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<\/small><\/p>\nFigure 1. <\/span>The life cycle of a cellular slime mold (Dictyostelium discoideum<\/i>)<\/span><\/strong>A Dictyostelium discoideum<\/i> that has germinated from a spore proliferates as a unicellular amoeba and, upon entering a state of starvation, forms an aggregate that moves around as a single multicellular body. When movement stops, it transforms into a fruiting body.<\/p>\n<\/div>\n This organism is actually a very familiar one; similar in appearance to a human white blood cell, it is a unicellular eukaryotic amoeba with a diameter of just 10 µm that lives in soils across the globe. It engulfs (feeds on) bacteria and other microorganisms smaller than itself, digesting and absorbing them as nutrients so that it can divide and increase its number. It has a smart strategy allowing it to feed efficiently by proactively moving toward its food by sensing folate secreted by its prey.<\/p>\n However, as is often the case in the natural world, once it has devoured all the available bacteria, it enters a state of starvation that exposes it to the risk of dying off. Cellular slime molds become multicellular as a strategy for avoiding death. This evolution into a multicellular state is both efficient and ingenious.<\/p>\n In order to take a multicellular form, the cellular slime mold first begins to secrete a signal molecule enabling it to coordinate with all the cells around it. The signal molecule it secretes is called acrasin; in the case of Dictyostelium discoideum<\/i>, we know that it is a type of nucleotide called cyclic adenosine monophosphate (cAMP), which is chemically related to the genetic material DNA. In cellular slime molds, acrasin acts as a chemotactic substance that has the effect of attracting surrounding cells. As a result of this chemotactic response, the cells aggregate and become multicellular.<\/p>\n The chemotactic response works in an astonishingly efficient way through the synchronization of individual cells with cAMP secretion. Called the cAMP relay, this process helps to attract cells located far away. The chemotactic response is extremely sensitive, and is known to take place when differences are detected in the spatial distribution of just a few chemotactic molecules on the cell surface.<\/p>\n As a result of the chemotactic response, around 100,000 amoebae form an aggregate, and then secrete polysaccharides (mucilaginous substances) from the surfaces of their cells to form a slug-like individual (grex). This grex actively moves around as a multicellular individual, equipped with highly sensitive sensory capabilities that enable it to sense light with its tip and detect temperature differences of just about 0.5°C.<\/p>\n Triggered by exposure to light and other stimuli, the grex enters the final stage of its multicellular movement. At this stage, the grex stops moving and develops into its final form—a fruiting body. The fruiting body is a structure with a height of just 1 mm, which resembles a balloon tied to a string. Cell differentiation takes place, with the upper sac differentiating into spores and the supporting stalk differentiating into stalk cells.<\/p>\n In the fruiting body formation process, the grex rises up and the tip turns into stalk cells that grow upward as they form a long, thin, stem-like structure. At this point, the stalk cells die, leaving only the cell walls behind; these form a robust cellulose framework that looks like a plant stem. The remaining amoebae that will become the spores climb up, using this stalk as a foothold, and form a round mass at the very top. At the same time as this mass forms, all prespore cells differentiate into spores at once, and these spores are then dispersed by the wind or other organisms.<\/p>\n The spores are ellipsoid structures with a diameter of around 5 µm. These spores live on, entering a dormant state in which they neither proliferate nor divide. Thanks to their hard casing, they can withstand adverse environments, including those that are dry or have high or low temperatures. When environmental conditions such as moisture, temperature, and nutrients improve, allowing the bacteria on which the cellular slime mold feeds to proliferate, the spore wall cracks, the amoeboid cell within emerges, and it begins dividing again as an amoeba.<\/p>\n The aforementioned part of the cellular slime mold life cycle during which a multicellular body is formed is completed in just 24 hours. In this short period of time, it completes the transition from a unicellular state to a multicellular one—that is to say, it forms a cellular aggregate, and the cell differentiation essential to a multicellular organism can be observed. This is why cellular slime molds—which are unicellular eukaryotes, yet also very primitive organisms that strategically form multicellular structures—have attracted attention as important model organisms for unraveling the mysteries of the evolutionary process involved in the development of multicellularity.<\/p>\n Based on whole-genome sequencing carried out in recent years, the cellular slime mold Dictyostelium discoideum<\/i> diverged before animals and plants appeared and is currently believed to belong to a group of eukaryotes called the Amoebozoa. This suggests that it evolved independently of the process via which animals and plants became multicellular. However, painstaking analysis of the genome shows that cellular slime molds really do combine the attributes of both animals and plants: among others, they have genes involved in the intercellular and intracellular transmission of information, which are required for the development of multicellularity and are common to all organisms, along with genes involved in cell motility, adhesion, and differentiation. What is more, they also have the cellulose synthesis genes required to maintain plant structure.<\/p>\n Scientists believe that not only did cellular slime molds acquire through evolution the special genes required to become multicellular, but that the genes they already had when they were unicellular were also reused during this transition, with the functions of those genes becoming more advanced. However, given that the present-day unicellular organisms cannot become multicellular simply by expressing genes for multicellularity in cellular slime molds, it is thought that cellular slime molds needed to evolve a complex, integrated gene control mechanism in order to become multicellular.<\/p>\n Although we humans are higher-order multicellular organisms that originated from a single cell type (ovum), which proliferated and differentiated to form various organs and tissues, most of the genes we use for multicellularity and cell differentiation are the same as those found in cellular slime molds (Figure 2). Although cellular slime mold differentiation involves just two very simple outcomes––stalk cells and spores, a single cell holds a very large number of genes—around 12,500. This is about half the number of human genes, and demonstrates how many genes are required for developing multicellularity, as well as the way in which genes were repurposed, without the need for a dramatic increase in their number in order to evolve into highly complex multicellular organisms such as humans. At the same time, their genome size (total amount of genetic material) is compact, at one-hundredth that of humans, so it would be fair to say that cellular slime molds are ideal model organisms for exploring the principles underlying the construction of multicellular systems.<\/p>\n Figure 2. <\/span>Cellular slime mold (Dictyostelium discoideum<\/i>) and human genes<\/span><\/strong>A single Dictyostelium discoideum<\/i> cell has about half as many genes as a human cell and shares many genes with humans. The evolution of highly complex multicellular organisms such as humans may have involved the ingenious reuse of existing genes.<\/p>\n<\/div>\n At present, scientists are moving forward with research focused on using cellular slime molds as model organisms for shedding light on systems involved in the development of multicellularity. This work makes full use of the latest biotechnology, including cutting-edge gene editing technology (CRISPR\/Cas9), RNA analysis and other genetic analysis technologies, and cell imaging technologies that employ fluorescent proteins. In our research, too, we have discovered that disrupting the gene RabGAP, which is involved in fat deposition and which human cells also have, shortens the lifespan of cellular slime molds. Conversely, overexpressing this gene extends their lifespan. The results of this research show that the cell fat deposition control mechanism possessed by RabGAP is linked to the key biological phenomenon of lifespan, and suggest that this mechanism has also been inherited by humans and other higher-order organisms.<\/p>\n Thus, many of the genes relating to important, universal biological phenomena have been identified from cellular slime molds, and the ways in which they work are becoming apparent. It is anticipated that hitherto unexplained aspects of the functional control of multicellular organisms as individuals and their integration mechanisms will become clear as scientists elucidate the spatiotemporal expression control mechanisms of genes and the molecular functions of those genes.<\/p>\n The soil in which cellular slime molds live has an ecosystem consisting of a complex blend of localized environments, including soil particles, a diverse array of microorganisms, moisture, and atmospheric components such as oxygen and nitrogen. The development of multicellularity by cellular slime molds could be described as a strategy for surviving in complex soils. However, many unicellular organisms still exist in soil today, including bacteria, yeasts, amoebae, and paramecia. So, why is it that, of all these organisms, cellular slime molds chose to evolve the ability to become multicellular upon entering a state of starvation? In addition to this, cellular slime molds have a system called apoptosis, in which stalk cells sacrifice their lives to elevate spores to a higher position. Apoptosis is a system that organisms acquired in order to become more advanced by such means as development of the organism, removing abnormal cells, and maintaining homeostasis, but it is fraught with the risk that the entire organism could die if the control of apoptosis becomes disordered. In fact, we know that, in a cellular slime mold’s amoebic state, forcibly turning on the switch controlling the formation of stalk cells causes all the cells to die. In the case of humans, too, the breakdown or excessive functioning of the apoptosis system leads to cells becoming cancerous, immunological deterioration, and other disorders.<\/p>\n There are actually cellular slime mold species that do not have an apoptosis mechanism. The genus Acytostelium<\/i> produces a cellulose stalk, but it is acellular, short, thin, and not very strong. It has no stalk cells, with all its cells becoming spores, but the fragility of its stalk means that it can support only a limited number of spores, resulting in less efficient spore dispersal. On the other hand, this characteristic suggests that apoptosis is not necessarily essential to the development of multicellularity in cellular slime molds. The phenomenon whereby some cellular slime molds evolved without apoptosis as they became multicellular raises such puzzling questions as why cells—including human cells—evolved to prioritize the maintenance of the aggregate in a cooperative manner, rather than prioritizing each cell’s interests as an individual, and how this mechanism became established. I am deeply interested in these mysteries.<\/p>\n My own research also revealed another unusual phenomenon involving cellular slime molds. Ordinarily, the chemotactic substance cAMP is involved in the formation of an aggregate that allows amoebae to become multicellular. In mutants that have lost this chemotaxis, each cell moves separately and should not form a multicellular body. However, in some variants, we observed a phenomenon in which the cells gather together to produce multiple wave-like cell clusters and maintain a set shape while moving around. Usually, if two masses collide with each other, they simply collapse, but water waves and similar phenomena can maintain their shape even when they collide. Such phenomena are called soliton waves. We observed a phenomenon similar to these soliton waves in cell movement, as well: although the cell clusters mix together temporarily at the time of the collision, they subsequently return to the same shape. Even more bafflingly, we also observed a phenomenon in which the cells in the clusters change places with each other before and after the collision. In other words, rather than individual cells having a fixed role, the shape of the group itself is remembered and reconstructed after the collision. As the multicellular body has a memory and forms an aggregate through cell adhesion, it is conceivably possible that a chemotactic substance or other such signal is not necessarily essential for multicellularity. At present, we are also trying to elucidate this phenomenon at the molecular level.<\/p>\n There are high hopes for cellular slime mold models not only for explaining the evolution of multicellular organisms, but also in drug discovery research. Just like all organisms, cellular slime molds produce primary metabolites such as sugars, which they require to live, and secondary metabolites. An enzyme called polyketide synthase is required in order to produce secondary metabolites; cellular slime molds have more than 40 genes related to polyketide synthases. Forty is a very high number for a eukaryotic microorganism, and even useful molds employed as drug discovery resources only possess around 10. In other words, there is a possibility that cellular slime molds can produce a more diverse array of secondary metabolites based on these 40 or so genes. While the chemotactic substance cAMP is also a secondary metabolite, cellular slime molds are known to produce a variety of metabolites, such as repellents, which keep away organisms disadvantageous to their survival, and substances for interacting with other organisms. Of these metabolites, DIF-1 and DIF-3—factors inducing differentiation into stalk cells in Dictyostelium discoideum<\/i>—are believed to potentially have antitumor effects, and research in this area is progressing.<\/p>\n The antibiotic penicillin and the immunosuppressant tacrolimus are both drugs that were developed from the metabolites produced by soil microorganisms. Scientists presume that there are many cellular slime molds other than the species discovered to date, and believe there is a strong possibility that substances with beneficial pharmacological effects will be discovered from the metabolites of both the known and unknown species.<\/p>\n As described above, cellular slime molds are organisms with tremendous hidden potential as the subject of research. In recent years, it has become comparatively easy to carry out genetic analysis, but the nature of metabolites will not become clear from genomic information alone. It will be necessary to actually extract compounds from slime molds cultured in large quantities, and to analyze the structures of each and every one. One challenge that we face is that, although this kind of cellular slime mold research will require a huge amount of time and effort, the pool of researchers is small at present, and the research infrastructure is not necessarily adequate. Going forward, I am keen to train future researchers and to move forward with my research in order to elucidate the fundamentals of human evolution.<\/p>\n Life evolved from unicellular organisms to multicellular organisms. Cellular slime molds have a dramatic life cycle: upon entering a state of starvation, unicellular amoebae aggregate to form a multicellular body and produce spores in the space of just 24 hours. Although they have genes common to humans and other multicellular organisms, including genes involved in apoptosis and cell differentiation, the size of their genome is one-hundredth that of humans. Equipped with the attributes of both animals and plants, they have undergone a unique evolutionary path and are regarded worldwide as an important model organism for exploring the origins of the development of multicellularity. Their diverse secondary metabolites are expected to have applications in drug discovery.<\/p>\n","protected":false},"author":2,"featured_media":2725,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[16],"tags":[],"class_list":["post-2732","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-biology"],"acf":{"author":"composition by Yumi Ohuchi Life evolved from unicellular to multicellular organisms. Cellular slime molds have a dramatic life cycle: upon entering a state of starvation, unicellular amoebae aggregate to form a multicellular body and produce spores in the space of just 24 hours. Although they have genes common to humans and other multicellular organisms, including genes involved in apoptosis and cell differentiation, the size of their genome is one-hundredth that of humans. Equipped with the attributes of both animals and plants, they have undergone a unique evolutionary path and are regarded worldwide as important model organisms for exploring the origins of the development of multicellularity. Their diverse secondary metabolites are expected to have applications in drug discovery.<\/p>","person":[{"acf_fc_layout":"personcontent","personimg":2724,"personsholder":"Professor, Institute of Life and Environmental Sciences, University of Tsukuba","personname":"Hidekazu Kuwayama","persondetail":"In 1994, he completed a doctoral program at Kyoto University’s Graduate School of Science and was awarded a Ph.D. in science. He then held the posts of research fellow in the Department of Biochemistry at the University of Groningen in the Netherlands, research associate at the University of Tsukuba’s Institute of Biological Sciences, and specially appointed researcher at Osaka University’s Graduate School of Frontier Biosciences. In 2006, he was appointed as a lecturer at the University of Tsukuba’s Graduate School of Life and Environmental Science, becoming an associate professor at the Institute of Life and Environmental Sciences in 2013. He has held his current post since 2022. His areas of interest include analysis of cell motility mechanisms using cellular slime molds."}],"issue":2713,"custom_css":""},"_links":{"self":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts\/2732","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/comments?post=2732"}],"version-history":[{"count":0,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts\/2732\/revisions"}],"acf:post":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/issue\/2713"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/media\/2725"}],"wp:attachment":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/media?parent=2732"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/categories?post=2732"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/tags?post=2732"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Completing the process of forming a multicellular body in just 24 hours<\/h2>\n
Using cellular slime molds to identify genes relating to biological phenomena<\/h2>\n
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<\/small><\/p>\nDiscovery of substances with pharmacological effects derived from metabolites<\/h2>\n
illustration by Rokuhisa Chino","intro":"