12.Nov – Publication (Toxicological characterization of compounds from Brazilian fauna)
During a project sponsored by the Humboldt foundation, Brazilian guest professor Elaine de Souza-Fagundes used our facilities and test methods to study bioactive compounds from the indigenous Brazilian flora and fauna. One subproject focused on modified spider toxins as basis for new drug templates.
Abdel-Salam M, Tavares J, Sousa Gomes K, Teixeira-Carvalho A, Kitten G, Nyffeler J, Dias F, Reis P, Pimenta A, Leist M, de Lima ME, EM (2018) The Synthetic Peptide LyeTxI-b Derived From Lycosa erythrognatha Spider Venom is cytotoxic to U-87 MG Glioblastoma Cells
Amino Acids, in press (Ms. No. AMAC-D-18-00302R1)
02.Nov – Publication (Neuron-glia interaction to balance stress response pathways and apoptosis)
It is well-known that neurons rely on glial cells for their thiol (glutathione) supply. We established a cell co-culture system to study this important mechanism more closely. We found that the glia can indeed prevent neuronal cell death triggered by mitochondrial toxicants or proteasome inhibitors. More importantly, we provided evidence that this is not a simple anti-oxidative effect, but rather involves a complex adaptation of human neuronal stress response pathways (e.g. down-tuning ATF-4 and up-regulating Nrf-1). Such knowledge may allow boosting of the brains own defense mechanisms, and could be used to increase the brains resilience towards toxicants or the progression of neurodegenerative disease.
Gutbier S, Spreng AS, Delp J, Schildknecht S, Karreman C, Suciu I, Brunner T, Groettrup M, Leist M (2018).
Cell Death Differ, in press (doi: 10.1038/s41418-018-0229-x)
22. October 2018: Publication on adverse outcome pathway for mitochondrial toxicants
In a multi-year effort, we assembled a systematic review in form of an adverse outcome pathway (AOP) for Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits. The work was together with international regulatory experts, and it finally was officially adopted by the OECD. The work had an overall impact on AOP guidelines, as it is the first AOP that contains a non-linear loop.
Background: AOP are generally catalogued in the OECD knowledge base (containing presently 244 AOP) https://aopkb.oecd.org/ .Detailed info is found on the AOPwiki (https://aopwiki.org/). The AOP are at different completion, review and curation stages. The recognition process comprises peer reviews, public consultations and rounds of amendments. We have now reached the final level (only reached by 3 other AOP) with official publication by the OECD:
Anna Bal-Price, Marcel Leist, Stefan Schildknecht, Florianne Tschudi-Monnet, Alicia Paini, Andrea Terron (2018) “Adverse Outcome Pathway on Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits”. OECD Series on Adverse Outcome Pathways, No 7, OECD Publishing, Paris
17. October 2018 –ESTIV conference (Berlin): presentations and overall organisation
We (CAAT-Europe) co-organized the 2018 conference of the European society of toxicology in vitro (ESTIV). Over 400 participants assembled in Berlin (15.-18. October), and the meeting (generously supported by the DFG and many industrial sponsors) turned out to be one of the most important toxicology events world-wide. The program (https://www.estiv2018.com/programme/scientific-programme/) focussed in particular on the practical application of new approach methodologies (NAM) in toxicological hazard and risk assessment (and was thus perfectly in line with the research topic of our chair)
13. October 2018 – Two publications from collaborative work
In the context of the European projects ToxRisk and InnoSysTox it was important to study the question on how long cells have to be exposed to toxicants to provide robust and sensitive data:
Gu X, Albrecht W, Edlund K, Kappenberg F, Rahnenführer J, Leist M, Moritz W, Godoy P, Cadenas C, Marchan R, Brecklinghaus T, Pardo LT, Castell JV, Gardner I, Han B, Hengstler JG, Stoeber R.
Arch Toxicol. 2018 Oct 13. doi: 10.1007/s00204-018-2302-0.
Our expertise in brain stem cells and trophic factor signaling was provided to a group in Sweden, working on brain damage of infants/newborns and potential new treatments:
Osato K, Sato Y, Osato A, Sato M, Zhu C, Leist M, Kuhn HG, Blomgren K.
Front Neurol. 2018 Sep 12;9:738. doi: 10.3389/fneur.2018.00738. eCollection 2018.
10. October 2018 – Lab outing
After a good and successful year, the whole lab went out for a treasure hunt/hike on the lake. Spectacular pumpkins were discovered....... And the day ended with all-you-can eat Dünnele (allemanic pizza) and all you can drink cider.
17. Sept 2018– Conference contributions: EFSA conference
M. Leist was invited as keynote speaker and podium panelist to the EFSA conference, which brings together about 1300 experts and stakeholders in food-related safety issues every three years. Discussion panel.
The conference is available also as video recording (here, start at 27 minutes)
https://www.efsa.europa.eu/en/events/event/180918, and slides can be downloaded (here)
02.Sept – Publication (Good in vitro methods practices)
The final version of the good in vitro methods task force (GIVIMP) has been accepted and officially published by the OECD. This document, assembled by a European team (with M. Leist) is meant to harmonize the use of in vitro methods for regulatory purposes in the major industrialized countries world-wide.
Antonelli MA, Astridou M, Bichlmaier Suchanová B, Bernasconi C, Bostroem AC, Bowe G, Coecke S, Cole T, Chong HD, Cortvrindt R, Cuevas L, Dudra A, Elmore E, Eskes C, Fant K, Gray A, Harbell J, Heringa M, Ivanov D, Jacobs G, Jaspers R, Joossens E, Langezaal I, Leist M, Lucotte T, McFarland R, Meloni M, Milcamps A, Pedersen E, Pioppo L, Prinz MJ, Rossi A, Rossi L, Stacey GN, Testai E, van Acker F, van der Linden S, Whelan M, Wilk-Zasadna I. (2018)
Guidance Document on Good In Vitro Method Practices (GIVIMP).
ENV monograph: Series on Testing and Assessment Guidance document No. 286.
ENV/JM/MONO(2018)19, 264 pages
31. August – Publication (Stress regulation in neuronal cells)
The collaborative work, with the Memorial Sloan Kettering Cancer center in New York (Studer lab) and other groups has been accepted by Nature Communications.
Nat Commun. 2018 Oct 19;9(1):4345. doi: 10.1038/s41467-018-06486-6
Title: HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons
The work is based mainly on contributions by former PhD students Bastian Zimmer (now Evotek) and Simon Gutbier (now Roche) to experiments producing SILAC labelled LUHMES neurons (cells incorporating amino acids with heavy isotopes for exact quantification of the proteome). This was used to calibrate iPSC neurons (a cell population that is too hard to label directly with isotopes). Then experiments were performed to identify changes of the chaperome (i.e, the entirety of all proteins involved in folding and stabilizing other proteins) of dopaminergic cells (the population of cells affected in Parkinson’s disease). The purpose was to point out new ways to study cellular stress responses, and possibly to use this knowledge for new strategies to cure disease.
30. August – Publication (Genetic background and toxicant sensitivity)
The collaborative work, supported by the Luxemburg Center of Systems Biology, has been accepted by Arch Toxicol.
Title: Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift
The study's main conclusion is that each test system requires a fit-for-purpose quality evaluation, meaning that its suitability can only be tested for a specific application/purpose, but not in general. Conversely, there is no great benefit from large and resource-consuming tick list evaluations, as they do not provide sufficient confidence into the performance of the test for its specific purpose.
These issues are exemplified by full sequencing, functional testing and standard phenotypic characterization of a human cell line (LUHMES) frequently used for neurotoxicity testing or different biomedical questions.
Read the entire article "online first" from the journal Archives of Toxicology https://www.ncbi.nlm.nih.gov/pubmed/?term=30298209https://www.ncbi.nlm.nih.gov/pubmed/?term=30298209
Gutbier, S., May, P., Berthelot, S. et al. Arch Toxicol (2018). https://doi.org/10.1007/s00204-018-2326-5
12. August 2018 – TV documentation of Leist lab and CAAT (engl.)
Our previous TV docu was processed by Deutsche Welle and overlayed with english voice commentary. It was broadcasted worldwide in a 9 minute documentary. Individual minutes can be seen as short videos
Tomorrow Today - The Science Magazine Deutsche Welle August 12, 2018 11:30pm-12:01am CEST
18. July 2018 – Conference organisation: READACROSS as animal-free approach of risk assessment
On 16.-18. July a workshop was organised (with the support of the University of Konstanz and other international organisations) to discuss international approaches towards the implementation and use of readacross (RAX). This approach uses knowledge on known toxicities of chemicals to derive information on the toxicity of yet non-tested chemicals. Very advanced computational methods (developed by CAAT; Thomas Hartung) were discussed that are based on the ‘big data’ that have become available in the field recently. The international aspect was covered by input from the USA, Canada, Australia, Japan and EURL-ECVAM (for the EU).
A workshop report will be prepared for publication.
14. July – Grant received by the Danish Environmental Protection Agency (DK-EPA)
For the first time such a big grant has been given to an international consortium (Leist lab (Konstanz), Prof. E. Fritsche (Düsseldorf), Dr. T. Shafer (EPA, USA), Dr. A. Bal-Price (advisor role; EURL-ECVAM). A panel of pesticides will be investigated in this project for the potential to cause developmental neurotoxicity. The novelty is that only in vitro methods will be used.
06. July – PhD defense (Simon Gutbier)
Roche in Basel is winning a very valuable asset, while we lose our good colleague. The transition is marked by a summa cum laude defense. Good luck and success to Simon and best wishes for papers from Konstanz work still to be published.
06. July 2018 – TV coverage: alternatives to animal testing – human neuronal models
Work by the chair in Konstanz and by our CAAT partner Prof. Thomas Hartung at Johns-Hopkins University (Baltimore) on neuronal cultures and organoids is presented in the context of New Approach Methods (NAM) to substitute animal experiments.
The TV production in our lab resulted in a 6 min movie (in German):
It is part of a larger production on all aspects of animal experiments and alternatives to animal experimentation (45 min) with lots of background text and individual theme movies. Altogether a good way to get comprehensive info on the topic:
05. July – Workshop (Respiratory function testing)
Johannes Delp organized a workshop on advanced uses of the Agilent-Seahorse analyzer. Case studies from the University of Konstanz research groups and the EU-ToxRisk project (co-organizer) were presented, together with new solutions (D. Gebhard & S. Vikstrom, Agilent) optimized for specialized biological systems, such as immune cells, neurons, bacteria and nematodes.
30. June – Publication (Chemical biology – new class of antioxidants)
Together with Prof. Sebastian Polarz (Chemistry in Konstanz) and PD David Schleheck (Biology in Konstanz) and several co-workers, we characterized novel fullerene-based surfactants designed in the Polarz group. The ms was published in Appl. Materials Interfaces (IF: 8.1)
Manuscript (Kunkel et al): https://pubs.acs.org/doi/10.1021/acsami.8b07032
25. June – Publication (Chemical biology – QSAR for neurotoxicity)
Together with our Brazilian guest researcher, Prof. E. Fagundez, and with different groups in Chemistry, we synthesized and characterized novel triazoles. A strucure-activity relationship for neurotoxicity was established in the manuscript: Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties”
11. June – Publication (Neuronal organoids)
A manuscript on the use of human neuronal organoids for study of toxicological resilience has just been accepted. This work was a collaboration with CAAT at Johns-Hopkins University (Baltimore) and followed up on our previous work
Reference to previous work:
25. May 2018 - Publication (Alzheimer's disease)
After a long delay, we managed to work through our previously-assembled large data set on Aß secretion from human neurons, and the modulation by secretase inhibitors. A remarkable finding was that there are situations in which treatment with protease inhibitors leads to a HIGHER release of the amyloid peptide (Aß). This findings supports the need for careful pharmacological studies over wide concentration ranges and under variable conditions (instead of the often-seen single perspective, single-dose, proof-of-principle studies).
Another remarkable side anecdote was that this was the first time we were caught for plagiarism by an automatic algorithm run by the publisher: the ‘plagiated’ work was the PhD thesis of the first author of the manuscript...... (nevertheless a disclaimer had to be added to the publication)
Manuscript source: https://www.ncbi.nlm.nih.gov/pubmed/29804308
16. May - EFSA workshop ‘Emerging risks’
ML gave a presentation at an European Food Agency (EFSA) workshop in Parma (I). The overall these was on emerging risks for society, relating to food, food ingredients and all aspects of the food production cycle. The specific talk topic was on the use of adverse outcome pathways (AOP) to bridge epidemiological and molecular data sets.
14./15. May 2018 – TV coverage
Work by the chair and by CAAT-Europe (including the historical track record of the University in this field) was put at the focus of a TV documentary. From the ‘scientific side’ we tried to capture good time lapse movies on how human neuronal networks form in culture dishes, and how they disintegrate upon toxicant stress. Let’s see what is coming out of it when all is processed.....
25. April 2018 - Publication
First article published in the BenchMarks Series. This is a new series of articles in ALTEX that addresses common technical problems and errors and that is co-ordinated by M. Leist. The inaugurating article deals with curve normalizations in toxicology/pharmacology/cell biology.
15. April 2018 – New Staff
Giorgia Pallocca joined our CAAT-Europe organisation. Giorgia obtained a PhD at Uni Konstanz in 2017, after working at the EURL-ECVAM (Ispra, I) and the University of Bologna. She has an excellent track record in animal replacement research (LUSH prize 2014) as well as development of NAM (several publications based on stem cells and transcriptome analysis), and she will be an important contributor for the H2020 project EU-ToxRisk.
6.-9. March 2018: Course on computational toxicology and modelling
CAAT-Europe organized a Summer School for European project partners (EU-ToxRisk and other projects, n = 30 participants) in the historical Konzil building on the use of computational toxicology tools such as quantitative in vitro-in vivo extrapolations (qIVIVE), physiology-based pharmacokinetic modelling (PBPK), metabolite predictions, quantitative AOP (qAOP) and Bayesian networks
27. February 2018: Publications
Following a workshop uniting specialists from Europe and the USA on developmental neurotoxicology (DNT) from academia national competence centers and and regulatory agencies, a catalog of Test Readiness Criteria was published. These were put into the context of regulatory application of New Approach Methods (NAM).
The publication was accompanied by a consensus statement on the state of DNT testing by international stakeholders.
27. February 2018: German Toxicology Summit
German Toxicology summit (DGPT annual meeting in Göttingen). Talk by M. Leist at Systems Toxicology Symposium on “A human stem cell differentiation system to screen for developmental toxicants”
22. February 2018
Tanja Waldmann receives the ‘best poster price’ at the EU-ToxRisk general assembly. Over 70 posters had been assembled and scored. Tanja’s work referred to a human stem cell based method to characterize developmental toxicants and to rank compounds known to trigger craniofacial malformations according to their hazard potential. The assay has been developed mainly by Nadine Dreser, Stefanie Klima, Nina Balmer and several others over many years, and it is has been used in several collaborative research projects.
Background literature: https://www.ncbi.nlm.nih.gov/pubmed/27188386
20. February 2018
The University submitted the proposals for the Excellence initiative (final evaluation round). We feel that it was an enormous challenge to design and shape a project like ‘ChemLife’. And now we are happy that (i) a really solid and excellent proposal has been assembled, and (ii) that this intense phase of work is over for a while :-).
We all hope for intense project kick-off activities again after the judgement day (end of September).
15. February 2018
We came out as winner of a public procurement process of the European Food Agency (EFSA; http://www.efsa.europa.eu/) in a bid to establish a test battery for developmental neurotoxicity. The Kick-off meeting of this EFSA project was held in Parma. For the next 18 months, we will develop together with the US-EPA, the European Comission JRC (EURL-ECVAM) and the Leibnitz Research institute for Environmental Medicine in Düsseldorf (Prof. E. Fritsche; http://www.iuf-duesseldorf.com/home.html) new tests for DNT
5. Februar 2018
Publication on ‘Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect’ in Cell Death and Disease (CDDis)
This collaboration with the group of Prof. Daniel Dietrich (Human and Environmental Toxicology, Konstanz) used metabolic analysis and our mitochondrial profiling approach to identify the potential for specific toxicity of an important diabetic drug. https://www.ncbi.nlm.nih.gov/pubmed/29445145
25. Januar 2018
Publication on ‘A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays’ in ALTEX
In this work, we collaborated with the National Toxicology Program of the USA (NTP), a renowned computational toxicology group in Barcelona (University Pompeu Fabra) and our Department of Computer and Information Science). We performed two screens for specific neurotoxicants and established several new principles on how to use screen assays in modern toxicology. https://www.ncbi.nlm.nih.gov/pubmed/29423527
12. Januar 2018
Publication on ‘Stage-specific metabolic features of differentiating neurons: Implications for toxicant sensitivity’ in Toxicology and Applied Pharmacology (TAAP)
This collaborative work brought together specialists in metabolomics, systems toxicology and metabolic flux analysis. It may at present be the most comprehensive description of a metabolic flux model in human neurons.
It also provides the first evidence for the dependence of toxicant sensitivities of neurons at different developmental stages. https://www.ncbi.nlm.nih.gov/pubmed/29278688
9. Januar 2018
Participation of Prof. M. Leist as founding member of the Bf3R committee in Berlin. This commission gives advice to the new center for animal protection (Bf3R) at the Federal institute of Risk assessment (BfR).
10. Dezember 2017
Publication on ‘An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition’ out in Arch Toxicol.
The large review (42 pages), together with EFSA, Danish EPA and EURL-ECVAM specialists relates toxicants affecting mitochondrial function to the risk of Parkinson’s disease. Here a new approach was pioneered to use structure-activity relationships to identify toxicant mode-of-action:
7. Dezember 2017
Talk of Marcel Leist at the ethics platform of the BOKU University Vienna on alternatives to animal experimentation: state of the art (available on YouTube)
1. Dezember 2017
Publication on ‘A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins’ out in Arch Toxicol.
Here a new approach was pioneered to use structure-activity relationships to identify toxicant mode-of-action: https://www.ncbi.nlm.nih.gov/pubmed/29164306
21.-23. November 2017
Invited talk of Johannes Delp at OpenTox workshop "Collaboration and integration: Toxicology and risk assessment in the time of dynamic data". The conference is to be held in Basel November 21-23
21. November 2017
Generation shift: PhD exam of Johanna Prüfung (now post-doc at the environmental protection agency of the USA (EPA), and start of the new students Ilinca Suciu, Christopher Scholz and Anna-Katharina Ückert: welcome!
6. November 2017
Today, one year ago, the prestigious LUSH prize was awarded for research in our group. See a video informing on the scientific concept of model developoment and systems toxicology:
21. October 2017
Marcel Leist receives the 2017 world-wide recognition award of the aaalac international
15. October 2017
Leist et al. (2017) Adverse outcome pathways: opportunities, limitations and open questions. Arch Toxicol, in press
Collaborative work with > 30 co-authors on strengths, weaknesses and opportunities of the adverse outcome pathway (AOP) concept promoted by the OECD.
31. September 2017
Results of the first evaluation round for research clusters of the excellence initiative: The ChemLife project proposal was selected for the second round. Our projects and systems toxicology play an important role.
21. - 25. September 2017
Tanja Waldmann and Johanna Nyffeler are invited to a workshop of the US national toxicology program (NTP) to present data generated from the University of Konstanz (UKN) test methods for developmental neurotoxicity (DNT). Twenty researchers from around the world were assembled by personal invitation to work out new test strategies.
Background on NTP: https://ntp.niehs.nih.gov/results/areas/index.html
1. September 2017
Our alumni Johanna Nyffeler joins the US environmental protection agency (EPA) to work on new systems toxicology approaches of toxicity assessment within the Tox21 program.
Info on the program: www.epa.gov/chemical-research/toxicology-testing-21st-century-tox21
11. August 2017
Production of a document on good in vitro practices in collaboration with the European Commission and the OECD.
The document went into the second public consultation round:
Background information: There is a scientific policy and regulatory desire for validated and internationally accepted in vitro methods (e.g. OECD test guidelines or ISO standards). To accommodate the needs of regulatory authorities, a number of in vitro methods, often based on the use of human cells and tissues, have been submitted to international validation bodies during the last two decennia. However, the experience gained during these validations revealed that many in vitro methods need significant improvements in design, robustness and reliability before they can be successfully implemented in a routine laboratory environment to generate data sets, which can be used to support regulatory decisions. GIVIMP specifies these improvements.
15. May 2017
Workshop on ‘developmental and reproductive toxicity (DART) test methods’
The workshop was held in collaboration with BASF and CAAT-Europe in the historical concilium building. International experts worked on a roadmap for improved DART testing to support development of new compounds, reduce the use of animals, and increase safety of the population
5. May 2017
Publication of our first screening paper to identify unknown toxicants together with the National Toxicology Program, USA (NTP) and the Computational Toxicology unit at University of Pompeu Fabra (Barcelona). We define strategies for ‘hit’ (= positive screen result) confirmation and hit follow-up in the field of toxicology.
Nyffeler J, Dolde X, Krebs A, Pinto-Gil K, Pastor M, Behl M, Waldmann T, Leist M. (2017) Combination of multiple neural crest migration assay to identify environmental toxicants from a proof-of-concept chemical library. Arch Toxicol, 10.1007/s00204-017-1977-y
29. April 2017
Publication of a large systems toxicology-oriented review on the MPTP Parkinson’s disease model, together with leading experts involved in the initial discovery of the underlying toxicant (D. DiMonte, DZNE, Bonn), and in contemporary landmark discoveries concerning new mechanisms (K. Tieu, Miami).
Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M (2017) Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol Sci, in press doi: 10.1016/j.tips.2017.03.010
27. April 2017
Workshop on ‘Data management and data processing in large European projects’ with 28 international participants in the Concilium location in Konstanz. Co-Organised by CAAT-Europe (M. Daneshian), Douglas Connect (Basel) and the European Bioinfomatics Institute (EBI, Cambridge)
5. April 2017
Our new paper on interferon developmental hazard is out
Pallocca G, Nyffeler J, Dolde X, Grinberg M, Gstraunthaler G, Waldmann T, Rahnenführer J, Sachinidis A, Leist M. Impairment of human neural crest cell migration by prolonged exposure to interferon-beta. Arch Toxicol. 2017
16. March 2017
The EFSA opinion ‘A new path to toxicity assessment’ is officially published
We worked hard on this, and on the embedded adverse outcome pathway (AOP) examining a relevant link of pesticides and Parkinson’s disease (link)
M. Leist receives the ‘GT-toxicology award’ at the German Toxicology Summit in Heidelberg for excellent publications in the previous year