Studying flatworms to understand human diseases
As a part of the Zoology seminar series, we had the pleasure of listening to Prof Eugene Berezikov’s (ERIBA, Netherlands) work on establishing Macrostomum lignano as a model to study stem cells, regeneration and ageing.
The free-living, hermaphroditic flatworm Macrostomum (~1.5 mm long) like apparently all Platyhelminthes has a relative large population of adult stem cells, that confers high adult homeostatic and regenerative capacities. The ease of culture, its small size, relatively short generation time (20 days), optical transparency and access to single cell embryos made it an attractive system to Eugene (perhaps because of having some similarity to Caenorhabditis elegans, that he worked with as a post-doc with Ronald Plasterk).
In his talk, Eugene presented all the pioneering work he has carried out to establish this relatively recently described species as a new model organism, leveraging its life history traits to study both ageing, fundamental aspects of stem cell biology that are relevant to human disease processes, particularly cancer. Eugene’s team have provided genome and the de-novo transcriptome assemblies and perhaps most significantly they have also established transgenic mis-expression approaches in Macrostomum (Wudarski et al., 2017) and based on this CRISPR/Cas9 based genome editing won’t be far behind. It is the first time anyone has achieved this in this group of animals and it will allow greater mechanistic insight into the study of their stem cells and regenerative ability.
One very pertinent topic of discussion that Eugene raised was whether we should use model organisms to focus on studying highly conserved genes involved in important biological processes, or whether in fact it is time to also look at novel genes that seem to be specific to a lineage. In this second case the functions and roles of new proteins have the potential to be applied to biomedical research. An exciting example is the Tardigrade protein (Dsup1) that confers radiation resistance when expressed in human cells (Hashimoto et al., 2016). Eugene gave an example from his own work of a gene that is unique to the worms (Mlig-sperm1) he studies, and has a function in conferring the amazing structural properties of M. lignano’s sperm cells (Grudniewska et al., 2018). These may be proteins with structural properties that can be exploited to understand how well known structural proteins work. The potential applications of this certainly trigger the imagination of possible futuristic outcomes from studying novel uncharacterized proteins.
A long-term and ongoing goal of Eugene’s research is to develop Macrostomum as a model for ageing. The data so far suggest constant rate of death over time, suggesting that these worms do not show an age related increase in mortality suggesting an overall absence of ageing at least over the first 26 months of life. The animals do increase the rate of potential phenotypic signs of aging, like the formation of fluid filled cysts due to failures in osmoregulation and decline in fertility rate. RNA-sequencing of 2 months and 26 months old worms revealed genes whose loss of activity are often associated with ageing are upregulated in older animals. Moreover, genes like UCP2/4, SIRT6 known to extend lifespan in C.elegans, are also upregulated, suggesting that conserved molecular mechanisms exist that can be regulated differently to offset the negative consequences of ageing.
Eugene ended his lecture, with some preliminary results showing how Macrostomum can resist a high dose of ionizing radiation (up to 70 Gy, nearly seven times over our natural threshold). RNA seq after irradiation has implicated macrostomum specific genes to be involved in the response to IR. We hope then to see some future data on how these novel proteins might confer this extreme resistance to radiation in flatworms. We all thoroughly enjoyed listening to Prof Berezikov and can agree that studying these flatworms can shed light on both understanding human diseases and perhaps novel molecular approaches to treat them by borrowing from elsewhere in Nature.
Sounak Sahu is a DPhil student in the Aboobaker laboratory, studying DNA damage response in planarian stem cells.
Hashimoto, T., Horikawa, D.D., Saito, Y., Kuwahara, H., Kozuka-Hata, H., Shin-I, T., Minakuchi, Y., Ohishi, K., Motoyama, A., Aizu, T., et al. (2016). Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein. Nat. Commun. 7, 12808–12814.
Wudarski, J., Simanov, D., Ustyantsev, K., de Mulder, K., Grelling, M., Grudniewska, M., Beltman, F., Glazenburg, L., Demircan, T., Wunderer, J., et al. (2017). Efficient transgenesis and annotated genome sequence of the regenerative flatworm model Macrostomum lignano. Nat. Commun. 8, 2120. https://www.ncbi.nlm.nih.gov/pubmed/29242515
Grudniewska, M., Mouton, S., Grelling, M., Wolters, A.H.G., Kuipers, J., Giepmans, B.N.G., and Berezikov, E. (2018). A novel flatworm-specific gene implicated in reproduction in Macrostomum lignano. Sci. Rep. 8, 3192.https://www.ncbi.nlm.nih.gov/pubmed/29453392