Credit: Wolfgang Marwan

Giant Cells Reveal Their Secrets

The genome of a giant amoeba provides clues to the early evolution of contemporary genes.

The “slime mold” Physarum polycephalum is an amazing creature. As a giant single cell it is visible with the naked eye. The yellow, slimy mass of protoplasm, which crawls over rotting logs engulfing its prey, seems as unusual as an alien from outer space. One specimen, which entered the Guinness Book of Records in 1989, covered a surface area of 5.5 square meters and weighed approximately 3 kgs –obviously deserving its title as the largest single cell ever grown. This enigmatic organism has also attracted the interest of physicists, engineers, and artists who have taken inspiration from Physarum for developing computer algorithms, and used these giant cells for steering robots, creating art projects and electronic music. However, for biologists Physarum has been a sleeping beauty during the past decades, because almost nothing was known about its genome and genes. This shortcoming has now changed fundamentally.

In an upcoming issue of Genome Biology and Evolution, an international group of scientists reports on the sequence of the 188 million nucleotides that make up the Physarum genome. Littered with simple and complex repeats, the Physarum genome proved exceptionally challenging to assemble, requiring significant improvements of existing technologies, according to Pat Minx from the McDonnell Genome Institute at Washington University. The effort proved to be worthwhile when the sequence revealed 34,000 genes, over 50% more than the human genome.

Comparison of these genes with those of other species proved what biologists already suspected. The so-called slime mold is in reality not a mold (fungus) but a giant amoeba, belonging to the amoebozoa group of organisms. In light of our contemporary understanding of molecular evolution, Physarum appears to be an ancient relic with similarity to the last common ancestor of Amoebozoa, fungi and animals (including humans): a prototypical cell from the era of early eukaryote evolution with some molecular features that were thought to be specific for either animals or plants.

“Eukaryotes” are cells that, like human cells and unlike bacteria, contain true, membrane-enclosed nuclei, wherein lie the DNA molecules comprising the genome—the blueprint—of the organism. Eukaryotic genomes are typically larger and more complex than the genomes of bacteria, encoding molecular regulatory mechanisms of more sophistication than those of bacteria, which allow ultimately for the complexities of multicellular plants and animals. Buried within the sequences of eukaryotic genomes are the secrets of multicellular life and remnants of the evolutionary sequence which brought living organisms to the present state of diversity.<

As expected, the genome sequence of Physarum has uncovered some fascinating clues to these basic questions. For a single-celled organism, Physarum has a very extensive system for signal detection and processing, perhaps necessitated by its need to forage for a variety of microscopic prey items. Physarum’s sensory network of interacting genes and proteins picks up signals from the cell’s external environment and internal state, processes the information in sophisticated ways, and makes decisions that control the behavior and development of the organism. The molecular complexity of this signaling system is comparable to, and in some respects exceeds, that of higher animals, making Physarum a good model organism for the analysis of how living cells interact with their environment. For example, Physarum has an unparalleled diversity of proteins to synthesize and detect the intracellular messenger molecules, cyclic AMP and cyclic GMP. Additionally, like animal cells but unlike plants or fungi, Physarum uses tyrosine-kinase signaling proteins for information processing. Because a related amoebozoon, Acanthamoeba, also employs tyrosine kinase signaling, one may conclude that tyrosine kinases were present in the last common ancestor of Amoebozoa, fungi, and animals rather than having appeared only later, in the animal lineage, as was commonly believed until recently, according to Pauline Schaap, a developmental biologist from Dundee University.

Tyrosine kinases are enzymes that play important roles in controlling normal cell fates, and their misbehaviors have been implicated in diseases such as cancer, arteriosclerosis and diabetes. Comparing human cells with their evolutionarily very distant cousin, Physarum, may ultimately help to understand core mechanisms of health and disease by abstracting what really matters for cellular regulation, says Gernot Glöckner from the University of Cologne, a main investigator in this project.

Of special interest in this regard are the mechanisms by which eukaryotic cells control their growth and division, two processes that go awry during cancer. Much of our knowledge of the cell division cycle has come from studies of fungi (budding yeast and fission yeast) and animals (frog and fruit fly embryos, and mammalian cell lines). Although there are deep functional similarities across all these organisms, which suggest a “universal” control mechanism of cell division for all eukaryotes, there are significant differences between regulators of cell cycle entry in yeasts and animals. Analysis of the Physarum genome and other amoeboid genomes shows conservation of key cell cycle regulators found in the animal cell cycle, according to Nicholas Buchler at Duke University. Given the drastic changes in cell cycle regulation that have occurred in fungi, Physarum would seem to be a much better model organism than yeast for studying conserved mechanisms of cell cycle regulation in the ancestor of ameobae and animals, says Buchler. Modern tools of molecular genetics mitigate many of the genetic difficulties that placed Physarum at a disadvantage, compared to yeast cells, during the boom years of molecular cell physiology in the 1980s and 1990s. An increasing number of biologists believe that analyzing changes in hundreds or even thousands of components in individual cells over time will be necessary to obtain essential information on how cellular functions are controlled. For any specific organism, this “systems approach” to cell physiology begins with a complete specification of its genome, followed by experimental characterization of its genes and proteins, and then comprehensive mathematical and computational modeling of the molecular control systems, says John Tyson, professor of molecular systems biology at Virginia Tech. Now that its genome has been sequenced, Physarum, a classical organism for studying the physiology of free-living single-celled creatures, may again take its rightful place as a model organism for modern studies of the molecular basis of life, of human health and disease, and of the evolutionary origins of eukaryotic cells.

Schaap P, Barrantes I, Minx P, Sasaki N, Anderson RW, Bénard M, Biggar KK,Buchler NE, Bundschuh R, Chen X, Fronick C, Fulton L, Golderer G, Jahn N, Knoop V, Landweber LF, Maric C, Miller D, Noegel AA, Peace R, Pierron G, Sasaki T, Schallenberg-Rüdinger M, Schleicher M, Singh R, Spaller T, Storey KB, Suzuki T, Tomlinson C, Tyson JJ, Warren WC, Werner ER, Werner-Felmayer G, Wilson RK, Winckler T, Gott JM, Glöckner G, Marwan W. The Physarum polycephalum Genome Reveals Extensive Use of Prokaryotic Two-component and Metazoan-type Tyrosine Kinase Signaling. Genome Biol Evol. 2015 Nov 27. pii: evv237. [Epub ahead of print] PubMed PMID: 26615215.