The toponome is the spatial network code of proteins and other biomolecules in morphologically intact cells and tissues. [1] It is mapped and decoded by imaging cycler microscopy (ICM) in situ able to co-map many thousand supermolecules in one sample (tissue section or cell sample at high subcellular resolution). The term "toponome" is derived from the ancient Greek nouns "topos" (τόπος; place, position) and "nomos" (νόμος; law), and the term "toponomics" refers to the study of the toponome. It was introduced by Walter Schubert in 2003. [2] It addresses the fact that the network of biomolecules in cells and tissues follows topological rules enabling coordinated actions. For example, the cell surface toponome provides the spatial protein interaction code for the execution of a cell movement, a "code of conduct". [2] [3] [4] This is intrinsically dependent on the specific spatial arrangement of similar and dissimilar compositions of supermolecules (compositional periodicity) with a specific spatial order along a cell surface membrane. This spatial order is periodically repeated when the cell tries to enter the exploratory state from the spherical state (spatial periodicity). [5] This spatial toponome code is hierarchically organized with lead biomolecule(s), anti-colocated (absent) biomolecule(s) [2] [3] and wildcard molecules which are variably associated with the lead biomolecule(s). It has been shown that inhibition of lead molecule(s) in a surface membrane leads to disassembly of the corresponding biomolecular network and loss of function. [3] [4]
A spatial network is a graph in which the vertices or edges are spatial elements associated with geometric objects, i.e. the nodes are located in a space equipped with a certain metric. The simplest mathematical realization is a lattice or a random geometric graph, where nodes are distributed uniformly at random over a two-dimensional plane; a pair of nodes are connected if the Euclidean distance is smaller than a given neighborhood radius. Transportation and mobility networks, Internet, mobile phone networks, power grids, social and contact networks and neural networks are all examples where the underlying space is relevant and where the graph's topology alone does not contain all the information. Characterizing and understanding the structure, resilience and the evolution of spatial networks is crucial for many different fields ranging from urbanism to epidemiology.
Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.
A biomolecule or biological molecule is a loosely used term for molecules and ions that are present in organisms, essential to some typically biological process such as cell division, morphogenesis, or development. Biomolecules include large macromolecules such as proteins, carbohydrates, lipids, and nucleic acids, as well as small molecules such as primary metabolites, secondary metabolites, and natural products. A more general name for this class of material is biological materials. Biomolecules are usually endogenous but may also be exogenous. For example, pharmaceutical drugs may be natural products or semisynthetic (biopharmaceuticals) or they may be totally synthetic.
A biological membrane or biomembrane is an enclosing or separating membrane that acts as a selectively permeable barrier within living things. Biological membranes, in the form of eukaryotic cell membranes, consist of a phospholipid bilayer with embedded, integral and peripheral proteins used in communication and transportation of chemicals and ions. The bulk of lipid in a cell membrane provides a fluid matrix for proteins to rotate and laterally diffuse for physiological functioning. Proteins are adapted to high membrane fluidity environment of lipid bilayer with the presence of an annular lipid shell, consisting of lipid molecules bound tightly to surface of integral membrane proteins. The cell membranes are different from the isolating tissues formed by layers of cells, such as mucous membranes, basement membranes, and serous membranes.
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of plasma membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis includes pinocytosis and phagocytosis. It is a form of active transport.
Integrins are transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.
Molecular biology is a branch of biology that concerns the molecular basis of biological activity between biomolecules in the various systems of a cell, including the interactions between DNA, RNA, proteins and their biosynthesis, as well as the regulation of these interactions. Writing in Nature in 1961, William Astbury described molecular biology as:
...not so much a technique as an approach, an approach from the viewpoint of the so-called basic sciences with the leading idea of searching below the large-scale manifestations of classical biology for the corresponding molecular plan. It is concerned particularly with the forms of biological molecules and [...] is predominantly three-dimensional and structural – which does not mean, however, that it is merely a refinement of morphology. It must at the same time inquire into genesis and function.
The lipid bilayer is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a lipid bilayer, as are the nuclear membrane surrounding the cell nucleus, and other membranes surrounding sub-cellular structures. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Lipid bilayers are ideally suited to this role, even though they are only a few nanometers in width, they are impermeable to most water-soluble (hydrophilic) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and pH by transporting ions across their membranes using proteins called ion pumps.
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows visualization of the distribution of the target molecule through the sample. The specific region an antibody recognizes on an antigen is called an epitope. There have been efforts in epitope mapping since many antibodies can bind the same epitope and levels of binding between antibodies that recognize the same epitope can vary. Additionally, the binding of the fluorophore to the antibody itself cannot interfere with the immunological specificity of the antibody or the binding capacity of its antigen. Immunofluorescence is a widely used example of immunostaining and is a specific example of immunohistochemistry. This technique primarily makes use of fluorophores to visualise the location of the antibodies.
A fluorescence microscope is an optical microscope that uses fluorescence and phosphorescence instead of, or in addition to, scattering, reflection, and attenuation or absorption, to study the properties of organic or inorganic substances. "Fluorescence microscope" refers to any microscope that uses fluorescence to generate an image, whether it is a more simple set up like an epifluorescence microscope or a more complicated design such as a confocal microscope, which uses optical sectioning to get better resolution of the fluorescence image.
In fluorescence microscopy, colocalization refers to observation of the spatial overlap between two different fluorescent labels, each having a separate emission wavelength, to see if the different "targets" are located in the same area of the cell or very near to one another. The definition can be split into two different phenomena, co-occurrence, which refers to the presence of two fluorophores in the same pixel, and correlation, a much more significant statistical relationship between the fluorophores indicative of a biological interaction. This technique is important to many cell biological and physiological studies during the demonstration of a relationship between pairs of bio-molecules.
Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis. Errors in signaling interactions and cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated more effectively and, theoretically, artificial tissues may be created.
In biology, membrane fluidity refers to the viscosity of the lipid bilayer of a cell membrane or a synthetic lipid membrane. Lipid packing can influence the fluidity of the membrane. Viscosity of the membrane can affect the rotation and diffusion of proteins and other bio-molecules within the membrane, there-by affecting the functions of these things.
Biomolecular engineering is the application of engineering principles and practices to the purposeful manipulation of molecules of biological origin. Biomolecular engineers integrate knowledge of biological processes with the core knowledge of chemical engineering in order to focus on molecular level solutions to issues and problems in the life sciences related to the environment, agriculture, energy, industry, food production, biotechnology and medicine.
Lysosome-associated membrane protein 2 (LAMP2) also known as CD107b, is a human gene. Its protein, LAMP2, is one of the lysosome-associated membrane glycoproteins.
Alice Yen-Ping Ting is Taiwanese-born American chemist. She is a professor of Genetics, Biology, and Chemistry at Stanford University. She is also a Chan Zuckerberg Biohub investigator.
Vertico spatially modulated illumination (Vertico-SMI) is the fastest light microscope for the 3D analysis of complete cells in the nanometer range. It is based on two technologies developed in 1996, SMI and SPDM. The effective optical resolution of this optical nanoscope has reached the vicinity of 5 nm in 2D and 40 nm in 3D and surpasses the 200 nm resolution limit predicted by Abbe‘s law. Abbe postulated in 1873 the theoretical limit of resolution of optical microscopy.
Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.
The following outline is provided as an overview of and topical guide to biophysics:
The cell membrane is a biological membrane that separates the interior of all cells from the outside environment which protects the cell from its environment consisting of a lipid bilayer with embedded proteins. The cell membrane controls the movement of substances in and out of cells and organelles. In this way, it is selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall, the carbohydrate layer called the glycocalyx, and the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.
Toponomics is a discipline in systems biology, molecular cell biology, and histology. It concerns the study of the toponome of organisms. The toponome is the spatial network code of proteins and other biomolecules in morphologically intact cells and tissues. The terms toponome and toponomics were introduced by Walter Schubert in 2003 based on observations with imaging cycler microscopes (ICM). The term “toponome” is derived from the ancient Greek nouns “topos” and “nomos”. Hence the term toponomics is descriptive term addressing the fact that the spatial network of biomolecules in cells follows topological rules enabling coordinated actions. This spatial organization is directly revealed by imaging cycler microscopy with parameter- and dimension-unlimited functional resolution. The resulting toponome structures are hierarchically organized and can be described by a three symbol code. Toponomics is the field of study that has at its goal to decode the complete toponome in health and disease – the next big challenge in human biotechnology after having decoded the human genome.
An imaging cycler microscope (ICM) is a fully automated (epi)fluorescence microscope which overcomes the spectral resolution limit resulting in parameter- and dimension-unlimited fluorescence imaging. The principle and robotic device was described by Walter Schubert in 1997 and has been further developed with his co-workers within the human toponome project. The ICM runs robotically controlled repetitive incubation-imaging-bleaching cycles with dye-conjugated probe libraries recognizing target structures in situ. This results in the transmission of a randomly large number of distinct biological informations by re-using the same fluorescence channel after bleaching for the transmission of another biological information using the same dye which is conjugated to another specific probe, a.s.o. Thereby noise-reduced quasi-multichannel fluorescence images with reproducible physical, geometrical, and biophysical stabilities are generated. The resulting power of combinatorial molecular discrimination (PCMD) per data point is given by 65,536k, where 65,536 is the number of grey value levels, and k is the number of co-mapped biomolecules and/or subdomains per biomolecule(s). High PCMD has been shown for k = 100, and in principle can be expanded for much higher numbers of k. In contrast to traditional multichannel–few-parameter fluorescence microscopy high PCMDs in an ICM lead to high functional and spatial resolution. Systematic ICM analysis of biological systems reveals the supramolecular segregation law that describes the principle of order of large, hierarchically organized biomolecular networks in situ (toponome). The ICM is the core technology for the systematic mapping of the complete protein network code in tissues. The original ICM method includes any modification of the bleaching step. Corresponding modifications have been reported for antibody retrieval and chemical dye-quenching debated recently. The Toponome Imaging Systems (TIS) and multi-epitope-ligand cartographs (MELC) represent different stages of the ICM technological development. Imaging cycler microscopy received the American ISAC best paper award in 2008 for the three symbol code of organized proteomes.