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A world champion of regeneration

Planarians can be cut into pieces, and each piece can regenerate into a complete organism. The flatworms are able to do this as they have a huge pool of adult totipotent stem cells that can differentiate into any body cell whatsoever, including germ cells. Scientists from the Heidelberg Institute for Theoretical Studies are using new algorithms to analyse the complex planarian genome structures with the aim of obtaining insights into the genetic mechanisms underlying this extraordinary ability to regenerate.

A new junior research group for Computational Biology has recently been established at the Heidelberg Institute for Theoretical Studies (HITS). The new group, which is headed up by computer scientist and human biologist Dr. Siegfried Schloissnig, is aiming to elucidate the genomes of flatworms (Plathelminthes) in order to gain insights into the mechanisms that govern the extraordinary regenerative capacity of this group of animals. The findings might also be of major importance for stem cell research in general as well as for human regenerative medicine.

Research involving Plathelminthes has a long tradition

Fragmentation and regeneration experiments carried out by T. H. Morgan in 1907 (A. Kühn: Vorlesungen über Entwicklungsphysiologie, 2. Ed. 1965). © Springer Verlag

Flatworms are common in many parts of the world; they comprise unpleasant parasitic groups such as tapeworms and liver flukes as well as free-living non-parasitic ones (Turbellaria) of which the planarians are the best known. It may seem strange to choose these animals as model organisms for elementary life processes. That said, this tradition goes back more than 200 years to the beginnings of experimental natural sciences: in 1778, Peter Simon Pallas discovered the amazing ability of planarians to regenerate into complete organisms from only small pieces of their body. In 1853, zoologist Oskar Schmidt, who compiled the first extensive monograph on planarians, wrote enthusiastically: “Man braucht, wie es scheint, wo man will nur zuzugreifen und ist der Ausbeute sicher”, alluding to the large number of new and morphologically important forms that can be found in a limited area. This prompted the father of modern genetics, Thomas Hunt Morgan, (who later carried out influential work on the fruit fly Drosophila, which went on to become a major model organism in modern biology) to look systematically at regeneration in planarians. Back in the 1960s when we were young students and were doing zoological courses at the University of Freiburg, we were still trying to repeat Morgan’s groundbreaking experiments with freshly caught freshwater planarians (Dugesia gonocephala), but with only moderate success due to lack of skill.

Old model organisms rediscovered

Freshwater Dugesia gonocephala planarian. © University of Freiburg

In the era of molecular biology, planarians largely fell into oblivion as research objects. This has only changed in recent years. Renewed interest has been down to the fact that Morgan’s classical experiments, followed by those of Hans Spemann (both were awarded Nobel Prizes for their achievements) enabled new research questions to be dealt with on the cellular and molecular level. These primitive flatworms are particularly attractive for regenerative medicine and stem cell research, as it turned out that their extraordinary regenerative ability was due to the large number of adult stem cells that enables them to renew virtually every part of their body, including the brain. This ability makes them a major exception among bilaterally symmetrical organisms (Bilateria, to which humans also belong). Nowadays, the freshwater planarian Schmidtea mediterranea (named in honour of Oskar Schmidt) that occurs in Corsica, Sardinia and other parts of the western Mediterranean area is the major model for the study of development and regeneration. This species is more robust and easier to maintain in the laboratory than our native Dugesia gonocephala planarians. 

Challenging flatworm genome sequencing

Dr. Siegfried Schloissnig (right) with his mentor, Prof. Dr. Eugene Myers (left), and Dr. h.c. Klaus Tschira, founder and managing director of HITS. © HITS gGmbH

The new junior research group at HITS will also begin by studying Schmidtea mediterranea, which Schloissnig regards as the most interesting flatworm for regenerative medicine. The researchers will subsequently proceed with other species of this phylum. By comparing the genetic material of numerous species, the researchers hope to gain new insights into the regenerative ability and plasticity of planarians. The sequencing of planarian genomes is far from routine. In fact, the genomes of flatworms have been considered indecipherable because of their complex structure. “Two-thirds of the worm genome keep recurring. It’s like a jigsaw puzzle. And two-thirds of it consist of nearly identical white particles that only differ minimally from one another,” explains Siegfried Schloissnig who previously worked as a postdoc at the European Molecular Biology Laboratory (EMBL). Together with his group, Schloissnig will develop new approaches to the so-called de novo assembly, which is the reconstruction of genome sequences from small DNA fragments. This is particularly difficult when no comparable genome is available and the genome has to be assembled anew (i.e. de novo). Schloissnig will use new algorithms to piece together the DNA jigsaw puzzle of flatworms. In the development of novel bioinformatics methods for deciphering these challenging genome sequences, Schloissnig works closely with his mentor, Professor Eugene “Gene” Myers.

Professor Gene Myers is one of the pioneers in bioinformatics. His gene sequencing software programmes have played a pivotal role in the complete sequencing of the human genome and in the successful completion of the Human Genome Project. Amongst other things, the American scientist developed BLAST, a programme that enables new sequences to be compared with sequences stored in public databases. BLAST is the most widely used search programme in molecular biology. Since June 2012, Myers has been the director and “Klaus Tschira Chair” at the Center for Systems Biology in Dresden.

Totipotent stem cells

Schmidtea mediterranea – a popular freshwater planarian used in scientific research. © Sánchez Alvarado, University of Utah

As already mentioned, the remarkable ability of planarians to replace parts of the body is the result of a dynamic population of totipotent somatic stem cells that are distributed throughout the planarian body. These stem cells are referred to as neoblasts. More than one hundred years ago, Morgan had already shown that a small planarian head fragment can give rise to all missing body parts, including functional sex organs and germ cells. In contrast to many other multicellular organisms – whether of humans, fruit flies or roundworms – there is no clear separation of soma and germline in the planarian embryo. The neoblasts are mitotically active and are the only cells that self-renew throughout the lifetime of the worm. They can give rise to all cell types found in planarians, including the germline. The type of cell into which the progeny cells of neoblasts differentiate depends on temporally and spatially differently active genes. However, the mechanisms and molecules responsible for this are poorly understood. This makes Schmidtea mediterranea an attractive model organism for regenerative biologists and stem cell researchers alike, as the identification of the genes that are active in neoblasts and their progeny as well as the underlying regulatory mechanisms might also provide insights into the differentiation of totipotent embryonic and pluripotent stem cells in higher organisms. The sequencing of the genome of Schmidtea and related planarians by Schloissnig and his team might contribute to speeding up the clarification of these fundamental processes.

The Heidelberg Institute for Theoretical Studies (HITS) is a research institute of the Klaus Tschira Foundation; it was established in January 2010 by Klaus Tschira, one of the founders of SAP AG, as a private, non-profit organisation dedicated to the promotion of scientific research and the processing and structuring of large quantities of data.

Scientific contact:
Dr. Siegfried Schloissnig
Junior Group Computational Biology
HITS Heidelberg Institute for Theoretical Studies
Tel.: +49-6221-533-307
Fax: +49-6221-533-298
E-mail: siegfried.schloissnig(at)h-its.org

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/a-world-champion-of-regeneration