Choosing the Right Experimental Organism for the

Our current understanding of the molecular functioning of cells rests on studies with viruses, bacteria, yeast, protozoa, slime molds, plants, frogs, sea urchins, worms, insects, fish, chickens, mice, and humans. For various reasons, some organisms are more appropriate than others for answering particular questions. Because of the evolutionary conservation of genes, proteins, organelles, cell types, and so forth, discoveries about biological structures and functions obtained with one experimental organism often apply to others. Thus researchers generally conduct studies with the organism that is most suitable for rapidly and completely answering the question being posed, knowing that the results obtained in one organism are likely to be broadly applicable. Figure 1-25 summarizes the typical experimental uses of various organisms whose genomes have been sequenced completely or nearly so. The availability of the genome sequences for these organisms makes them particularly useful for genetics and genomics studies.

Bacteria have several advantages as experimental organisms: They grow rapidly, possess elegant mechanisms for controlling gene activity, and have powerful genetics. This

► FIGURE 1-25 Each experimental organism used in cell biology has advantages for certain types of studies. Viruses and bacteria have small genomes amenable to genetic dissection. Many insights into gene control initially came from studies with these organisms. The yeast Saccharomyces cerevisiae has the cellular organization of a eukaryote but is a relatively simple single-celled organism that is easy to grow and to manipulate genetically. In the nematode worm Caenorhabditis elegans, which has a small number of cells arranged in a nearly identical way in every worm, the formation of each individual cell can be traced. The fruit fly Drosophila melanogaster, first used to discover the properties of chromosomes, has been especially valuable in identifying genes that control embryonic development. Many of these genes are evolutionary conserved in humans. The zebrafish Danio rerio is used for rapid genetic screens to identify genes that control development and organogenesis. Of the experimental animal systems, mice (Mus musculus) are evolutionary the closest to humans and have provided models for studying numerous human genetic and infectious diseases. The mustard-family weed Arabidopsis thaliana, sometimes described as the Drosophila of the plant kingdom, has been used for genetic screens to identify genes involved in nearly every aspect of plant life. Genome sequencing is completed for many viruses and bacterial species, the yeast Saccharomyces cerevisiae, the roundworm C. elegans, the fruit fly D. melanogaster, humans, and the plant Arabidopsis thaliana. It is mostly completed for mice and in progress for zebrafish. Other organisms, particularly frogs, sea urchins, chickens, and slime molds, continue to be immensely valuable for cell biology research. Increasingly, a wide variety of other species are used, especially for studies of evolution of cells and mechanisms. [Part (a) Visuals Unlimited, Inc. Part (b) Kari Lountmaa/Science Photo Library/ Photo Researchers, Inc. Part (c) Scimat/Photo Researchers, Inc. Part (d) Photo Researchers, Inc. Part (e) Darwin Dale/Photo Researchers, Inc. Part (f) Inge Spence/Visuals Unlimited, Inc. Part (g) J. M. Labat/Jancana/Visuals Unlimited, Inc. Part (h) Darwin Dale/Photo Researchers, Inc.]

latter property relates to the small size of bacterial genomes, the ease of obtaining mutants, the availability of techniques for transferring genes into bacteria, an enormous wealth of knowledge about bacterial gene control and protein functions, and the relative simplicity of mapping genes relative to one another in the genome. Single-celled yeasts not only have some of the same advantages as bacteria, but also possess the cell organization, marked by the presence of a nucleus and organelles, that is characteristic of all eukaryotes.

Studies of cells in specialized tissues make use of animal and plant "models," that is, experimental organisms with attributes typical of many others. Nerve cells and muscle cells, for instance, traditionally were studied in mammals or in creatures with especially large or accessible cells, such as the giant neural cells of the squid and sea hare or the flight muscles of birds. More recently, muscle and nerve development have been extensively studied in fruit flies (Drosophila melanogaster), roundworms (Caenorhabditis elegans), and zebrafish in which mutants can be readily isolated. Organisms with large-celled embryos that develop outside the

Viruses

Proteins involved in DNA, RNA, protein synthesis Gene regulation Cancer and control of cell proliferation Transport of proteins and organelles inside cells Infection and immunity Possible gene therapy approaches

Bacteria

Proteins involved in DNA, RNA, protein synthesis, metabolism Gene regulation Targets for new antibiotics Cell cycle Signaling

Yeast (Saccharomyces cerevisiae)

Control of cell cycle and cell division Protein secretion and membrane biogenesis Function of the cytoskeleton Cell differentiation Aging

Gene regulation and chromosome structure

Roundworm (Caenorhabditis elegans)

Development of the body plan Cell lineage

Formation and function of the nervous system Control of programmed cell death Cell proliferation and cancer genes Aging Behavior

Gene regulation and chromosome structure

Fruit fly (Drosophila melanogaster)

Development of the body plan Generation of differentiated cell lineages

Formation of the nervous system, heart, and musculature Programmed cell death Genetic control of behavior Cancer genes and control of cell proliferation Control of cell polarization Effects of drugs, alcohol, pesticides

Zebrafish

Development of vertebrate body tissues

Formation and function of brain and nervous system Birth defects Cancer

Mice, including cultured cells

Development of body tissues Function of mammalian immune system

Formation and function of brain and nervous system Models of cancers and other human diseases Gene regulation and inheritance Infectious disease

Plant (Arabidopsis thaliana)

Development and patterning of tissues Genetics of cell biology Agricultural applications Physiology Gene regulation Immunity Infectious disease mother (e.g., frogs, sea urchins, fish, and chickens) are extremely useful for tracing the fates of cells as they form different tissues and for making extracts for biochemical studies. For instance, a key protein in regulating mitosis was first identified in studies with frog and sea urchin embryos and subsequently purified from extracts (Chapter 21).

Using recombinant DNA techniques researchers can engineer specific genes to contain mutations that inactivate or increase production of their encoded proteins. Such genes can be introduced into the embryos of worms, flies, frogs, sea urchins, chickens, mice, a variety of plants, and other organisms, permitting the effects of activating a gene abnormally or inhibiting a normal gene function to be assessed. This approach is being used extensively to produce mouse versions of human genetic diseases. New techniques specifically for inactivating particular genes by injecting short pieces of RNA are making quick tests of gene functions possible in many organisms.

Mice have one enormous advantage over other experimental organisms: they are the closest to humans of any animal for which powerful genetic approaches are feasible. Engineered mouse genes carrying mutations similar to those associated with a particular inherited disease in humans can be introduced into mouse embryonic stem (ES) cells. These cells can be injected into an early embryo, which is then implanted into a pseudopregnant female mouse (Chapter 9). If the mice that develop from the injected ES cells exhibit diseases similar to the human disease, then the link between the disease and mutations in a particular gene or genes is supported. Once mouse models of a human disease are available, further studies on the molecular defects causing the disease can be done and new treatments can be tested, thereby minimizing human exposure to untested treatments.

A continuous unplanned genetic screen has been performed on human populations for millennia. Thousands of inherited traits have been identified and, more recently, mapped to locations on the chromosomes. Some of these traits are inherited propensities to get a disease; others are eye color or other minor characteristics. Genetic variations in virtually every aspect of cell biology can be found in human populations, allowing studies of normal and disease states and of variant cells in culture.

Less-common experimental organisms offer possibilities for exploring unique or exotic properties of cells and for studying standard properties of cells that are exaggerated in a useful fashion in a particular animal. For example, the ends of chromosomes, the telomeres, are extremely dilute in most cells. Human cells typically contain 92 telomeres (46 chromosomes X 2 ends per chromosome). In contrast, some protozoa with unusual "fragmented" chromosomes contain millions of telomeres per cell. Recent discoveries about telomere structure have benefited greatly from using this natural variation for experimental advantage.

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