There are some features that make echinoderms so interesting to study. First, their sensitivity to environmental changes in seawater ecosystems. It is well known that the disappearance of fragile species from certain geographic areas is in direct relationship with high contamination of seawater and sedi ments, and echinoderms are one such fragile species. In particular, embryos, juveniles and adults of the classes Echinoidea and Asteroidea are well utilised in studies on marine pollution, since they highly resent it. Second, their ability to regenerate parts of the body (particularly Ophiuroidea and Asteroidea), based on stem cell recruitment. This phenomenon makes a fundamental contribution to the adaptive capacities of the whole species. Third, their ability to cause remarkable transformations in submarine substrates. Since the echino-derms are one of the most important marine invertebrates that do not feed on filtration, as they graze on substrate (except for holothurians and crinoids), they can induce changes in the ratios and distributions of other marine species (fishes and others), and eventually cause segregation as well as speci-ation. These three features of echinoderms are just some examples of the huge number of ways in which echinoderms can be of help in the understanding of important biological phenomena, and in dissecting them at the molecular level.
Echinoderms for Biomedical Research: A Simple Model to Study Biological Events Occurring in Higher Organisms
Recently, a number of studies have offered new notions that non-mammalian models may represent important future directions for studies on human diseases, since the results obtained from these models are in many cases applicable to mammals including humans. Few people realise that research on simple marine organisms has led to some of our greatest medical advances, as well as to new insights into environmental pollution. One of the advantages of using echinoderms is that they produce thousands of virtually identical embryos, and that the morphological abnormalities are readily visualised in the live organism under the light microscope. In the following text, some aspects of the medical advances achieved from such studies will be briefly outlined.
Screening and Testing of Toxic Substances
Sea urchin gametes, embryos and larvae can be used for fast, low-cost and reliable screening and testing of toxic substances and for detailed studies on their mechanism of action. One example is the screening for the toxicity caused by retinoids utilised in dermatological practice, since it has been shown that foetal malformation is a major form of toxicity associated with some of them (Kahn et al. 1988; Sciarrino and Matranga 1995). The sea urchin embryo has also been used as a model for screening for suspected mammalian developmental neurotoxicants and for anticancer drug testing (Nish-ioka et al. 2003; Qiao et al. 2003). This test system is applicable also for exami nation of new and known pharmacologically active substances, including their adverse effects and potential antidotes. Interestingly, a method has been developed to study the invasive properties of metastatic cells and to test the differential effects of anti-tumoural substances on their invasive capacity, which makes use of the sea urchin embryo basement membrane (Livant et al. 1995; Dyer et al. 2002). This structure is selectively permeable and can be obtained intact with the associated extracellular matrix (ECM) from sea urchin embryos (Livant et al. 1995). It has been demonstrated that all metasta-tic tumour cells placed in contact with these basement membranes were able to invade them and the invasion was rapid and efficient; on the other hand, as expected, non-metastatic cells failed in the invasion. These results suggest that molecules participating in basement membrane recognition and invasion have been functionally conserved during evolution and that their constitutive activity may allow metastatic cells to escape their tissues of origin (Livant et al. 1995).
From Echinoderm Molecules to Mammalian Diseases: How Fundamental Research Points to Clinical Trials
The analysis of genome sequences led to the finding of novel non-traditional targets involved in disease pathogenesis, whose usage has the advantage of removing infection without inducing resistance. For example, it has been shown that novel polysaccharides present on echinoderm surfaces seem able to stimulate early host defence and microbial clearance, but not the later phases of inflammatory tissue injury associated with sepsis. These are the most promising alternative or integrative treatments for pneumonia that are under development (Cazzola et al. 2004).
In the last 10 years, a number of molecules with different effects on mammalian cells have been purified from echinoderms. These include compounds with anti-coagulant activity on human blood cells, such as the peptide "plancinin" isolated from the sea star (Koyama et al. 1998), a promising drug for anti-thrombotic therapy. Other compounds display considerable cytotoxicity against a small panel of human solid tumour cell lines, such as polyhy-droxysterols and saponins isolated from the sea star (Wang et al. 2004) and the glycolipid A-5 extracted from sea urchin intestine (Sahara et al. 1997, 2002). The latter compounds have been suggested as useful drugs for cancer chemotherapy.
Recently, Meijer and Raymond (2003) have reviewed the steps that lead to the identification of new drugs; that are now under evaluation for therapeutic use against cancer, neurodegenerative diseases and cardiovascular disorders. This is an example of how results obtained from basic research, i.e. studies on the cell cycle in the starfish oocyte model, can be utilised in applied medical research and treatment. The starfish cyclin-dependent kinase CDK1/cyclin B
was initially identified as a universal M-phase-promoting factor and then used as a screening target to identify pharmacological inhibitors. From the first inhibitors discovered, a more selective one was optimised, which is now entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis (Meijer and Raymond 2003).
Highly Conserved Proteins Associated with Important Biological Functions
The study of echinoderms also led to the identification of proteins with high levels of homology to vertebrate proteins expressed in particular syndromes or tumour cells. A sea urchin gene showing very strong sequence and structural homology with the gene coding for dystrophin, which is defective in Duchenne muscular dystrophy, has been identified. The partial characterisation of this gene helped in the construction of an evolutionary tree connecting the vertebrate dystrophin gene family with related genes in invertebrates (Wang et al. 1998). A novel protein homologue to the sea urchin fascin (an actin-bundling protein) has been found to be over-expressed in pancreatic ductal adenocarcinoma, suggesting its use as a tumour marker with potential diagnostic and therapeutic implications for pancreatic carcinoma (Maitra et al. 2002).
Sea urchin sperm homologues of polycystin-1 and polycystin-2, the proteins mutated in autosomal-dominant polycystic kidney disease, have been sequenced (Mengerink et al. 2002; Neill et al. 2004). Both proteins have been shown to co-localise exclusively to the plasma membrane over the sperm acrosomal vesicle, where they may function as a cation channel mediating the sperm acrosome reaction. These data provide the first suggestion for the role of a polycystin-1 protein in a specific cellular process (Mengerink et al. 2002).
Recently, a fasciclin-I-like protein has been purified from sea urchin ovaries and, by in vitro assays, it has been shown to be active in promoting HT1080 human fibrosarcoma cell attachment (Sato et al. 2004). Fasciclin-I is a neuronal cell adhesion molecule and up to now various proteins belonging to the family have been identified in different species, including bacteria, plants and vertebrates, and in the sea urchin embryo and eggs (Brennan and Robinson 1994; Wessel et al. 2000), although their biological function had not been characterised. However, latest findings indicate that the protein is highly conserved in evolution and suggest important biological roles (Sato et al. 2004).
There are also examples of the isolation of new human genes whose function has been hypothesised on the basis of their high homology to already known and characterised echinoderm genes. A novel human homologue of the gene coding for echinoderm microtubule-associated protein (EMAP) has been isolated from a locus of Usher syndrome type 1, an autosomal recessive genetically heterogeneous disorder. The finding of its high level of homology to the echinoderm cytoskeletal component EMAP, especially at the micro-
tubule-binding domain, and the proposed cytoskeletal nature of Usher disease, define the human EMAP as a good candidate for the USHla syndrome origin (Eudy et al. 1997).
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