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1869 results in Biomedical engineering

Page 22 of 94

  • 7 - Membrane Trafficking: Flow and Barriers Create Asymmetries

  • from Part II - Design and operation of complex functions
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 145-165

  • Summary

    There are two distinct systems involved in the establishment of membranecompartmentalized functions in cells. Synthesis and secretion are involved in producing new materials, whereas endocytosis and recycling are involved in metabolism and turnover. Both are involved in the sorting of components for maintaining the compartments. In the synthetic pathway, it is critical for cells to move membranes from the site of protein and lipid synthesis to the correct membrane compartments. In the endocytic pathway, endocytosis of the plasma membrane brings in components from the environment that are sorted and processed for cell growth and activity. These functions rely upon two major mechanisms to move membranes from one compartment to another, either vesicle fission/fusion or fusion of membranes and flow followed by fission. The material to be transported is selected by coat proteins or other filters. The endocytic and synthetic pathways involve bidirectional flows of material that sort components for recycling or forward transport. In the endocytic pathway, most endocytosed components are rapidly recycled, while some are processed before recycling, and an even smaller fraction are degraded. In the synthetic pathway, the ER synthesizes the whole volume of the cellular membranes in a day for a typical growth rate (higher rates are found for specialized secretory cells). Newly synthesized membrane proteins are typically glycosylated in the ER and moved to the Golgi for further glycosylation before transport to either secretory vesicles, lysosomes, or peroxisomes. Flow through these pathways can be likened to liquid flow between a series of pools in that the inhibition of the inflow will cause shrinkage and of the outflow will cause expansion of the pool. Membrane bending stiffness, bilayer asymmetry and tension all play significant roles in membrane trafficking and the proteins involved are designed to sense and respond to each one of these membrane factors. In terms of robust systems engineering, the dynamic membrane system is designed to create linked compartments for sequential processing of proteins either as part of synthesis or metabolism.

    Membrane dynamics is critical for many functions, including secretion, renewal, nutrient supply, and signaling. Cells have the capacity to transport large amounts of membrane and perform sorting operations that confine many components to a compartment while selectively removing others for further processing. Normally the transport mechanisms are robust, and this enables tasks to be performed, albeit at a slower rate, even when one or another protein sorting system is lost.

  • 6 - Engineering Lipid Bilayers to Provide Fluid Boundaries and Mechanical Controls

  • from Part II - Design and operation of complex functions
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 119-144

  • Summary

    Membranes form the boundaries of cells. In eukaryotic cells, membranes also create internal organelles that are critical for compartmentalizing cell functions and making the system more robust (note, from textbox below, that 95–98% of cell membrane mass is internal). As physical boundaries, they define the cell and organelle volumes and must be moved in cell motility and membrane trafficking. As chemical boundaries, they keep critical components in the cytoplasm and other factors outside the cytoplasm and possibly the cell. The hydrophobic barrier provided by lipid bilayers blocks movement of charged and hydrophilic substances into and out of the cell. An important robust property of cells is that plasma membranes can often be lysed multiple times before a cell will die. They serve a gateway function in that they need to facilitate entry of some components and the exit of others. Also, chemical and physical elements of the cellular microenvironment, including its architecture, need to be communicated to the cytoplasm. Cell shape is typically defined by the cytoskeleton for most mammalian cells, but membrane area to cell volume ratio affects the shape as well as the mechanical properties of the membrane. Membrane mechanics play a critical role in many cytoplasmic as well as cellular phenomena because cell membranes have a significant bending stiffness and resistance to stretch as well as a fluid nature.

    Membranes as Compartment Boundaries

    The basic role of membranes is to compartmentalize cells by blocking the free diffusion of water-soluble components. Biological membranes are organized around lipid bilayers that have a hydrophobic core and two hydrophilic surfaces. Hydrophobic molecules and surfaces cause an increase in the order of water by not forming hydrogen bonds and creating a surface like an air–water interface. Because order causes a decrease in entropy, the hydrocarbon layer of the bilayer separates readily from water by hiding in the center of the bilayer, making the bilayers quite stable. Breaking a bilayer and exposing the hydrophobic edges to water is energetically very unfavorable. For this reason, holes in bilayers reseal rapidly to cover the exposed hydrocarbon tails. Many membrane proteins extend across the bilayer and they have a hydrophobic surface that fits with the hydrophobic domain of the bilayer. The specific transport of ions and certain molecules by transmembrane proteins occurs through hydrophilic channels in those proteins (Chapter 8).

  • 4 - Cells Exhibit Multiple States, Each with Different Functions

  • from Part I - Principles of complex functions in robust machines
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 69-94

  • Summary

    We are well aware that organisms exhibit different states of awareness, from sleep to heightened tension. Cells can likewise be in different states (phases) where different response networks and different functions are active. The different phases of the cell cycle are obvious examples of how the same cell can exhibit different behaviors when stimulated in a defined way without changing its differentiation state. Furthermore, a given function may have different activators and different levels of activity in different phases. Thus, it is important to control the cell phase when studying any given function. With a large population of cells in a variety of cell phases, the assay of a function will potentially give a mixture of activity levels. There are many different possible phases for cells, including changes in type of motility or metabolic activity in addition to the well-characterized phases of the cell cycle, senescence, or apoptosis. It is important to consider how the cell decides to transition from one phase to another. As was discussed in the previous chapter, the inability of a cell to complete a desired function can be a stimulus to change to an alternative pathway that can involve a change in phase. Further, phase changes can also be induced by the internal cell clock, or external stimuli. Another issue is that widely different cell types can exhibit very similar phases (e.g. mitosis is similar for different types of cells). Thus, many of the characteristic functions associated with different phases are present in many cell types but need specialized conditions to become activated. The same function may have varied outputs in different cell types, but the basic elements would be common to all cells. Often the transitions between phases occur in a very short time and constitute a concerted change. The probability that cells in a population will be in the same phase can be controlled in the lab using patterned substrates and defined conditions. However, single-cell studies can provide a better understanding of the cell phase when a given subcellular function is analyzed. Using defined molecular markers for specific phases, it is possible to follow phase changes at a single-cell level in multicellular tissues.

  • 15 - Turning RNA into Functional Proteins and Removing Unwanted Proteins

  • from Part II - Design and operation of complex functions
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 324-340

  • Summary

    Most proteins in a cell are synthesized in close proximity to the nucleus through a process known as ‘translation,’ in which ribosomes translate mRNA into protein following its export from the nucleus. Proteins that will be secreted or integrated into membranes must be processed within the endoplasmic reticulum (ER). This requires a signal sequence that enables the docking of the ribosome to the ER. During translation, the protein is moved into the lumen of the ER, where it will be processed. Other mRNAs are targeted for transport to selected regions of the cytoplasm or for sequestration until proper signals are received. The number of proteins synthesized from a single mRNA is highly variable, but is usually in the range of 100–1000 copies. The subsequent lifetime of the protein depends largely upon whether it is properly synthesized. Defective, misfolded proteins, or proteins that are no longer required, will be actively removed from the cytoplasm. This is achieved through a process of ubiquitinylation, which flags the protein for degradation by a proteasome. This process is dependent upon the activation of ubiquitin ligases that are downstream in a number of signaling pathways. Both localized protein synthesis and targeted degradation can facilitate cellular functions by dramatically altering the concentrations of proteins at critical times.

    Protein production is truly the hallmark of life as we know it, as proteins form the machinery that performs most cellular functions. As such, the translation of mRNA into protein is an extremely sophisticated process and one can imagine that virtually every mutation of the proteins in the ribosome and in the ribosomal RNA have been tested by cells or organisms. Any improvements would be shared with other organisms and, thus, the current ribosomes should be viewed as particularly robust. In this chapter, we will first discuss the actual process of protein production and the sophisticated adaptations for larger eukaryotes, including localized synthesis, protein folding, and processing. Protein degradation is the balance to synthesis and is used to rapidly block functions as well as to remove denatured proteins or recycle proteins in starvation conditions. Assuming proper nutrient levels, the goal of protein production and turnover is to provide the cell with the tools needed to perform the differentiated cell functions as well as face many environmental challenges from hyperthermia and trauma to various bacterial and viral challenges.

  • 7 - Digital Hearing Aids

  • Andrew G. Webb
  • Book:
    Principles of Biomedical Instrumentation
    Published online:
    11 August 2019
    Print publication:
    11 January 2018, pp 196-234

  • Summary

    Introduction

    Roughly 10% of the world's population suffers from some form of hearing loss, with over 5% or 360 million individuals suffering from hearing impairment that is considered to be disabling by World Health Organization (WHO) standards. The most common cause of hearing loss is damage to the cochlea, which results in reduced frequency selectivity and associated blurring of complex sounds. According to statistics compiled by the National Institute on Deafness and Other Communication Disorders (NIDCD) approximately 2 to 3 out of every 1000 children in the United States are born with a detectable level of hearing loss in one or both ears. One in eight people in the United States aged 12 years or older has hearing loss in both ears. Approximately 2% of adults aged 45 to 54, 8.5% aged 55 to 64, 25% aged 65 to 74, and 50% of those 75 and older have disabling hearing loss. Figure 7.1 shows the frequency and temporal characteristics of human speech, as well as the loss in different frequency ranges and classification of hearing loss from mild to profound.

    Among people aged 70 and older who could benefit from hearing aids, only ~30% have ever used them, and the percentage for younger adults is significantly lower. The main reasons are the physical visibility of the device (related to social issues), the need for manual adjustments and problems in sub-optimal conditions such as strong winds and distracting background sounds (technical issues). In order to address the societal issue hearing aids are continually being designed to be smaller, with many of the miniaturization techniques outlined throughout this book enabling the reduction in size. Technical issues are being addressed via new developments in both hardware design as well as more powerful signal processing software. Each of these developments presents design challenges in terms of the requirement to package an ever-greater number of electronics in a more limited space, and to ensure that these electronics can operate in a power-efficient manner so as to maintain long battery life.

    This chapter outlines the basic design of digital hearing aids, and the principles behind these designs [1]. The first sections in this chapter consider the physiology and acoustic properties of the human auditory system, the causes of hearing loss and the basics of hearing-aid design.

  • 1 - Robust Self-replicating Machines Shaped by Evolution

  • from Part I - Principles of complex functions in robust machines
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 3-24

  • Summary

    Biological cells are wonderfully robust self-replicating machines that selfishly propagate their DNA until environmental factors such as nutrients limit them. Cells have mastered the use of nanoscale devices in a water environment to fabricate their progeny and perform many critical functions for survival. To understand how cellular machines work, we need to understand the identity and structure of molecular components as well as the network of interactions between these molecules. We also need to study the complex cell functions in which an orchestra of molecules interacts transiently in space and time to cause an observable cellular behavior. Such an integrated systems engineering view of the cell is currently far from our reach; however, there are sufficient tools and techniques in place to provide us with many useful insights into the complex functions of the wonderful machines that are cells.

    In this book, we will mainly discuss eukaryotic cells and where possible the details of mouse embryo fibroblasts (3T3 cells) and a human cancer line (HeLa). Because there are over 300 different cell types with important specializations, we have chosen a relatively general cell type to describe what cells do. Many complex functions are missing in fibroblasts and there will be some necessary extrapolations at certain points. 3T3 and HeLa cells do not form multicellular tissues; cell–cell interactions and the higher-order functions of tissues will be discussed in later chapters. The level of integration and complexity needed for the control of multicellular complex functions is at least an order of magnitude greater than for single cell complex functions. We first focus on dissecting the individual complex functions in single cells, because it is then possible to analyze multicellular complex functions in a modular fashion.

    In this chapter, we will define the biological cell that we wish to understand and discuss how evolution has made it more robust over the last two billion years (Huxley, 1958). A cutaway diagram of a cell in suspension (Figure 1.1) provides an illustration of the basic organelle compartments that are found in mammalian cells. Compartmentalization of functions is critical for a complex machine like a cell. Each compartment performs some basic function(s) and communicates bidirectionally with the rest of the cell. Often compartments, like the cell itself, are bounded by lipid bilayers, whose hydrophobic cores effectively prevent open movements of ions and charged materials into or out of the compartments.

  • Preface and acknowledgments

  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp vii-x

  • Summary

    The motivation for this book is to provide an approach for understanding and integrating the complex functions of cells that shape tissues and drive growth and differentiation. Correlative information in the catalogs of DNA sequences, mRNA levels, interactomes, and biochemical reactions involved in complex cellular functions provides an insufficient understanding. Having the parts list of a complex machine does not enable one to assemble that machine, much less to understand how it works. In contrast, a bioengineering approach that focuses on the physical aspects of cells and tissues provides only a part of the function. A detailed engineering diagram of the steps involved and how the physical parameters relate to the biochemical functions is needed to understand most cell functions. For example, the biochemical reactions involved in the uncontrolled cell proliferation of cancer cells are known, as are the physical behaviors of tumor cells, but how physical signals from the cell environment are integrated with the biochemistry of growth is not known. In normal cells, physical feedback from matrix rigidity and morphology controls normal cell growth, whereas in cancer cells, those same parameters are misread, resulting in uncontrolled growth. By considering the reverse engineering of complex cell functions as a problem similar to reverse engineering a complex automobile, it should be possible to understand cellular functions.

    The premise of this book is that cells are small, self-replicating machines that exploit fundamental physical and physical–chemical principles of mesoscale objects to pass on the DNA of the organism that they form. From the revolution in molecular biology, we know the sequences of many genomes, as well as the sequences of the mRNAs in many specific cell types, which identify the proteins that are present. Further, we know many of the mutations that correlate with specific genetic diseases or altered phenotypes. Thus, we possess a cellular parts list. Fortunately, there are now ways to measure subcellular forces, protein positions at the nanometer level, and protein dynamics. By coupling those tools with real-time observations of cell functions, it will be possible to determine the steps in very complex functions.

    Our approach is to model the cell as a complex machine that has been selected for robustness over many millions of years.

  • 13 - DNA Packaging for Information Retrieval and Propagation

  • from Part II - Design and operation of complex functions
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 291-307

  • Summary

    If stretched out, the double-stranded DNA in a human cell nucleus would be almost 2 m in length. The complete DNA is packaged in a nucleus of 7–9 μm in diameter with histones and associated proteins. During the cell cycle, the DNA is available for transcription and replication, which will cause supercoiling and strand crossovers. In mammalian nuclei, the negatively charged DNA strands are first wound around a 6 nm, positively charged histone core. This forms a basic structure known as a nucleosome. Further compaction sees nucleosomes organized sometimes into 30 nm solenoids, which are subsequently condensed into looped chromatin structures. Dynamics in the solenoids allows DNA binding proteins to access the DNA strands on their surface. Despite the lack of observable nuclear movements in the light microscope, the nucleus is a hotbed of activity. For example, there is considerable evidence to indicate that DNA strands move through polymerizing enzymes and are scanned by other proteins. The nucleosomes are actively positioned by mechanoenzymes and although not fully understood, chromatin condensation at the core of chromosomes is known to be an energy-dependent process. In surface loop regions of chromatin, there is active transcription and recent studies indicate that chromatin is organized as flexible strings of uncondensed nucleosomes. Thus, inactive regions are hidden inside and active regions are on the outside of chromosomes.

    Much More DNA than in Genes

    The DNA sequence is often described as being the blueprint for the organism. However, this blueprint includes plans for self-repair and the mechanisms for avoiding damage from environmental challenges such as high temperature. As a result, there is considerable complexity in how the genetic information is propagated, as well as how the necessary portions are robustly read and transcribed. Some aspects of DNA structure and processing are understood, such as the checks that ensure only a single copy of the DNA is made in the S phase of the cell cycle. However, the roles of many features are not clear. For example, the majority of human DNA does not encode human genes that can be translated into proteins. Although normally silent, nearly 25% of the genome encodes for viruses that may be activated. In addition, there are large stretches of repetitive DNA sequences with no known purpose.

  • 16 - How to Approach a Coordinated Function: Cell Rigidity-sensing and Force Generation across Length Scales

  • from Part III - Coordination of complex functions
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 343-363

  • Summary

    Having discussed specific complex functions in a cell, it is good to understand how a cell integrates them when carrying out a specific process. This will be done in this chapter using fibroblast spreading and adhesion formation as an example. Before this, however, we will recap some of the fundamental concepts discussed in Chapters 1–4. At a whole-cell level, there are many complex functions that we would like to understand in more detail. However, it is difficult to isolate an individual function from the multitude of alternative functions that modify the function of interest. Isolating individual complex functions is made easier by standardizing the in vitro conditions in which cells are growing, so as to cut down on the number of uncontrolled variables. The cells should be synchronized to start from a well-defined state, rather than an array of states. The function of interest must then be followed, from initiation to a later stage, as this can enable the complete sequence of events to be analyzed. At present, this approach has only been used for a handful of complex functions in mammalian cells at the single cell level. By better defining these few functions, however, new paradigms have been provided in which to consider other established functions. Clathrin-dependent endocytosis and cell–matrix adhesion formation are two complex functions where many of the proteins involved are known, and a rough sequence of events has been described in some special circumstances. Those circumstances include specification of the cell environment, cell state, and several other factors that then enable reproducible observations of the cell functions. In the case of cell binding to matrix, there are rapid transitions between distinct cell states. This provides a good example of how cell state changes are needed for complex functions, but they complicate our understanding of the process. In a general context, the descriptions of complex cell functions read like the engineering descriptions of complex functions in factories.

    At a practical level, the analysis of functions in single cells requires a number of conditions to be met and we will see in a special case how that can be done. In Chapter 3, complex cellular functions were described as multistep processes that employed many different functional modules. For complex cellular functions to operate under the wide variety of cellular conditions, they need to adapt to the changes in cell behavior that will follow environmental challenges.

  • 3 - Integrated Complex Functions with Dynamic Feedback

  • from Part I - Principles of complex functions in robust machines
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 50-68

  • Summary

    In previous chapters, we described the cell as a robust machine that carries out complex functions through the activity of distinct functional modules. At the next level, it is important to understand how the cell accomplishes these complex functions by coordinating the activity of multiple functional modules. Clathrindependent endocytosis and plasma membrane protein synthesis are just two complex functions that result from an integrated sequence of events. For a good understanding of functions, we suggest that they should be dissected at the nanometer (protein–protein complex) level. The production of almost anything in the macroscopic world needs a plan that outlines the number of steps in its production, as well as a decision tree to provide for modifications and/or quality control. This will ensure that the final product meets all required standards. In the production of cars or computers, components are added in a series of steps that often occur in a prescribed order and depend upon the satisfactory completion of each step before subsequent steps can commence. Similarly, complex functions in cells, including clathrin-dependent endocytosis and plasma membrane protein synthesis, all occur in a series of often repetitive steps that depend upon the sequential completion of prior steps. This results in a classical ‘if/then’ decision tree that will ensure that the complex function is completed properly. In some cases, there are multiple complex functions that the cell can choose depending upon the conditions (e.g. if a cell encounters another cell, it will change its behavior). For us to understand any given integrated complex function, we need to define the steps (which are typically driven by distinct functional modules) and the critical components needed to complete the task.

    To understand the multiple levels of complex functions, it is useful here to consider an easily applicable example, again using cars. To raise or lower a car window, several machine elements come into play. Only a basic understanding of the mechanism is required to raise and lower the window. However, to be able to repair a car window, the mechanism must be understood in much greater detail. Here, a complete list of the parts, right down to the screws that hold them in place, may be required.

  • 14 - Transcribing the Right Information and Packaging for Delivery

  • from Part II - Design and operation of complex functions
  • Michael Sheetz, Columbia University, New York, Hanry Yu, National University of Singapore
  • Book:
    The Cell as a Machine
    Published online:
    06 August 2018
    Print publication:
    11 January 2018, pp 308-323

  • Summary

    The production of RNA (mRNA, rRNA, miRNA, etc.) occurs through a process known as transcription. This process occurs in a well-defined sequence, starting with the selection of one or two sites on the DNA that encode for the appropriate RNA. A polymerase complex will then assemble, and begin translocating along the DNA, producing the RNA as it moves. Finally, the RNA must be processed and transported out of the nucleus and processing is different for mRNA versus the other types. In differentiated mammalian cells, transcription initiation sites are partially determined by the silencing of major portions of the chromatin through post-translational modifications. In addition, there are tissue-specific aspects of mRNA production that include alternative splicing of the mRNA, and micro-RNAs, which decrease the lifetime of mRNA subsets. There has been considerable interest in how the cell transcribes the right DNA, processes and then packages the transcript for transport to the cytoplasm. To fully understand the primary signals that govern gene expression, the expression levels of various transcription factors must be defined, and more comprehensive data on the changes in transcription patterns attained. For sufficient specificity, and regulation of the transcription process, we would expect several factors to interact with the DNA or transcription machinery. Thus, the definition of the site of transcription is the critical aspect and the subsequent process of mRNA production and processing follows as expected.

    Steps in mRNA production and processing:

  • (A) Identify regions of the genome to be transcribed.

  • (B) Activate transcription.

  • (C) Process mRNA transcript.

  • (D) Recruit RNA binding proteins and release from transcription site.

  • (E) Diffuse to nuclear pore and move to cytoplasm.

  • (F) Move and/or diffuse to translation site.

  • (G) Degradation.

    • To introduce the topic of RNA production and processing, we will first consider how proteins are produced in cells. Cells transcribe DNA into RNA as a first step towards producing functional protein complexes. Once again, the principles of manufacturing a car are analogous in many ways to this important cellular process. In a well-run automobile factory, each car is produced from a set number of parts, each of which is incorporated in a set sequence. Highly specialized machines are required to both produce the parts and incorporate them into the final product. It would be wasteful to produce an excess of any one part, and incorporating a part out of sequence will render the car unusable, and slow down further production.

Page 22 of 94