or hypertension. In my studies, I am using mouse models of pregnancy, VEGF-B overexpression, cardiac ischemia, and elevated cardiac pressure, to investigate the earliest transcriptomic, proteomic, and metabolomic changes that occur in cardiac tissue in response to either type of cardiac hypertrophy. My aim is to correlate my findings to patient data and to help identify key molecular pathways that distinguish the prognosis of either type of cardiac hypertrophy. By using gene delivery as a translational tool, my studies could potentially provide tools to intervene in the progression of pathological cardiac hypertrophy and target molecular pathways to revert it.Cardiovascular6000€
Tuohinto KristaSOX18 TRANSCRIPTION FACTOR AS AN ATTRACTIVE MOLECULAR TARGET FOR KAPOSI’S SARCOMA, A VIRAL CANCERKaposi’s sarcoma herpesvirus (KSHV, HHV-8) is an oncogenic virus and can cause Kaposi’s sarcoma (KS). KSHV infection displays a unique infection program in lymphatic endothelial cells (LECs), characterized by high amounts of viral genome copies and release of significant amounts of infectious virus. We recently found that the key lymphatic transcription factor, SOX18, is expressed in KS tumors and needed for the unique infection program in LECs. SOX18 binds to the origins of KSHV DNA replication and increases the intracellular viral genome copies. SOX18 depletion or chemical inhibition by small molecule inhibitor dramatically decreased both the viral genome copies and released infectious virus. By using lymphatic endothelial precursor cells as an infection model, we recently showed that SOX18 inhibition also significantly diminished the infected cell spindle phenotype in vivo in NSG mice. This suggests that SOX18 could represent a potential molecular target for KS. Now we are investigating the molecular mechanism of how SOX18 facilitates KSHV genome replication. Our data demonstrate that only SOX18 WT, but not transactivation domain or DNA-binding deficient mutants can increase the KSHV DNA synthesis rate in infected cells. We have discovered viral and cellular SOX18 interacting proteins functioning in the dynamics of KSHV replication. This study will unravel the mechanistic basis and provide further proof for the efficacy of SOX18 inhibition as a potential KS therapy.Cancer and Cell Based Cancer Research4000€
Viippola EssiRepresentation learning in large-scale epidemiological studiesIncreasingly available and growing health registry data provide comprehensive insights into population health, but traditional statistical approaches struggle with the high-dimensional, sparse, heterogeneous, longitudinal, and interconnected nature of the data, producing results that are difficult to interpret. Representation learning methods, such as variational autoencoders, offer a promising solution by generating compact and interpretable representations of such data. 

In this project, we aim to apply representation learning to nationwide health register data from Finland’s entire population. Our objective is to investigate the familial risk associated with diverse health-related events, leveraging latent representations from parents’ health trajectories. By further incorporating genetic information, we aim to unravel the influence of genetic factors on latent representations and their predictive power for health outcomes. 

This study offers unprecedented possibilities to enhance our understanding of the interplay between genetics, familial risk, and health-related events by using unique Finnish data resources. The insights will help identify methods to compress information in large-scale epidemiological datasets, provide interpretable dimensions for disease characterization, and shed light on the heritability of health trajectories in the entire population of Finland.

Startup Grant

NameTitleAbstract of research proposal Fund
Heiland LilithAntimicrobial effects of amyloid β may explain neuroinflammation and degenerationAlzheimer’s disease (AD) accounts for approximately 70 % of all dementia cases. The pathological pathway for AD is hypothesized to be caused by the accumulation of amyloid beta (Aβ) and hyperphosphorylation of tau. The physiological function of Aβ is still not fully understood. Recent discoveries have indicated that the cause of AD is correlated with previous infectious diseases and research has shown that Aβ can kill microbes. The association of Aβ with a microbe or microbial molecule may explain the accumulation of Aβ in the brain of an AD patient. Of particular interest is Borrelia burgdorferi, which has been observed in the brains of AD patients.
During my Master’s thesis, I showed that Aβ inhibits the growth of relapsing fever causing Borrelia spp., but not of Lyme disease causing Borrelia spp. With the grant, I will continue studying the growth of microbes with different Aβ oligomers, the binding of Aβ to different microbial molecules (including FhbA, OspE and OspA) and the effect of Aβ binding to Borrelia spp. on phagocytosis by the phagocytic brain cells: microglia.
These research goals aim to study the physiological function of Aβ in relation to microbial infections and specifically Borrelia infections, which are already known for their complement immune evasion. The understanding gained from this research can further the development of new, effective drugs and treatments that will interfere with the pathological forms causing AD. 
Borrelia research4000€
Holmström Amanda Tumor educated platelets in pediatric brain cancer diagnosticsBrain tumors are the most common solid cancer type in children and adolescents. They are traditionally diagnosed via tissue biopsy or resection. Thus, tissue biopsy is not always feasible due to the location of the tumor and there may be a high risk for complications during the sampling. Recently, new approaches for solid tumor diagnostics have been introduced, such as liquid biopsies (LBs). 

LBs enable the detection of biomolecular changes connected with specific diseases. This study will focus on the tumor educated platelets (TEPs) in pediatric brain tumors. Previous studies have shown that platelets undergo functional and molecular changes when interacting with tumors. Analysis of these TEPs has potential to improve the diagnostics of solid tumors as sample material can be collected by a simple blood draw. In adult glioblastoma, this method has been shown to distinguish pseudo progression from true progression.  

In this study, we will collect blood samples from pediatric brain tumor patients and age-matched controls. Platelets will be isolated, and RNA-sequencing will be conducted to investigate transcriptome of TEPs in pediatric brain cancers. RNA expression profile of TEPs will be correlated with clinical variables, e.g., initial diagnosis and disease progression. The main aim is to explore the suitability of TEP derived RNA analyses for the diagnostics of pediatric brain tumors. This approach may offer safer alternatives for current diagnostic modalities.
Kandolin Miska Yleisimpien perinnöllisten sairauksien geenivirheiden kantajuus suomalaisessa geeniperimässä &
Perinnöllisyyslääketieteen ammattilaisten asenteet laajennettua kantajuusseulontaa kohtaan

Tutkimuksessa selvitetään tiettyjen perinnöllisten sairauksien geenivirheiden kantajuuden yleisyyttä suomalaisessa geeniperimässä hyödyntäen laajan gnomAD-tietokannan suomalaista otosta. Lisäksi tarkoituksena on selvittää edellytyksiä mahdollisen laajennetun kantajuusseulonnan järjestämiselle Suomessa ja kartoittaa suomalaisten perinnöllisyyslääketieteen ammattilaisten näkemyksiä kantajuusseulonnan sekä vastasyntyneiden mahdollisen geneettisen seulonnan (newborn screening) osalta. Vakavimmat perinnölliset sairaudet alkavat varhain lapsuudessa, ja ne ovat pahimmillaan fataaleja tai vaativat omaishoitajana toimimista vanhemmilta. Usein sairauksiin liittyy merkittäviä oireita lapsipotilaille, eikä useinkaan vakaviin perinnöllisiin sairauksiin ole tarjolla parantavaa hoitoa, vaan lapsen hoito on oireenmukaista.

Tutkimuksen ensimmäinen osa pohjautuu avoimen gnomAD-tietokannan aineiston data-analyysiin erityisesti suomalaisväestössä (otos n. 12 500). Tutkimuksen toinen osa toteutetaan suomalaisille perinnöllisyyslääketieteen ammattilaisille kohdistetulla sähköisellä kyselyllä. Mahdollisten riskipariskuntien tunnistaminen jo ennen sairaan lapsen syntymistä auttaisi tarjoamaan perheille heidän niin toivoessaan mahdollisuuksia joko alkio- tai sikiödiagnostiikkaan, lahjasukusoluhoitoon tai toisaalta adoptioonkin.
Rannila ErikaAivojen valkean aineen sairauden kliinisen kulun tutkimus käyttäen päälle puettavia mittareitaLBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) on perinnöllinen aivojen valkean aineen sairaus. Vaikka LBSL on maailmanlaajuisesti erittäin harvinainen sairaus, sitä aiheuttavien geenivarianttien kantajuus ja taudin suhteellinen esiintyvyys ovat Suomessa poikkeavan korkeat.

LBSL aiheuttaa etenevän aivojen ja selkäytimen valkean aineen vaurioon, joka johtaa neuromotorisen oirekuvan kehittymiseen. Sairauden oireet, vaikeusaste ja etenemisnopeus vaihtelevat yksilötasolla. Tällä hetkellä sairauteen ei ole ennustetta parantavaa hoitoa ja ymmärrys taudin kliinisestä kuvasta ja sen etenemisestä on puutteellista. Myös kliinisten biomarkkereiden puute taudin seurannassa ja diagnostiikassa on ilmeistä. Näitä tietoja tarvitaan tautitaakan ymmärtämiseen sekä tulevaisuudessa uusien mekanismeihin pohjautuvien hoitojen testaamiseen.

Yhteistyökumppanimme Kennedy Krieger Instituutissa ovat kehittäneet tavan käyttää päälle puettavia liikesensoreita ataksian kvantitatiiviseen arviointiin. Näin saadaan tarkkaa objektiivista dataa, joka mahdollistaa hyvän toistettavuuden pitkälläkin aikavälillä. Tässä tutkimuksessa tarkoituksena on hyödyntää yhteistyökumppaneidemme käyttämiä mittalaitteita LBSL-potilaiden seurannassa ja kerätä tietoa taudin luonnollisesta etenemisestä. Tutkimuksen avulla voimme löytää kliinisiä mittareita diagnostiikan tueksi, taudin yksilöllisen etenemisen arvioimiseksi ja hoitokokeiden mahdollistamiseksi.
Neurological and Cerebrovascular Disorder4000€
Saijets NelliUutta tietoa rintasyövän perinnöllisyydestäRintasyöpään sairastuu Suomessa vuosittain noin 5000 naista. Osaan liittyy periytyvä alttius. Tunnetuimmat perinnöllistä rintasyöpäalttiutta aiheuttavat geenit ovat BRCA1- ja BRCA2. Yksittäisten geenivirheiden aiheuttaman sairastumisriskin lisäksi suuret genominlaajuiset assosiaatioanalyysit ovat osoittaneet, että rintasyövällä on merkittävä polygeeninen alttius. Tätä polygeenistä riskitietoa voidaan kuvata polygeenisellä riskisummalla (PRS).

Väitöskirjatutkimuksessani selvitämme HUS:n Kliinisen genetiikan yksikön perinnöllisyysneuvontaan tulevien rintasyöpäpotilaiden perinnöllistä rintasyöpäriskiä. Tutkimuksessa geenivirheet ja PRS tutkitaan kaikilta. Koska tällä hetkellä vain osalle perinnöllisyysneuvontaan tuleville tehdään geenipaneelitutkimus, eikä PRS tutkita kliinisessä asetelmassa lainkaan, tutkimus antaa uutta tietoa, joka auttaa kehittämään kliinisiä käytäntöjä. Lisäksi tutkimme korkean PRS:n yhteyttä syövän laatuun ja ennusteeseen sekä selvitämme PRS:n vaikutusta korkeassa riskissä olevien terveiden sukulaisten asenteisiin ja käyttäytymiseen.

Yhtenä osatyönä on suunniteltu artikkeli BRCA2-geenin c.476-3C>A kliiniseltä merkitykseltään epäselvän muutoksen merkityksestä, siihen liittyvästä kliinisestä kuvasta ja sairastumisriskeistä. Kyseinen muutos on kliinisessä työssä rinta- ja munasarjasyöpäpotilailta toistuvasti todettu muutos, joka on rikastunut syöpäpotilaisiin verrattuna gnomAD-tietokannan syövän suhteen terveeseen väestöön.
Virkkunen Julia Nielurisojen osapoistoleikkauksen vaikuttavuus lasten kuorsauksen ja unihäiriön hoidossaLasten kuorsauksen esiintyvyyden on arvioitu olevan jopa 35%. Kuorsaava lapsi voi kärsiä samanaikaisesti unihäiriöstä, joka voi hoitamattomana vaikuttaa negatiivisesti lapsen kehitykseen. 2000-luvulla nielurisojen kokopoistoleikkausten (tonsillektomia) sijaan on ryhdytty tekemään yhä enenevissä määrin nielurisojen osapoistoleikkauksia (tonsillotomia), jossa etuna on nopeampi toipuminen ja pienempi leikkauksen jälkeinen verenvuotoriski. Tonsillotomia vaikuttaa olevan yhtä tehokas nielurisojen liikakasvun aiheuttaman unihäiriön hoidossa kuin tonsillektomia, mutta tietoa tonsillotomian pitkäaikaisvaikutuksista on vähän. Ensimmäisen tutkimuksen tavoitteena on vertailla tonsillotomian ja tonsillektomian vaikuttavuutta kuorsauksen ja unihäiriön hoidossa sekä selvittää leikattujen mahdollisia nieluoireita yli 10 vuotta leikkauksen jälkeen. Tutkimus toteutetaan kyselytutkimuksena vuosina 2010-2011 HYKS korva-, nenä- ja kurkkutautien klinikassa nielurisaleikatuille potilaille. Toisessa tutkimuksessa selvitetään lasten kuorsauksen ja unihäiriöiden nykyhoidon vaikuttavuutta oirekyselykaavakkeiden ja kotona tehtävän unirekisteröinnin avulla. Tutkimukseen rekrytoidaan 100 2-12 -vuotiasta kuorsaavaa lasta, joista 50:lle tehdään nielurisojen osapoistoleikkaus ja 50:tä seurataan ilman toimenpiteitä. Tutkimuksessa selvitämme, kuinka hyvin pystymme kliinisen arvion ja kyselyiden perusteella löytämään nielurisojen osapoistoleikkausta tarvitsevat ja siitä hyötyvät potilaat.4000€
Zheng VincentLasten epilepsiakirurgia Suomessa: pitkäaikaistulokset ja komplikaatiotVäitöskirjassa tutkitaan HUS:issa lapsena tehtyjen resektiivisten (ei SEEG, DBS, VNS) epilepsiakirurgiatoimenpiteiden tuloksia ja vaikuttavuutta. Osatöiden tarkoituksena on tuoda lisää tietoa muun muassa optimaaliseen potilasvalintaan, hemisferotomioiden komplikaatioihin ja radiologisiin tuloksiin, sekä raportoida Helsingissä leikattujen potilaiden pitkäaikaistulosta. Osatyöt tulevat muodostamaan Suomen ensimmäinen pediatrista epilepsiakirurgiaa käsittelevän väitöskirjan.

Ensimmäisessä osatyössä keskitytään vertikaaliseen hemisferotomiaan (VPH) ja sen kliiniseen- ja radiologiseen lopputulokseen. Toisessa osatyössä tarkastellaan esikouluikäisenä leikattujen lasten pitkäaikaistulosta ja keskitytään erityisesti, mitkä tekijät ennakoivat suotuisaa tulosta kognition ja epilepsian osalta. Kolmannessa osatyössä selvitämme laajalla aineistolla lapsena epilepsian takia leikattujen potilaiden pitkäaikaista elämänlaatua.

Lasten ja nuorten vaativa epilepsiakirurgia on Suomessa keskitetty HUS:iin. Vuodesssa yksittäisiä lasten epilepsiakirurgisia toimenpiteitä tehdään lisäksi KYS:sa (0–4/v). Aikaisemmissa selvittelyissä Suomessa tulisi tehdä vuosittain 90 kohtauksettomuuteen tähtäävää epilepsiakirurgista leikkausta vuodessa, kun määrä tällä hetkellä on vuosittain noin 50 (Immonen et al., 2008). Keskitetyn toiminnan takia voimme arvioida kokonaisvaltaisesti lasten epilepsiakirurgian tilannetta valtakunnallisella tasolla, jota ei ole Suomessa aikaisemmin tehty.

Biomedicum Helsinki Foundation Prize 2023

The Biomedicum Helsinki Foundation Prize 2023 for an exceptional publication in health sciences from the local community during the previous year was revorded to Rafael Moliner for the following publication Psychedelics promote plasticity by directly binding to BDNF receptor TrkB .Nature Neuroscience volume 26, pages1032–1041 (2023)