Research

Anton Gartner Synopsis of Research and Teaching and Public Engagement Activities

Our studies on C. elegans are facilitated by the simplicity of the organism at the developmental and anatomical level, by the ease of its maintenance, as well as by the power of forward and reverse genetic procedures. Despite of its simplicity, C. elegans is a multicellular organism that shares many fundamental genetic programs with humans. We aim to address key biological problems in the context of an entire organism. We consider it important to carefully observe phenotypes in wild type and mutant worms. We take on an aphorism by Barbara McClintock recommending to ‘Just look at an organism and see what it tells us’. With respect teaching we equally take a hands-on approach ranging from interacting with advanced high school students to senior postdoctoral researchers.

Apoptosis and DNA damage signalling in the germ line

DNA damage checkpoint pathways are needed to detect DNA damage and to transduce signals that elicit cell cycle arrest, DNA repair, and/or programmed cell death. Defects in DNA damage checkpoint signalling have are implicated in tumorogenesis, as well as in some genetic instability disorders like, for instance, Li-Fraumeni syndrome and Ataxia Telangiectasia. Although the link between these genetic instability disorders and a failure in the proper DNA lesion processing is clearly established, the signalling network that communicates between DNA perturbation and the cell death machinery remains ill defined. We use the small nematode C. elegans as a model system to study DNA damage signalling and apoptosis. We particularly focus on apoptosis in the female germ line. It was recently shown that the elimination of genetically compromised germ cells uses very same pathways in mammals. We aim to focus on how apoptosis induction occurs. Thus we will continue looking at the regulation of CEP-1, a primordial p53 like transcription factor we have implemented in germ cell apoptosis induction. Over the past years we have found that pathways acting in parallel to CEP-1 are also required for apoptosis induction. We aim to further understand those regulatory mechanisms.

Homologous Recombination during DNA Repair and Meiosis

Homologous recombination is needed for the error free repair of DNA double strand breaks, as well as for meiotic recombination in order to ensure faithful chromosome segregation and genetic diversity. Also the DNA damage response pathway coordinates recombinational repair and failure of appropriate repair leads to apoptosis induction. A crucial intermediate of recombinational repair are Holliday Junctions, four way cruciform intermediates first postulated to exist more than 40 years ago. While Holliday Junction (HJ) resolving enzymes were known in bacteria for more than 20 years, only very recently HJ resolving enzymes, that symmetrically cut HJs were found in animals. We independently found on such enzyme, GEN-1 in an unbiased genetic screen and were the first to show that gen-1 mutants are defective in DNA double strand break repair and DNA damage signalling. Unexpectedly GEN-1 does not have a role in meiotic recombination, but we found that combinations of nucleases might also be able to resolve HJs during meiosis. Our current working model is that the XPF-1 nuclease aided by the Blooms helicase is able to process HJs, while SLX-1 and MUS-81 nucleases act in a parallel HJ resolution pathway.

Directly assessing genome stability

The maintenance of genome stability is essential for survival, but mutations are important to allow for evolution to occur. We know relatively little about mutagenesis rates in vivo and to what extend this is kept at bay by various DNA repair pathways in unchallenged organisms. C. elegans was the first animal to be sequenced, and next generation sequencing can now do this at and massive scale and with minimal costs. Also, C. elegans can be clonally propagated, thus providing and ideal system to study mutation rates and mutational spectra, occurring in wild type and DNA damage response defective worms, with and without DNA damaging agents at a genome wide scale. We stated a large scale collaborating with the Sanger Centre to analyse C. elgans mutation profiles, and aim to establish the worm genome sequencing as a test system to study the effect of known and suspected carcinogens. We aim to compare mutational spectra with those occurring in cancer patients. We also aim to directly assess how DNA response mutants affect mutant profiles. Our early results provided important preliminary data for a joint strategic award linking the Sanger centre, our laboratory and several other UK repair and toxicology labs, to follow up this approach at a much larger scale, using worms, yeasts and human cell lines.

Models of Neurodegeneration

Parkinson’s PD disease is a neurodegenerative disease that affects ~2% of the population above 65 years of age. PD results for the loss of dopaminergic neurons. There are no drugs that prevent this loss, but drugs that ameliorate symptoms are available. Understanding why dopaminergic neurons degenerate in individuals affected by PD is obviously hampered by the sheer complexity of the human brain, and by ethical and practical concerns relating to experimentation with human subjects. PD is associated with environmental toxins, and the accidental toxin exposure can trigger the loss of dopaminergic neurons and cause PD like symptoms. We started to use the nematode worm C. elegans to model key aspects of PD pathology to better understand how to prevent neuronal loss. Worms have only 302 neurons, eight of which functionally and biochemically correspond to human dopaminergic neurons. These neurons can be marked by appropriate GFP fusions in living animals and their degeneration in response to neurotoxins such as 6-OHDA can be assessed. We are looking for and are characterizing mutants that confer increased or decreased sensitivity to 6-OHDA mediated neurodegenerative. We are currently focusing on one locus which we shown to effectively protect dompaminergic neurons and also started to uncover the function of LRK-1, a conserved kinase, mutations of which lead to inherited form of PDs. Furthermore, we recently conducted a genetic screen leading to the identification of several mutations preventing neurodegeneration.

Collaborative Efforts; Organismal Biology

The ease of our experimental systems allows us to contribute to the phenotypic analysis of genes studied in our department and at the Dundee CLS. At the same time we benefit from the biochemical expertise of our colleagues. We learned to use and employ SILAC based approach to quantitatively measure the C. elgeans proteome together with the Lamond lab. We recently started to use these procedures to study global changes in protein turnover during worm aging and stress and have very first results. Furthermore, we interact with the Blow lab to visualize key aspects of DNA replication licensing by using in vivo imaging procedures. Also a joint postdoc with the Hay lab is looking at the C. elegans Sumo regulation.

Scholarship and learning and teaching

As is the case for research I think that passion, appreciation and pride for achievement is equally important for teaching. Concerning approaches to teaching, for the age group above 16, I consider the classic and ancient apprenticeship model as most appropriate. Developing a passion for joinery is most likely achieved by being instructed by a joiner and by working in a joinery, even if the pedagogic qualification of the mentor at times might not be the best. Basics have to be learned and memorized very well, but even at an early stage entire pieces, for instance a nicely carved side table, have to be independently completed. I think that science teaching at any level is not much different.

Also, as was the case for medieval guilds students are now privileged to, and should be further encouraged to travel and gain experience as undergraduates, master students and later as PhDs and Postdocs. I am proud that to my best knowledge all my Dundee Honors students (mostly from Bonn Rein Sieg, but two also from Dundee) moved on to do PhDs in various European laboratories, and that four of my former PhD students already hold or accepted fully (3) or semi-independent PI positions in Germany, France and the UK. Two of my former students, Bjoern and Sebastian hold prestigious European ERC fellowships.

As part of the Dundee undergraduate curriculum I believe in the continued reform of our curriculum. I also support the effort to increase the selectivity of our uptake. Indeed it is great to see that we recruit more and more international students. Also I am looking forward to now focus my lecturing in two major blocks, both at the core of my interest in subject areas I feel to be able to make a difference. One will be related to genome stability in the 3rd years GRE course, and one block will be on diploid genetics in the 3rd year Genetics course. Also, if deemed possible, I am to further improve and implement the GRE summer school, which I established and now run in the third year. This was first fully established in last years summer term, and I was impressed by the standard of science but also by the quality and enthusiasm of the final presentations of often very young students. Last year we were already most successful in obtaining several competitive fellowships. I am confident in this approach, akin an ancient apprenticeship, both for summer placements, but also for placing our future, hopefully much better prepared Honours students.

Growing up in a cultural background where the public often negatively perceives science I all the more appreciate the importance of public engagement. I aim to continue taking on high school students for work experience. Also I am very positive about the interactions I have with the charities that fund our research. As to those I am especially engaged with Parkinson’s UK. I speak to several patients groups a year located in various places in Scotland. Also I helped with their 2011 Christmas funding appeal that focused on our work and raised ~£140,000. Finally it is fun to interact with Dave the worm, our very special friend, a sociable but also informed worm living in the open and wide spaces of the Internet. I support Dave in his quest to explain basic science and its importance to the wider public.

"You have made your way from worm to man, and much within you is still a worm" (Nieztsche)