From fluorescence nanoscopy to nanoscopic medicine

Abstract

NanomedicineVol. 3, No. 1 EditorialFree AccessFrom fluorescence nanoscopy to nanoscopic medicineReiner PetersReiner PetersUniversity of Muenster, Institute of Medical Physics & Biophysics & Center of Nanotechnology (CeNTech), Heisenbergstrasse 11, 48149 Muenster, Germany. Search for more papers by this authorEmail the corresponding author at reiner.peters@uni-muenster.dePublished Online:30 Jan 2008https://doi.org/10.2217/17435889.3.1.1AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Recent progress in genomics, proteomics and structural studies has provided ample evidence for the contention that the cell contains a selection of nanoscopic protein complexes, which execute multistep reactions in inimitably effective ways. This view has been complemented and extended substantially by the finding that protein complexes cooperate in functional modules and, moreover, form, on the level of the whole cell, one coherent network. The protein-complex network seems to be the actual fundament of cell function and thus life in general. The existence and implicated functional role of the cellular protein-complex network calls for a change of paradigm in biomedicine. Although the analysis of isolated cellular components is still indispensable, the focus should shift increasingly to the state of protein complexes and their network in the living cell. Here, we briefly recapitulate some of the facts that have led to the protein-complex network hypothesis and consider its implications for future medicine.The cell as a network of nanoscopic protein complexesLife involves processes on the atomic, cellular and organism level. The cognate length scales form a broad continuum extending from approximately 12-12 meters to tens of meters. However, within the continuum of length scales, certain domains are particularly important. Thus, current medicine is based on the recognition [1] that the biological cell is the one and only origin of human health and disease. The establishment of cell theory in the 19th century depended to a large degree on light microscopy and new histological staining techniques making the micrometer domain accessible.In the 20th century, cell theory was carried on to the molecular and atomic level. Cells were fractionated and their purified components studied by a variety of chemical and physical techniques, an approach culminating in the analysis of the human genome. Importantly, also, the atomic structure of many proteins was determined. Although the inventory of proteins is still full of gaps, its completion is within reach.Meanwhile, the nanometer domain of the cell has become accessible. Techniques used initially for the study of atoms and small molecules, such as x-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy, were extended to macromolecules and other nanometer-sized structures. Electron microscopy was refined by cryo-fixation and tomography. In addition, a whole class of scanning-probe microscopes was introduced providing atomic resolution of surfaces. One recent, most significant result of analyzing the nanometer domain of the cell is the discovery that most protein molecules are organized in complexes [2,3]. That proteins form complexes is not new. New, however, is the large extent and degree of complex formation among proteins, the exceptional properties of protein complexes and the fundamental role protein complexes have in cell function.Consider, as an example, the nuclear pore complex (NPC) [4]. It consists of approximately 30 different proteins that occur in multiples of eight, yielding a total of 400–600 protein molecules per NPC. These proteins form a roughly cylindrical central framework of 120 nm diameter and 70 nm height, which carries filaments extending 50–100 nm into cytoplasm or nucleus. Spanning the nuclear envelope, the NPC mediates the nucleo-cytoplasmic transport of all sorts of molecules, ranging from small inorganic ions to large ribonucleoprotein complexes, such as ribosomal subunits. Mysteriously, the NPC displays properties of both a passive molecular sieve with an effective pore diameter of approximately 10 nm or a highly selective and efficient translocation channel of approximately 50 nm diameter. The clue to translocation through the NPC seems to lie in the interaction of translocated molecules with so-called FG (phenyl alanine) repeats, which are abundant in many NPC proteins. Paradoxically, binding of transport substrates to FG repeats enhances their translocation greatly. The NPC is part of a ‘production line’, which comprises other remarkable protein complexes, such as RNA polymerase, spliceosome, ribosome, translocon and proteasome, and which, as a functional module, synthesizes, distributes and eventually degrades proteins. In addition, the NPC is part of other functional modules concerned with cell division and nuclear positioning. Remarkably, also, the NPC can be disassembled and reassembled quickly, for instance, at the onset and completion of mitosis. During mitosis, certain NPC proteins localize to other protein complexes, such as kinetochors, and exert yet unknown functions.The NPC is only one of many protein complexes. Human cells alone contain an estimated 5000 different protein complexes [5,6], of which only a small fraction has been identified and characterized. However, many of the general features of the NPC hold for other protein complexes as well, for instance, an intricate molecular architecture, a highly complex function, a high efficiency, the integration into functional modules, the sharing of subunits with other protein complexes and, last but not least, the easy creation by self-assembly.Within the highly compartmentalized nano-cosmos of the cell, the various functional modules formed by protein complexes extend across compartment borders and are linked with each other by direct interactions, sharing subunits or passing on substrates. Thus, on the level of the whole cell, the protein complexes apparently form a giant coherent network [7]. This cell-wide network is, to all we know, the physical entity that actually ‘runs’ the cell, including the maintenance, perpetuation and use of the genetic material, and, thus, is the fundament of cell function and life in general.Prospects for the further analysis of the cellular protein-complex networkCurrently, the protein-complex network of the cell cannot be reconstituted in vitro and it is difficult to image how this could ever be achieved. Therefore, it is no longer sufficient, although it is still necessary, to analyze isolated or recombinant protein complexes in vitro. The time has come to tackle the structural and functional analysis of single protein complexes and their interactions in living cells.Most of the techniques used for the characterization of protein complexes (e.g., electron microscopy, x-ray diffraction and NMR spectroscopy) cannot be applied to living cells. Among techniques that can be applied to living cells, fluorescence microscopy assumes an outstanding role because it features molecular specificity, single molecule sensitivity, substrate multiplexing, parallel data acquisition and a high time resolution. Furthermore, fluorescence microscopy can be used not only for imaging (i.e., structural studies), but also for quantitative measurements of molecular dynamics, colocalization and reactions. Traditionally, a drawback of fluorescence microscopy was resolution, which, according to classical diffraction theory, is limited to 220 nm in the focal plane and 600 nm in the direction of the optical axis. This is not sufficient for analyzing nanoscopic protein complexes. Recently, however, several ways have been found to circumvent classical resolution limits and to furnish fluorescence microscopy with, in principle, unlimited resolution (reviewed in [8]). Even if the image of a single fluorescent molecule is blurred by diffraction, the center of the image can be determined at high precision. If molecules are localized this way one by one, using multiple cycles of photoactivation and photobleaching, their spatial distribution can be determined with a precision of one or a few nanometers. Moreover, a true nanometer resolution can be achieved by interference techniques, such as those used in 4Pi microscopy or by nonlinear excitation schemes, such as those used in stimulated emission and depletion (STED) microscopy. In practice, a resolution of approximately 20 nm has been achieved with experimental and of approximately 100 nm with commercial instruments.Implications for medicineCurrent medicine is based on tried and tested principles. Characteristically, the international classification of diseases used by the WHO lists 21 categories, comprising, among others, infectious and parasitic diseases, neoplasms, endocrine, nutritional and metabolic disorders, and diseases of the circulatory, respiratory and digestive system. Expressed in a simplifying manner, disease classification is based currently on body parts. Why is it difficult, impractical or even impossible to adopt an etiological classification? Consider an apparently ‘simple’ disease category: monogenic diseases (i.e., diseases that are caused by mutations in a single gene). Well-known examples are cystic fibrosis and Huntington’s disease. Even in cases that are caused by one and the same point mutation, the manifestation and course of the disease varies among individuals within wide limits. This unpredictability is attributed [9] to the pleotropy (multifunctionality) of genes, the regulation of one gene by others (epistasis) and the influence of environmental factors. Most genetic diseases are not caused by defects in single genes, however. Common diseases, such as cardiomyopathies, diabetes mellitus, colon and breast cancer, have been linked [10] to several, in some instances up to 40, genes. In these cases, an etiological classification appears difficult indeed.We have suggested, however, that diseases converge on the level of protein complexes, that is, diseases manifest themselves, independent of their different and complex etiologies, as failures of single or several cooperating protein complexes [5,6]. Accordingly, an inventory of protein-complex diseases could provide a basis for a new rational disease classification and a better guidance for therapy. In fact, the approach exists already in rudimentary form because there are, for instance, ‘channelopathies’, referring to disorders of ion channels, and ‘laminopathies’, subsuming diseases caused by mutations in proteins of the nuclear lamina. However, these beginnings have yet to be extended, based on live cell analysis and extended to the functional modules and networks formed by protein complexes.The analysis (diagnosis) and manipulation (therapy) of single protein complexes and protein-complex networks in the living human organism might appear futuristic. However, many prerequisites for putting nanoscopic medicine, as the concept might be called, into practice are already available. What is needed most urgently is a joint effort of several currently separated disciplines to work on the following problems: • Improvement of fluorescent labeling. Currently, the specific fluorescent labeling of protein complexes in living cells is usually achieved by recombinant techniques. On the DNA level, a subunit of a protein complex is tagged with a fluorescent protein. Cells are transfected with the construct to express the corresponding fusion proteins. This approach is very successful with cell cultures and model organisms but has to be ruled out with humans. For medical purposes, radically different strategies are required that involve nontoxic small fluorescent molecules, which can penetrate into cells and bind specifically, by peptide–peptide interactions, to subunits of protein complexes.• Increase of spatial and temporal resolution of fluorescence nanoscopy. Currently, commercial set-ups reach a spatial resolution of approximately 100 nm. With experimental set-ups, a resolution of up to 20 nm has been demonstrated. To visualize topographic details of protein complexes and their pathological alteration, a resolution of approximately 1 nm appears to be necessary and sufficient. Similarly, the time resolution of fluorescence nanoscopy has to be improved, although a microsecond time resolution has been already demonstrated in certain mobility measurements.• Extension of penetration depth. Currently, fluorescence nanoscopy is limited to thin samples, such as cell monolayers. To extend nanoscopy to living tissue and, eventually, the whole body, new techniques involving both hardware improvements, such as adaptive optics, and software refinements, such as improved image-restoration algorithms, will be required. In addition, the combination of fluorescence nanoscopy with advanced endoscopy techniques and whole-body molecular imaging approaches as pursued in radiology should be fruitful.• Improvement of nanoscopic manipulation techniques. A laser beam focused down to the nanometer level cannot only be used for imaging. It also is a powerful means for mechanical manipulation (optical tweezers), photo-thermal cutting (optical scalpel) and for triggering photochemical reactions. Although laser beams have been amply used for such purposes on a micrometer scale, the systematic extension to the nanometer level and, in particular, to single protein complexes in living cells has yet to be accomplished.Financial disclosureThe work was supported by the National Institute of Health, grant number 1 R01 GM071329–01 and the Deutsche Forschungsgemeinschaft, grant PE-138/19–1. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Mazzarello P: A unifying concept: the history of cell theory. Nat. 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The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download