Preface And Acknowledgments Abbreviations
ContentsPreface and Acknowl edgmentsAbbreviationsI NTRODUCTION. Sciences Converge in Biology to Transform Healthxixiii1Nanotechnology in Biology and Medicine4The Emergence of Quantitative Biology:The New Physics of Life5The Transformation of Biology and Medicine10Transmaterial Futures151.Embracing Biology’s Complexity, At Last19Hierarchical Universe, Hierarchical Life22Zooming In on Biological Complexity: ReducingBiology to Its Building Blocks24Zooming Out: The Emergence of BiologicalBe hav ior out of Complexity28Using the Tools of Nanotechnology to Investigate Biology39Observing the Function of Biomolecules:A Protein Performing Nano- Walks43
viiiC ontentsCellular Be hav ior on Multiple Scales46How Do Whole Cells Respond to Forces and theMechanical Environment?49Translating Mechanics into Biology51Bridging Scales with Mechanical andElectrical Signals57Bioelectricity Programs Organs’ Activity58Hierarchical Biology, Hierarchical Brain . . . and Mind60By Embracing Biology’s Complexity, Science IsClosing a Historical Loop of Thousands of Years642.Learning by Making:DNA and Protein Nanotechnology67The Birth of DNA Nanotechnology69Making Nanostructures with DNA73DNA Origami76DNA Nanorobots77Scaling Up DNA Nanotechnology79Protein Nanotechnology81Nanostructures That Optimize Themselvesthrough Biological Evolution91Building Biomimetic Materials and Deviceswith Nanotechnology92 Future Devices: Quantum Physics MeetsBiology Meets Nanotechnology94
Contents ix3.Nano in Medicine97A Brief History of Drug Discovery and theArrival of Nanomedicine98Antibiotic Re sis tance and Nanotechnology104Rational Drug Design Using Designer Proteins111DNA Nanorobots for Programmable ChemicalSynthesis114Nanotechnology for Targeted Delivery of Drugs115Nanotechnology to Enhance Cancer Immunotherapy121Nanoparticles for Gene Editing and Gene Delivery126Controlled Release of Drugs and Molecules fromPolymeric Materials128Controlled Release of Drugs from Skin Patches UsingBioresponsive Materials130Implants for Improved Immunotherapies131 Toward the Super- Enhanced Immune System1324.Recreating Tissues and Organs136From the Discovery of Cells to Stem Cells138Early Tissue Engineering142Artificial Materials to Control the Fate of Stem Cells145Nanostructured Materials for Tissue Engineering147Engineering Organs1493- D Bioprinting153Organs on a Chip155
xC ontentsUsing Biology, Physics, and Mathe matics for Engineeringand Regenerating Tissues156The First Biohybrid, Transmaterial Robot1595.Conclusions: Life Changes Every t hingE PILOGUE. Biology Becomes Physics: Our Comingof Age as a Technological Species?161171Scientists Strive for New Technological Cultures173Technology and Equality177Creating Visions of Positive Technological Futures182“Walk Forward in the Radiance of the Past”185Notes189Index207
INTRODUCTIONSCIENCES CONVERGE IN BIOLOGYTO TRANSFORM HEALTHBiology is the most intensely investigated subject of modern science. Beyond perpetual human preoccupations with health, mortality, and finding our place and identity in the universe, thepower hidden in biology’s complexity is causing almost all thebranches of science and technology to gravitate t oward the studyof life. Biology ceases to be the sovereign territory of biologists,biochemists, and medical scientists; in the twenty- first century,physical, mathematical, and engineering sciences converge withthe more traditional biological disciplines to seek a deeper understanding of life in all its multifaceted, dynamic structures andfunctions. In our turbulent and disoriented times, the inner workings of biology and its profound insight into the meaning of lifehave become the focus of human creativity, spawning technological and cultural innovations that may contribute e ither to oursurvival or to our extinction.The sciences’ appetite for biology seeks satisfaction on all itsspatial scales— from nanometer- size molecules to cells tens of micrometers large to meter- scale eukaryotes1— and in all its manifestations, from the mind- boggling diversity of shape and action
2I ntroductionfound in its molecular inventory to the forces and pro cesses thatdrive the precise assembly of an intricate protein, lipid membrane,or coil of DNA. Science seeks knowledge about individual molecules, cells, tissues, organisms, and ecosystems; this includes thestudy of how biological structures give rise to the individual andcollective “intelligences”2 that enable living creatures to persist onEarth.Apart from the pure search for knowledge, economic gain andsocial influence are the workaday drivers of science (and evenmore so of research funding); thus one can observe that the motivation of the current scientific desire for all t hings biological isoften technological. The potential technological payoffs of biology are as diverse as the new disciplines evolving out of the knowledge extracted from it. For example, computer scientists are keento learn the fine details of the human brain’s organ ization so thatthey can mirror the layered connectivity between its neurons inthe structure of their algorithms; they hope this will lead to much- improved artificial intelligence (AI) as well as to better understanding of our own thinking ability. Materials scientists androboticists look to the assembly of biological structures for inspiration in the design of novel bioinspired materials and robots. Inphysics departments, scientists study the plant proteins responsible for photosynthesis, prospecting for biological r ecipes thatcan be adopted in the quantum computers of the future.However vigorous and dedicated the biological research activity of t hese new players, medicine still takes center stage as themain intellectual, social, and economic engine of biological research. Medicine helps to attract the money, but more fundamentally, plays the role of integrator of knowledge. The sciencesand technologies drawn to biology arrive by dif fer ent paths andaim at disparate goals, but medicine dispels the cultural barriers
Introduction 3among disciplines, facilitating their fusion in the pursuit of betterstrategies for uncovering the ultimate c auses of disease and better interventions to preserve and restore health.Understanding disease and curing it is such a complex challenge that it requires “all hands on deck”— all the technical andscientific knowledge available. Cutting- edge medical research already combines the latest advances in AI, materials science, androbotics, and will undoubtedly use quantum computers as theybecome available. As anyone who has been in a modern hospitalcan attest, most human technologies end up being adapted for usein the clinic in one way or another: from the h umble thermometer to the physics of positrons in PET scans for imaging tumors,and from mobile phone apps to control fertility to gene editing toeradicate diseases. The hospital is the most nourishing culture medium for scientific and technical knowledge to combine andgrow in.The diversity, intensity, and speed of advance of current research unequivocally indicate that we are living in prerevolutionary times in both biology and medicine. Confident answers to thelong- standing questions that have enthralled humans, such as theorigin and diversity of life and the source of our intelligence andconsciousness, are perhaps still far from being found. However,the accelerating and ever- more- potent interdisciplinary mergersmake us feel that we are now at an inflection point, and will soonslide irrevocably t oward the advent of the technologies that w illtransform our understanding and control of our biology. In extraordinarily novel and efficient ways, these will give us the powers to heal ourselves and to prolong and transform our lives.
4I ntroductionNANOTECHNOLOGY IN BIOLOGY AND MEDICINEA necessary step toward this brink of breakthrough was, and continues to be, the development of nanotechnology— the capacityto visualize, interact with, manipulate, and create matter at thenanometer scale. This is primarily because the main molecularplayers in biology, and the main drug and treatment targets inmedicine— proteins and DNA— are nano- size. Nanotechnology isthe technological interface with the nanoscale. It directly links themacroscopic world of our perceptions with the nanoscopic worldof individual biomolecules. To arrive in medical heaven— thepower to restore perfect health—we would need to know howmolecules work in a specific environment, why and how they malfunction in a disease, and most importantly, how to reach them,to target them, and to deactivate or activate them. In this “spatial” sense, medicine parallels nanotechnology: to cure, we needto traverse the spectrum of scale from the macroscopic size of thedoctor to the nanometer scale of biomolecules, navigating the veryintricate “multiscale” landscape of organs, tissues, and cells in between. Since the early days of nanotechnology, one of its mainmissions has been to create tools that are able to interact with keybiological molecules one at a time, directly in their complex medium, and in this way to bring closer to realization the targetingof individual molecules in the medical context. We are still working on it, and this book is in part an effort to show how far wehave come.As well as introducing nano- tools that enable new biologicaland medical research, nanotechnology has made a more fundamental contribution: attracting physical scientists to biology. Inthe last de cades of the twentieth c entury, artificial nanomaterials and the tools of nanotechnology— microscopes and nano-
Introduction 5manipulation devices— came into existence. Using them, a significant number of physical scientists interested in matter at thenanometer scale sought to know how and why biology first constructed itself using nano- size building blocks in the medium of(salty) water. Fascinated by the coupling of physics and chemistry that gives rise to biological function, they focused on usingnanotechnology’s methods to learn the workings of proteins,DNA, and other impor tant nano- size biomolecules. In the pro cess, they turned themselves into biological physicists, seeking answers to deep scientific questions such as: What was it about theproperties of the nanoscale that made it special for the emergenceof life? O thers, more practical, saw opportunities to design nanomaterials that could be used to address disease in a more preciseand rational manner, improving on current pharmacologicaltreatments; they became nanomedicine scientists.This cross- disciplinary activity led to the development of toolsspecifically built for studying biological pro cesses and their nano- actors in physiological conditions (warm, salty water). As pioneering nano- bioscientists enlarged their knowledge of biology,they eroded the bound aries between materials sciences, physics,chemistry, and biology, emerging as a new generation of researchers who naturally worked across disciplines and no longer recognized intellectual or cultural barriers to interaction with any otherscientific field.THE EMERGENCE OF QUANTITATIVE BIOLOGY:THE NEW PHYSICS OF LIFEThe arrival of nanotechnology in the life sciences has contributedto a rising wave of physical scientists entering biology, bringingfresh eyes to old prob lems. The experiments of these scientists
6I ntroductiondiffer from most biological and biochemical research in that theyare driven by mechanistic hypotheses: that is, they pursue quantitative data that help to explain the actual functioning mechanismof the pro cess under study. The usual question of a biological scientist is, “Who [which molecule] does that?” For a physicist it is,“How and why does it do that, and can I model it with mathe matics?” When you look at biological systems through the eyesof a physicist, you are looking for the key par ameters that explainhow the biological system works: Is it size, temperature, energy,speed, structure, stiffness, charge, chemical activity?Crucially, the ultimate goal of physicists is to create mathematical models of biological pro cesses that can be used to describe those mechanisms. If the mathematical model reproducesand even predicts the biology of the pro cess, then we start toknow the actual fundamental quantities and forces that drive it.The strength of this “quantitative approach” to biology is that itunleashes a formidable power: accurate mathematical modelscan be used to predict the be hav ior of specific biological pro cesses in the computer, or in modern scientific jargon, in silico,without experiments. This means that, if successful, mathematical models can be used to progressively abandon the trial- and- error methods of the traditional biological, medical, and pharmacological sciences. These are painfully slow and costly, and, asthe development of new drugs often shows, inefficient. The computer modeling approach is already in use in modern civil engineering, aeronautics, and architecture, where computer simulations combined with quantitative knowledge of the mechanicalproperties (e.g., elasticity, viscosity, strength, rigidity) of materials used in construction are routinely employed by engineers totest the feasibility of designs in silico before any actual buildingwork is done.
Introduction 7Without the invention of techniques able to quantitativelymonitor biology in all its dynamic, hierarchically structuredcomplexity— from the nanometer scale of proteins and DNA tocells to tissues in living bodies— adopting this quantitative approach in medicine was totally impossible. These techniques notonly need to visualize structures and their movements at all thedif fer ent scales, but need to be able to extract the key physical orchemical par ameters (stiffness, charge, temperature, e tc.) thatallow the development of correct mathematical models to makecomputer modeling viable.Once experimental information at the nanometer scale of single molecules becomes available, it can be used to construct models that describe the functioning of, for example, proteins orDNA in their natu ral environment and in disease. The capacityto model individual molecules will be progressively integratedwith the emergence of techniques able to collect vast amounts ofquantitative data about those molecules in complex biological environments and in real time. Furthermore, AI algorithms (suchas those of machine learning) will be used more and more to aidin the analy sis of biological “big data.”3 The integration of biological physics with biological big data and AI models will lead toincreasingly accurate and “smart” models of life. However,twentieth- century physics teaches us that in very complex and interconnected systems, knowing the workings of the buildingblocks is not enough to predict the be hav ior of the whole: at largerscales, biology exhibits be hav iors that the smaller constituents donot exhibit, or that cannot be explained from the relationships between their molecular building blocks. This is because complexlyor ga nized matter pre sents collective phenomena arising from cooperative interactions between the building blocks—or, as we sayin physics, these properties emerge. Some examples of emergent
8I ntroductionbe hav ior are cellular movements, mechanical vibrations in thebrain, electrical signaling across the membranes of cells, andchanges in shape or stiffness, none of which can be predicted fromjust knowing the molecules that constitute a par tic u lar structure.This means that in practical terms, as we zoom out from the nanoscale to the microscale, nanoscale models have to be “coarse- grained” to be integrated and consistent with models that correctlydescribe the cellular be hav iors emergent from nanometer- scaleactivity.Similarly, the cellular level then needs to be integrated intomodels of the tissue and organ levels. An example would be amathematical model of a tumor that is able to relate its shape, size,and growth pattern to the properties of individual tumor cells andtheir molecular environment; at the next level down in size, themodel should incorporate how cellular properties are connectedto their molecular and ge ne tic activity. This model could in princi ple be used to design a multimodal treatment regimen that targets individual molecules both directly and indirectly. Combining nano- precise drug delivery with a physical treatment such asapplying electrical or mechanical signals to the tumor would single out specific molecules and also affect them through the physical and chemical phenomena that link the dif fer ent spatial andtemporal scales of the tumor. In other words, it would allow simultaneous targeting of the molecular, the cellular, and the tissue- level biology of the tumor. The undertaking is formidable, butthe tools that would make it pos si ble are slowly being developedand coming together.We can draw some parallels with the past. At the beginning ofthe twentieth century, the arrival of tools to study atoms conducedto the development of the field of quantum mechanics.4 This, inturn, led to the very creative mathematical models underpinning
Introduction 9NANOSCALE (1–100 nm)BiomoleculesMICROSCALE (0.5–100 microns) MACROSCALE (mm–cm–m)CellsTissues (muscle, heart, skin )DNAE coli bacterium 1 micronProteinstypically 3–100 nmAnimal cell10–100 micron(or more)QUANTITATIVE MEASUREMENT of movement, shape, mechanics, charge, moleculesinvolved, what genes are active Techniques (a fewexamples): AFM, opticaltweezers, microscopiesMATHEMATICAL MODELS:Models of biomolecularfunctionMicroscopies, genomics,proteomics, AFMMicroscopy, histology,rheology, ultrasoundModels of cellular behaviorModels of tissueMULTISCALE SMART MODEL INTEGRATES IT ALL!Combines physics, modeling, simulation, and AIFig 0.1. The new physics of life tries to build mechanistic models of biology at eachof the relevant scales, and then integrate the models into larger “multiscale” modelsthat include all the relevant scales. (nm nanometer)solid- state physics, which successfully explained how the macroscopic properties of crystalline solids5 emerged from the order andnature of their atoms. This ultimately laid the theoretical foundation for the modern electronics pre sent in our mobile phonesand other electronic devices.While biology is im mensely more complex than crystalline solids, current trends of research in all the sciences converging onbiology indisputably indicate that this colossally arduous task isalready under way. We are moving, still slowly, but at an inexorable pace, toward the quantitative, mathematical description ofbiological phenomena—in other words, the physics of life.In this new landscape, the reductionist vision of the previousgeneration, which strove to pre sent organisms as mere biochemical
10I ntroductioncomputers executing a program, an algorithm encoded in genes,has been called into serious question. Confronting the often skeptical eyes of more- traditionally trained biologists, nano- andphysics- and mathematics- savvy scientists are slowly deployingtheir plans to quantitatively interpret the interwoven ge ne tic,chemical, and physical mechanisms under lying life and health,and to mathematically predict the biology under lying disease andtrauma. Significantly for medicine, they seek to implement theirrational health- restoring strategies one patient at a time. Theirfinal goal is to design— using mathe matics and computer models— treatments for specific prob lems in par tic u lar patients, ratherthan to discover, by endless rounds of trial and error, prescriptionsthat work for an acceptable majority of patients, as we do now.THE TRANSFORMATION OF BIOLOGYAND MEDICINEIn this book I seek to make sense of the real ity that I am livingand witnessing as a scientist working across disciplines. I amuniquely placed to tell the story of how the combined efforts ofphysical and mathematical scientists,
Protein Nanotechnology 81 Nanostructures That Optimize Themselves through Biological Evolution 91 Building Biomimetic Materials and Devices with Nanotechnology 92 Future Devices: Quantum Physics Meets Biology Meets Nanotechnology 94. CONTENTS ix 3. Nano in Medicine 97
Feb 06, 2012 · abbreviations general notes mechanical symbols and abbreviations note: all symbols and abbreviations shown are not necessarily used on the drawings . with hvac equipment is the responsibility of the contractor. the contractor shall coordinate the lo
Acronyms & Abbreviations 1 page . Acronyms and Abbreviations. List of Acronyms and Abbreviations % percent %g Percent acceleration of gravity C degrees Celsius . NCDC NOAA's National Climatic Data Center NEHRP . National Earthquake Hazard Reduction Program . NEPA National Environmental Policy Act NESEC .
Symbols, Abbreviations and Trademarks Symbols, Abbreviations This manual uses several symbols and abbreviations. The meaning of those symbols and abbreviations are as follows: Symbol What it means Clip ring Screw Connector Clamp E-ring Flat Flexible Cable Timing Belt SEF Short Edge Feed LEF Long Edge Feed
Following is a list of crochet abbreviations used in patterns by yarn industry designers and publishers. The most commonly used abbreviations are highlighted. In addition, designers and publishers may use special abbreviations in a pattern, which you might not find on this list. Generally, a definition of special abbreviations is given at the
Abbreviations Where any doubt or ambiguity may arise, please use full terminology. These are the only accepted OT abbreviations which can be used within the OT documentation, nursing, medical and MDT Paperwork. This is not a definitive list and for audit purposes any abbreviations used within a medical dictionary is an accepted abbreviation. .
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Preface to the Fifth Edition 6 Preface to the Fourth Edition 8 Preface to the Third Edition 11 Preface to the Second Edition 14 Preface to the First Edition (JCIMT) 17 II. BASIC PHYSICIAN TRAINING General Guidelines 28 Training Guidelines 30 III. HIGHER PHYSICIAN TRAINING Specialty Boards 39 General Guidelines 40 IV.
These notes were prepared during the lectures given to MSc students at IIT Guwahati, July 2000 and 2001. Acknowledgments As of now none but myself IIT Guwahati Charudatt Kadolkar. Contents Preface iii Preface Head iii Acknowledgments ii
