Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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The fundamental and technological importance of these materials is due to the unique physical and chemical properties. Over the years, numerous methods have been developed for the synthesis of high-efficient semiconductors. Moreover, a variety of approach and characterization methods have been used to study the numerous and fascinating properties of the semiconducting materials. This book collects new developments about semiconductors, from the fundamental issues to their synthesis and applications. Special attention has been devoted to electrochemical growth and characterization.",isbn:"978-953-51-3884-6",printIsbn:"978-953-51-3883-9",pdfIsbn:"978-953-51-4032-0",doi:"10.5772/68094",price:119,priceEur:129,priceUsd:155,slug:"semiconductors-growth-and-characterization",numberOfPages:186,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"53bed47ef5d839f8d10d5f1a3b050c49",bookSignature:"Rosalinda Inguanta and Carmelo Sunseri",publishedDate:"March 7th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6083.jpg",numberOfDownloads:10696,numberOfWosCitations:23,numberOfCrossrefCitations:15,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:32,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:70,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 6th 2017",dateEndSecondStepPublish:"March 27th 2017",dateEndThirdStepPublish:"October 29th 2017",dateEndFourthStepPublish:"November 29th 2017",dateEndFifthStepPublish:"January 29th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"174858",title:"Prof.",name:"Rosalinda",middleName:null,surname:"Inguanta",slug:"rosalinda-inguanta",fullName:"Rosalinda Inguanta",profilePictureURL:"https://mts.intechopen.com/storage/users/174858/images/7013_n.jpg",biography:"Rosalinda Inguanta is currently an assistant professor of Applied Physical Chemistry at the University of Palermo. She received her PhD degree in 2008 at the University of Palermo. Her research interests include the synthesis of nanostructured electrochemical devices for electrochemical sensors, batteries, solar cells, and electrolysers and the synthesis of biocoatings to prevent the corrosion of medical devices in human body and the recovery of precious metals from electronic waste. She has developed a new method for the synthesis of nanostructures and thin film of different materials based on galvanic synthesis. In the field of semiconductors, she has studied the electrochemical deposition of different semiconductors, such as CIGS and CZTS; currently, her research team is employed on the study of perovskite thin film starting from electrodeposition of PbO2 layers.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Palermo",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"174862",title:"Prof.",name:"Carmelo",middleName:null,surname:"Sunseri",slug:"carmelo-sunseri",fullName:"Carmelo Sunseri",profilePictureURL:"https://mts.intechopen.com/storage/users/174862/images/7014_n.jpg",biography:"Carmelo Sunseri is a full professor of Applied Thermodynamic at the University of Palermo. His main research interests are in the fields of thermodynamic and kinetic study of electrochemical reactions on both metallic and semiconducting electrodes, electrochemical synthesis and characterization of nanostructured materials, and photoelectrochemical investigation of semiconductor surfaces. His research activity is focused on materials and systems of technological interest in view of their potential application in the following fields: electrochemical storage and conversion of energy (battery and fuel cells), photovoltaics, fabrication of thin-film devices, and electrochemical fabrication of porous devices.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Palermo",institutionURL:null,country:{name:"Italy"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"159",title:"Semiconductor",slug:"semiconductor"}],chapters:[{id:"58741",title:"Investigation of the Nanostructured Semiconductor Metamaterials",doi:"10.5772/intechopen.72801",slug:"investigation-of-the-nanostructured-semiconductor-metamaterials",totalDownloads:1295,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The presence of electromagnetic waves on two-dimensional interfaces has been extensively studied over the last several decades. Surface plasmonic polariton (SPP), which normally exists at the interface between a noble metal and a dielectric, is treated as the most widely investigated surface wave. SPPs have promoted new applications in many fields such as microelectronics, photovoltaics, etc. Recently, it has been shown that by nanostructuring the metal surface, it is possible to modify the dispersion of SPPs in a prescribed manner. Herein, we demonstrate the existence of a new kind of surface wave between two anisotropic meta-materials. In contrast to extensively studied surface waves such as SPPs and Dyakonov waves, the surface waves supported by the nanostructured semiconductor metamaterial cross the light line, and a substantial portion at lower frequencies lies above the free-space light line. Consequently, the proposed structure will interact with the material via leaky waves.",signatures:"Aleksej Trofimov, Tatjana Gric and Ortwin Hess",downloadPdfUrl:"/chapter/pdf-download/58741",previewPdfUrl:"/chapter/pdf-preview/58741",authors:[{id:"212653",title:"Prof.",name:"Tatjana",surname:"Gric",slug:"tatjana-gric",fullName:"Tatjana Gric"},{id:"212660",title:"Prof.",name:"Ortwin",surname:"Hess",slug:"ortwin-hess",fullName:"Ortwin Hess"},{id:"231188",title:"MSc.",name:"Aleksej",surname:"Trofimov",slug:"aleksej-trofimov",fullName:"Aleksej Trofimov"}],corrections:null},{id:"57748",title:"Understanding the Mechanisms that Affect the Quality of Electrochemically Grown Semiconducting Nanowires",doi:"10.5772/intechopen.71631",slug:"understanding-the-mechanisms-that-affect-the-quality-of-electrochemically-grown-semiconducting-nanow",totalDownloads:1410,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Template-assisted synthesis of nanowires is a simple electrochemical technique commonly used in the fabrication of semiconducting nanowires. It is an easy and cost-effective approach compared to conventional lithography, which requires expensive equipment. The focus of this chapter is on the various mechanisms involving mass transport of ions during successive stages of the template-assisted electrochemical growth of indium antimonide (InSb) nanowires. The nanowires were grown in two different templates such as commercially available anodic aluminum oxide (AAO) templates and polycarbonate membranes. The chapter also presents the results of characterizing the InSb nanowires connected in a field effect transistor (FET) configuration. The Sb-rich InSb nanowires that were fabricated by DC electrodeposition in nanoporous AAO exhibited hole-dominated transport (p-type conduction). Temperature-dependent transport measurement shows the semiconducting nature of these nanowires.",signatures:"Abhay Singh and Usha Philipose",downloadPdfUrl:"/chapter/pdf-download/57748",previewPdfUrl:"/chapter/pdf-preview/57748",authors:[{id:"24712",title:"Dr.",name:"Usha",surname:"Philipose",slug:"usha-philipose",fullName:"Usha Philipose"},{id:"208020",title:"Dr.",name:"Abhay",surname:"Singh",slug:"abhay-singh",fullName:"Abhay Singh"}],corrections:null},{id:"59407",title:"Semiconductor Quantum Wells with BenDaniel-Duke Boundary Conditions and Janus Nanorods",doi:"10.5772/intechopen.73837",slug:"semiconductor-quantum-wells-with-bendaniel-duke-boundary-conditions-and-janus-nanorods",totalDownloads:1031,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The energy levels of bound states of an electron in a quantum well with BenDaniel-Duke boundary condition are studied. Analytic, explicit, simple, and accurate formulae have been obtained for the ground state and the first excited state. In our approach, the exact, transcendental eigenvalues equations were replaced with approximate, tractable, algebraic equations, using algebraic approximations for some trigonometric functions. Our method can be applied to both type I and type II semiconductors and easily extended to quantum dots. The same approach was used for the semi-quantitative analyze of two toy models of Janus nanorods.",signatures:"Victor Barsan",downloadPdfUrl:"/chapter/pdf-download/59407",previewPdfUrl:"/chapter/pdf-preview/59407",authors:[{id:"100805",title:"Dr.",name:"Victor",surname:"Barsan",slug:"victor-barsan",fullName:"Victor Barsan"}],corrections:null},{id:"59109",title:"Nanostructured ZnO, Cu2ZnSnS4, Cd1−xZnxTe Thin Films Obtained by Spray Pyrolysis Method",doi:"10.5772/intechopen.72988",slug:"nanostructured-zno-cu2znsns4-cd1-xznxte-thin-films-obtained-by-spray-pyrolysis-method",totalDownloads:1387,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The paper presents the investigation on the influence of substrate temperature Ts and the sprayed initial solution volume Vs on structural, substructural, optical properties, and elemental composition of ZnO and Cu2ZnSnS4 (CZTS) films as well as state-of-the-art of studying the Cd1−xZnxTe (CZT) films obtained by spray pyrolysis technique. The single-phase nanocrystalline ZnO films with average crystallite size of DC = 25–270 nm and thickness of d = 0.8–1.2 μm can be deposited at substrate temperatures of Ts > 473 K. The continuous CZTS films with optimal thickness (d = 1.3 μm) for application as absorber layers in solar cells were deposited at the sprayed initial precursor volume of Vs = 5 ml. The increase of the substrate temperature up to 673 K caused the significant improvements in the stoichiometry of ZnO films. The optimal stoichiometry ratio of CZTS films for application in solar cells was obtained at Vs = 3–4 ml. Optical study of ZnO films showed that these films have a high-transmission coefficient values of T = 60–80%. To the best of our knowledge, there is the lack of works devoted to the study of CZT films obtained by spray pyrolysis technique.",signatures:"Oleksandr Dobrozhan, Denys Kurbatov, Petro Danilchenko and\nAnatoliy Opanasyuk",downloadPdfUrl:"/chapter/pdf-download/59109",previewPdfUrl:"/chapter/pdf-preview/59109",authors:[{id:"144156",title:"Dr.",name:"Anatoliy",surname:"Opanasyuk",slug:"anatoliy-opanasyuk",fullName:"Anatoliy Opanasyuk"},{id:"223520",title:"Dr.",name:"Denys",surname:"Kurbatov",slug:"denys-kurbatov",fullName:"Denys Kurbatov"},{id:"237396",title:"MSc.",name:"Oleksandr",surname:"Dobrozhan",slug:"oleksandr-dobrozhan",fullName:"Oleksandr Dobrozhan"},{id:"237398",title:"MSc.",name:"Petro",surname:"Danilchenko",slug:"petro-danilchenko",fullName:"Petro Danilchenko"}],corrections:null},{id:"57273",title:"E-ALD: Tailoring the Optoeletronic Properties of Metal Chalcogenides on Ag Single Crystals",doi:"10.5772/intechopen.71014",slug:"e-ald-tailoring-the-optoeletronic-properties-of-metal-chalcogenides-on-ag-single-crystals",totalDownloads:1187,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Technological development in nanoelectronics and solar energy devices demands nanostructured surfaces with controlled geometries and composition. Electrochemical atomic layer deposition (E-ALD) is recognized as a valid alternative to vacuum and chemical bath depositions in terms of growth control, quality and performance of semiconducting systems, such as single 2D semiconductors and multilayered materials. This chapter is specific to the E-ALD of metal chalcogenides on Ag single crystals and highlights the electrochemistry for the layer-by-layer deposition of thin films through surface limited reactions (SLRs). Also discussed herein is the theoretical framework of the under potential deposition (UPD), whose thermodynamic treatment open questions to the correct interpretation of the experimental data. Careful design of the E-ALD process allows fine control over both thickness and composition of the deposited layers, thus tailoring the optoelectronic properties of semiconductor compounds. Specifically, the possibility to tune the band gap by varying either the number of deposition cycles or the growth sequence of ternary compounds paves the way toward the formation of advanced photovoltaic materials.",signatures:"Emanuele Salvietti, Andrea Giaccherini, Filippo Gambinossi, Maria\nLuisa Foresti, Maurizio Passaponti, Francesco Di Benedetto and\nMassimo Innocenti",downloadPdfUrl:"/chapter/pdf-download/57273",previewPdfUrl:"/chapter/pdf-preview/57273",authors:[{id:"189009",title:"Prof.",name:"Massimo",surname:"Innocenti",slug:"massimo-innocenti",fullName:"Massimo Innocenti"},{id:"189015",title:"Dr.",name:"Francesco",surname:"Di Benedetto",slug:"francesco-di-benedetto",fullName:"Francesco Di Benedetto"},{id:"189017",title:"MSc.",name:"Andrea",surname:"Giaccherini",slug:"andrea-giaccherini",fullName:"Andrea Giaccherini"},{id:"218978",title:"Dr.",name:"Emanuele",surname:"Salvietti",slug:"emanuele-salvietti",fullName:"Emanuele Salvietti"},{id:"218979",title:"Dr.",name:"Filippo",surname:"Gambinossi",slug:"filippo-gambinossi",fullName:"Filippo Gambinossi"},{id:"218980",title:"MSc.",name:"Maurizio",surname:"Passaponti",slug:"maurizio-passaponti",fullName:"Maurizio Passaponti"},{id:"218981",title:"Prof.",name:"Maria Luisa",surname:"Foresti",slug:"maria-luisa-foresti",fullName:"Maria Luisa Foresti"}],corrections:null},{id:"58740",title:"Pulsed Electrochemical Deposition of CuInSe2 and Cu(In,Ga)Se2 Semiconductor Thin Films",doi:"10.5772/intechopen.71857",slug:"pulsed-electrochemical-deposition-of-cuinse2-and-cu-in-ga-se2-semiconductor-thin-films",totalDownloads:1443,totalCrossrefCites:7,totalDimensionsCites:15,hasAltmetrics:0,abstract:"CuInSe2 (CIS) and Cu(In,Ga)Se2 (CIGS) semiconductors are the most studied absorber materials for thin films solar cells due to their direct bandgap and large absorption coefficient. The highly efficient CIGS devices are often fabricated using expensive vacuum based technologies; however, recently electrodeposition has been demonstrated to produce CIGS devices with high efficiencies and it is easily amenable for large area films of high quality with effective material use and high deposition rate. In this context, this chapter discusses the recent developments in CIS and CIGS technologies using electrodeposition. In addition, the fundamental features of electrodeposition such as direct current, pulse and pulse-reverse plating and their application in the fabrication of CIS and CIGS films are discussed. In conclusion, the chapter summarizes the utilization of pulse electrodeposition for fabrication of CIS and CIGS films while making a recommendation for exploring the group’s unique pulse electroplating method.",signatures:"Sreekanth Mandati, Bulusu V. Sarada, Suhash R. Dey and Shrikant V.\nJoshi",downloadPdfUrl:"/chapter/pdf-download/58740",previewPdfUrl:"/chapter/pdf-preview/58740",authors:[{id:"207526",title:"Dr.",name:"Sreekanth",surname:"Mandati",slug:"sreekanth-mandati",fullName:"Sreekanth Mandati"},{id:"207714",title:"Dr.",name:"Bulusu V.",surname:"Sarada",slug:"bulusu-v.-sarada",fullName:"Bulusu V. Sarada"},{id:"207715",title:"Dr.",name:"Suhash Ranjan",surname:"Dey",slug:"suhash-ranjan-dey",fullName:"Suhash Ranjan Dey"},{id:"207717",title:"Prof.",name:"Shrikant V.",surname:"Joshi",slug:"shrikant-v.-joshi",fullName:"Shrikant V. Joshi"}],corrections:null},{id:"58469",title:"The Electrochemical Performance of Deposited Manganese Oxide-Based Film as Electrode Material for Electrochemical Capacitor Application",doi:"10.5772/intechopen.71957",slug:"the-electrochemical-performance-of-deposited-manganese-oxide-based-film-as-electrode-material-for-el",totalDownloads:1721,totalCrossrefCites:4,totalDimensionsCites:8,hasAltmetrics:0,abstract:"The transition metal oxide has been recognized as one of the promising electrode materials for electrochemical capacitor application. Due to the participation of charge transfer reactions, the capacitance offered by transition metal oxide can be higher compared to double layer capacitance. The investigation on hydrous ruthenium oxide has revealed the surface redox reactions that contributed to the wide potential window shown on cyclic voltammetry curve. Although the performance of ruthenium oxide is impressive, its toxicity has limited itself from commercial application. Manganese oxide is a pseudocapacitive material behaves similar to ruthenium oxide. It consists of various oxidation states which allow the occurrence of redox reactions. It is also environmental friendly, low cost, and natural abundant. The charge storage of manganese oxide film takes into account of the redox reactions between Mn3+ and Mn4+ and can be accounted to two mechanisms. The first one involves the intercalation/deintercalation of electrolyte ions and/or protons upon reduction/oxidation processes. The second contributor for the charge storage is due to the surface adsorption of electrolyte ions on the electrode surface.",signatures:"Chan Pei Yi and Siti Rohana Majid",downloadPdfUrl:"/chapter/pdf-download/58469",previewPdfUrl:"/chapter/pdf-preview/58469",authors:[{id:"197956",title:"Associate Prof.",name:"S.R.",surname:"Majid",slug:"s.r.-majid",fullName:"S.R. Majid"},{id:"216449",title:"Ms.",name:"Pei Yi",surname:"Chan",slug:"pei-yi-chan",fullName:"Pei Yi Chan"}],corrections:null},{id:"58476",title:"Semiconducting Electrospun Nanofibers for Energy Conversion",doi:"10.5772/intechopen.72817",slug:"semiconducting-electrospun-nanofibers-for-energy-conversion",totalDownloads:1228,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nowadays, semiconducting thin films, thanks to their unique and excellent properties, play a crucial role for the design of devices for energy conversion and storage, such as solar cells, perovskite solar cells, lithium-ion batteries (LIBs), and fuel cells. Since the nanostructured arrangements can improve the behavior of the materials in several application fields, in this chapter we propose the electrospinning process as electro-hydrodynamic deposition to obtain semiconducting materials, in the form of nanofiber mats. The nanostructured mats are able to provide high surface-area-to-volume ratio and a microporous structure, which are crucial aspects for energetic application. In this chapter, we deeply describe the electrospinning process and how nanofibers obtained can be used in energy devices, satisfying all the requirements to improve overall final performances.",signatures:"Giulia Massaglia and Marzia Quaglio",downloadPdfUrl:"/chapter/pdf-download/58476",previewPdfUrl:"/chapter/pdf-preview/58476",authors:[{id:"36458",title:"Dr.",name:"Marzia",surname:"Quaglio",slug:"marzia-quaglio",fullName:"Marzia Quaglio"},{id:"223653",title:"Dr.",name:"Giulia",surname:"Massaglia",slug:"giulia-massaglia",fullName:"Giulia Massaglia"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8866",title:"Silicon Materials",subtitle:null,isOpenForSubmission:!1,hash:"c7cfb39af7a429ef119b71a2e1f221e7",slug:"silicon-materials",bookSignature:"Beddiaf Zaidi and Slimen Belghit",coverURL:"https://cdn.intechopen.com/books/images_new/8866.jpg",editedByType:"Edited by",editors:[{id:"230574",title:"Dr.",name:"Beddiaf",surname:"Zaidi",slug:"beddiaf-zaidi",fullName:"Beddiaf Zaidi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6845",title:"Graphene and Its Derivatives",subtitle:"Synthesis and Applications",isOpenForSubmission:!1,hash:"63a9783e678fc42ce981efb35be02096",slug:"graphene-and-its-derivatives-synthesis-and-applications",bookSignature:"Ishaq Ahmad and Fabian I. 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1. Introduction
We, animals, live in a microbe-dominated planet. We are all covered, filled, and fueled by bacteria. All body surfaces like the skin, gastrointestinal tract, urogenital, and respiratory tract are in constant contact with the environment and are, therefore, colonized by bacteria. The realities of life associated with a microbe-dominated planet have led to the coevolution of animals with bacteria. This coevolution has led to close inhabitation of bacteria on different surfaces of the human body, especially the gut. Here, many bacteria and their phages, viruses, fungi, archaea, protists, and nematodes intermingle to form a microbial consortia collectively called “microbiome” or “microbiota”. The presence and abundance of each taxonomic group may vary within population based on their access to adequate health care and local sanitation condition or within individuals based on their metabolic, medical, diet, and various other factors.
Despite being embedded deeply in the human body, the gut is essentially an open ecosystem—with constant exposure to environmental factors. The closure of the NIH-funded human microbiome project has given advanced understanding about the composition and functional characteristics of the gut microbiota composition. The composition of the human microbiome varies significantly depending on the habitat [1]. For example, the gut microbiota is mainly populated by bacteria [2], while the skin harbors mainly fungi [3]. It was always considered that human microbiome outnumbered human nucleated cells by at least a factor of 10. However, reports suggest that the ratio is closer to 1 [4]. Recently metagenomic analysis concluded that the gene set of the human microbiome is 150 times larger than the human gene complement raising the possibility that the large bacterial genetic repertoire aids the human component in performing the essential functions that are not encoded by the human genome. Since more than 99% of these genes are bacterial in origin, the number of bacterial species were calculated to be around 1000–1150 bacterial species. The figures collectively emphasize the biological importance of the microbiome, and the genetic complement can be rightly considered as the second genome [2]. However, the taxonomic diversity of the gut microbiome notwithstanding, this chapter will deal only with the bacterial populations and all further references to gut microbiota means gut bacterial microbiota.
A typical human gut microbiota contains about 1014 bacteria and is made up of more than 1000 bacterial species [5, 6]. The human gut microbiota is composed of six bacterial phyla—Firmicutes, Proteobacteria, Bacteroides, Fusobacteria, Actinobacteria, and Verrucomicrobia. Of this, Bacteroides and Firmicutes occupy 70–90% of the total bacteria present in a healthy gut, while others are present in lower abundances [7]. Under healthy circumstances Proteobacteria and Verrucomicrobia members are also present but in lesser abundance [8]. The huge complexity and the variability of the microbiome make the determination of precise metabolic functions and the host-microbe cross talk very difficult. However, recent advances in deep sequencing and computational biology have contributed to large advances into understanding the unique biology of the gut microbiota and the subject is still in its infancy.
The functions bestowed by the bacterial gut flora are so enormous that it can be considered as an endocrine organ on its own [9]. It is well understood that the gut microbiota and their metabolites play important roles in host homeostasis, such as providing important nutrients like secondary bile salts and B/K group vitamins [10, 11], help in fermenting the otherwise indigestible complex plant carbohydrates such as dietary fibers into short-chain fatty acids (SCFA) [12], contributing to an effective intestinal epithelial barrier and activation of both innate/adaptive immune responses of the host [13]. In addition, the healthy gut microbiome drives intestinal development by promoting vascularization, villus thickening, mucosal surface widening, mucus production, cellular proliferation, and maintaining epithelial junctions [14, 15, 16]. The influence of the gut microbiota, either directly or indirectly, affects the physiology of most host organs even the brain [14, 17, 18, 19, 20].
The taxonomic composition of the microbiota is very subtle—subject to change with variations in the diet [21], feeding time changes [22], sleep wake cycles, and even jet lag [23]. The unique taxonomic signature of the gut microbiota has to be strictly maintained for a healthy gut. Any disruption of the taxonomic composition of the gut could lead to conditions such as inflammatory bowel syndrome (IBS), asthma, obesity, metabolic syndrome, and cancer [24]. In some cases, resuscitation of the gut microbiota using probiotic bacteria like Bifidobacteria and Lactobacillus leads to the mitigation of gut inflammation consequently regaining health.
In this chapter, we will sequentially detail how the microbiota establishes itself in a human body, how minor or major variations in the gut microbiome introduces diseased conditions, and how the recent therapeutic approaches aimed at resuscitating the healthy microbiota can cure many dysbiotic microbiota-associated conditions.
2. Our internal garden—on how gut microbiota is planted and nurtured
How do we become colonized with gut microbiota? Where do we get our initial inoculum from and how does this initial inoculum proceed in to a well-flourished, well-established microbiota? The first step to understanding this is to identify the initial inoculum and how this inoculum develops into a the full-fledged adult ecosystem following a series of ecological succession steps.
2.1 The initial colonization
The most prevalent concept, and a very incorrect one, is that babies are borne sterile and after birth, the body becomes immediately colonized with microbes from the surrounding environment. Placental mammals such as humans are borne through a birth canal, which is colonized by microbes. A baby acquires its first inoculum from the birth canal. A healthy vaginal microbiota is composed of few bacterial species [25, 26] and is predominated by Lactobacilli [27]. Consequently, naturally borne babies acquire vaginal microbes like Lactobacillus, Prevotella, and Sneathia spp. [28]. The bacteria are present in the mouth, skin, and even in the meconium. Therefore, all neonates are colonized by essentially the same vaginally derived bacteria obtained vertically from the mother. Once this microbiota is established, the microbiota becomes highly differentiated depending on their ability to colonize different body sites. For example, in the gut, facultative anaerobes establish and reduce the environment [29]. This highly reduced environment facilitates the colonization of obligate anaerobes [30, 31, 32, 33]. In addition, breastfeeding will also enrich vaginally acquired lactic-acid-producing bacteria in the baby’s intestine [34]. From then on, it is the physiology of the host habitat that selects the community that becomes well adapted to colonize that particular habitat. For example, the physiochemical, immunological, and the diet play an important role in determining the microbial community that will colonize the small and large intestines. The host genotype also appeared to influence the composition of the gut microbiota [35].
Cesarean section babies, in contrast to vaginally borne babies, are dominated by skin-associated bacteria like Staphylococcus, Corynebacterium, and Propionibacterium spp. [28]. The Staphylococcal-rich microbiota could be obtained from the skin of the humans the baby is in contact with. The lack of a natural first inoculum in C-section babies affects the bacterial community in the GI tract [36, 37]. This variation from the naturally borne baby’s microbiome will increase the susceptibility of the C-section babies to certain pathogens. For example, about 70% of the MRSA-caused skin infection happens to C-section babies. In addition, there is an additional risk to atopic diseases [38], allergies, and asthma [28, 39].
2.2 Development of the microbiota
The establishment, composition, and the density of the microbiome in the gastrointestinal (GI) tract depends on the biochemical factors like pH, oxygen gradient, antimicrobial peptides (AMPs), bile salts, etc. There is a pH gradient across the GI tract—lowest in the stomach and gradually increase to the terminal ileum, and a drop in caecum and increases toward the distal colon. Oxygen also exhibits a gradient across the length of the tract. The levels are highest in the upper GI tract, which decrease to anaerobic conditions in the distal colon. Radially across the tract too, there exists a oxygen gradient. Anoxic conditions exist in the lumen, while there is an increase in the oxygen tension near the mucosa, and this oxygen is rapidly consumed by the facultative anaerobes [40]. Each area in the gut produces its own AMPs. Saliva contains lysozyme, which is antibacterial. Small intestine produces α-defensins, C-type lectins, lysozyme, and phospholipase A2. The large intestine produces β-defensins, C-type lectins, cathelicidins, galectins, and lipocalin. Mucus also plays an important role in the distribution of the gut microbiota. The mucus in the stomach and colon can be discriminated into two layers—outer loose layer, which is densely populated by bacteria, and the inner “solid” layer, where bacteria is sparce [41, 42]. Only mucin-degrading bacteria like Akkermansia muciniphila reach to the inner solid layer. Some pathogens like Helicobacter pylori, Salmonella, Yersinia, Campylobacter, etc. can also reach the inner mucus layer [43, 44]. All these factors play an important role in the establishment and the distribution of the gut microbiota.
The initially colonized microbiome has relatively few bacterial species. But during the initial phase of life, bacterial diversity increases in the microbiota. This may be because of the constant exposure of the baby to the environment. The gradual increase in the length of the GI tract can also provide a new niche for the bacteria to colonize. The bacterial diversity also depends on the diet as the introduction of a more plant-based diet increases the proportion of the Firmicutes [45]. Though lifestyle, illness, puberty, and other variable factors affect the microbiome, family members tend to have similar microbiomes with shared bacterial strains [35]. Thus, during the first year of life, the microbiome proceeds through a very variable phase. A distinct composition resembling the “adult microbiome composition” is established once an adult diet is established after weaning [35]. Once established, the gut microbiome composition seems to remain stable for a long time, possibly lifelong [46].
3. Maintain the flora!—on how any alterations could be disastrous
Biologically, the gut microbiome is very essential for the normal functioning of the human body. This complex ecosystem is responsible for many critical functions like (1) metabolism and energy regulation [47]—up to 10% of our daily consumed calories are provided by the microbes who break down complex plant-derived carbohydrates into short-chain fatty acids (SCFA), the main energy source of the enterocytes. From this perspective, alterations in the gut microbiome can contribute to obesity [48, 49] and consequently type II diabetes [50]; (2) immune system activation [51, 52, 53]—the colonic mucosal immune system plays a dual role and in that it must tolerate the gut microbiome and at the same time react against pathogenic organisms. This homeostasis is achieved by the intricate interplay between the microbiome and the host; (3) colonization resistance—physiologically colonized body surfaces are intrinsically protected from pathogen colonization. It is the intricate interplay between the above mentioned three major functions of the gut microbiota that brings about the physiological healthy state of the host.
Colonization resistance is the native ability of the host to suppress the invasion by exogenous microorganisms [54]. The concept of colonization resistance originated from the studies of Dubos in 1965 who demonstrated that indigenous gut microbiota neutralize colonization by a potential pathogen [55]. Slightly earlier, it was noted that loss of obligate anaerobic bacterial population in the lower intestinal tract correlated with infection, suggesting that the commensal anaerobic organisms were providing colonization resistance [56, 57, 58, 59]. At the time, colonization resistance was thought to result from microbe-mediated inhibition. We now know that the multiple mechanisms like microbiota-mediated activation of host immune responses are also involved. Colonization resistance provides broad protection against bacteria, virus, and other categories of pathogens [60]. On the other hand pathogenic microorganisms can out compete commensal microorganisms, subvert the immune response and invade the epithelia. For example, some pathogens can cause inflammation in the gut and utilize the consequent nutrient-rich inflammatory environment to outgrow other Proteobacteria. However, in a healthy intestine, the gut microbiota maintains the stiff colonization resistance by three mechanisms (1) directly inhibiting or killing the invading organism, (2) maintaining a protective musical barrier, and (3) stimulating a strong immune response that can neutralize a pathogen.
3.1 Direct inhibition
Bacteria produce many bioactive molecules, such as antimicrobial peptides, bacteriocins, etc., to selectively kill or inhibit the growth of competing bacteria [61]. These bioactive molecules are the primary source of antibiotics in the pharmaceutical industry [62].
3.2 Barrier maintenance
Gut microbiota regulates the strength of the intestinal barrier and sequesters themselves within the intestine. For example, the mucus layer is an important deterrent for many pathogenic microorganisms to reach the underlying epithelial cells. Mucus production is enhanced when a germ-free mice epithelium is exposed to some bacterial products [63], which means that an intact microbiota is essential to maintain the required thickness of the mucosal layer to keep pathogenic microorganism at bay. Diet can also influence the thickness of the mucosal layer. An assessment of intestinal microbiota localization with immunofluorescence shows that the absence of microbiota-accessible carbohydrates in the diet resulted in a thinner mucosal layer, thus exposing the underlying epithelial cells to pathogenic organisms [64]. The thinning of the mucosal layer made mouse susceptible to colitis.
3.3 Immune maturation and inflammation
A healthy microbiota is essential for a healthy immune system. Almost one and half decades ago, it was observed that microbial products secreted from the microbiota induced the colonic immune system by activating anti-inflammatory cells and cytokines. In 2005, a polysaccharide from Bacteroides fragilis, an important member of the gut microbiota, was shown to be important in the cellular and physical maturation of a developing immune system [51]. Perhaps, the most immunologically characterized bacterial metabolite synthesized by the microbiota is the Short Chain Fatty Acid (SCFA). In 2009, it was shown that SCFA directly bind G-protein-coupled receptor (GPR43) and activated immune responses [65]. Butyrate is the most characterized SCFA. Butyrate was shown to induce the differentiation of colonic regulatory T cells (Treg) cells in mice. A comparative NMR-based metabolome analysis showed that the concentration luminal butyrate correlated with the number of Treg cells in the colon [52]. Treg cells expressing transcription factor Foxp3 are also important in regulating intestinal inflammation. It was also found that SCFA plays an important role in regulating the function and the size of the colonic Treg pool [53].
Microbes can also directly activate the colonic immune system. Segmented filamentous bacterium (SFB) from the microbiota was shown to adhere tightly to epithelial cells of the terminal ileum with Th17 cells, and this adherence correlated with the induction of inflammatory/antimicrobial defense genes [66]. More recently, bacteria in human feces were subjected to selection based on their potential to induce anti-inflammatory T regulatory cells. It was found that bacteria belonging to cluster XIVa clostridial group induced anti-inflammatory T regulatory cells along with bacteroides species [67, 68]. Gut microbiota can also activate the expression of bacterial C-type lectins in intestinal epithelial cells. The lectin, RegIIIγ, is essential to create a 50-μm clearance zone between the gut microbiota and small intestinal epithelial cells. Abrogation of the RegIIIγ synthesis increased the proximity of gut microbiota to the epithelial cells [69]. This shows that microbiota-activated lectin synthesis can directly act to suppress bacterial activity. In addition, gut microbiota can also enhance systemic antiviral activity [70]. Therefore, it is very important to maintain a healthy microbiota to drive efficient pro-inflammatory and anti-inflammatory immune responses in the host.
Simple alterations to the gut microbiota can often lead to very unhealthy consequences. For example, in the esophagus, the composition of the microbiome is heavily dependent on the microbes originating from the oral cavity and is dominated by Streptococcus, Prevotella, Veillonella, and Fusobacterium [71, 72, 73]. Any alteration to the microbiota composition could lead to inflammation and tumorigenesis. Such altered microbiota compositions were consistent with conditions like gastro-esophageal reflux disease (GERD), Barrett’s esophagus (BE), and adenocarcinoma of the gastro-esophageal (GE) junction. Here, Streptococcus were found to be depleted while Veillonella, Prevotella, Campylobacter, Fusobacterium, Haemophilus, and Neisseria were enriched [74, 75]. Certain taxa present in the oral cavity like Campylobacter concisus and Campylobacter rectus were found to be enriched in the diseased mucosa-associated with GERD and BE [76, 77]. Similarly, for eosinophilic esophagitis (EoE), increased levels of Neisseria, Corynebacterium, and Haemophilus are reported [78].
The most important stomach associated bacterium is H. pylori. H. pylori has symbiotically co-evolved with humans and therefore are highly adapted to humans [79]. Early life time infection of H. pylori is beneficial for humans because it significantly lowers the risk of asthma in later years [80]. This beneficial association is brought about by the immune system modulation by the bacterium due to the high induction of regulatory T cells. The bacterium therefore qualifies for the position of a pathobiont -host determines whether the bacteria remains as a harmless symbiont or becomes pathogenic in nature. In a diseased condition of the host, the bacterium outcompetes the normal microbiota in numbers and becomes the most dominant pathogen.
Sampling the fecal material represents the colonic microbial population. However, sampling the small intestine is difficult because it is accessible only by invasive sampling. The small intestine is populated by distinct microbial communities that are less diverse and are dominated by Veillonella, Streptococcus, Lactobacillus, and Clostridium [81, 82, 83]. In the small intestine, alterations in the microbiome are associated with celiac disease (CeD). Gut microbiota is able to differentially degrade gluten. In CeD patients, there is an over growth of an opportunistic pathogen Pseudomonas aeruginosa producing a elastase called LasB. This enzyme degrades gluten and releases peptides that translocate the intestinal barrier, triggering a T-cell response [84]. A small-intestine-associated autoimmune disease where microbiome plays an important role is graft versus host disease (GvHD)—caused by the activation of T cells where host cells are recognized as antigens cause autoimmune attacks in the GI tract, liver, lung, and skin [85]. Germ-free mice had less propensity to develop GvHD—this led to the thought that microbiome could play an important role [86, 87, 88]. Loss of microbiome diversity and consequent butyrate deprivation pushed cells to apoptosis bearing hallmark histological signs associated with GvHD. An overabundance of Enterococcus (E. faecium and E. faecalis) was observed in patients with GvHD associated with hematopoietic stem cell transfer confirming the association of GvHD with alteration in the microbiome diversity [89].
3.4 Antibiotic-associated colitis
Antibiotics considered as “wonder drugs” were implemented into therapy years before and have saved millions of lives. Even though antibiotics can reduce morbidity and mortality associated with bacterial illness, no antibiotic is pathogen selective. The application of antibiotics lead to collateral damage of accompanying microorganisms in a population, for example in a microbiota. Studies investigating the impact of antibiotics on microbiota confirm that antibiotic treatment increases the susceptibility of an individual to bacterial pathogens by compromising colonization resistance [90, 91, 92, 93].
The observation that antibiotic therapy reduced colonization resistance making the host susceptible to bacterial infections was observed very early in the literature [56, 57, 58, 59]. Gut microbial compositional analysis of an antibiotic-treated mice showed the expansion of γ-proteobacteria and enterococci, suggesting that gut microbiota somehow suppressed the expansion of oxygen-tolerant species [94, 95]. A study on healthy volunteers treated for a week or less with antibiotics reported persistent effects on their bacterial flora that included a loss of biodiversity on the gut flora, insurgence of antibiotic resistance strains, and upregulation of antibiotic resistance genes [96]. Antibiotic treatment can also induce long-term defects in the microbiota. For example, a single dose of clindamycin induced long-term susceptibility to Clostridium difficile infection [92]. A prior treatment with antibiotics not only disturbed the gut microbiota enabling the expansion of pathogenic commensals but also helped exogenic bacterial pathogens to establish inside the gut. When antibiotic-treated mice was infected with vancomycin-resistant Enterococci (VRE), the bacteria displaced the whole normal microbiota of the small and large intestine. In the clinical setting, this initial domination by the VRE preceded the bloodstream infections in patients undergoing hematopoietic stem cell transplant [91].
Microbiota establishes itself very early in the life cycle of every human, and this development is very crucial for a healthy lifestyle [97]. So, administration of antibiotics in the early stages of life predisposes the individual to diseases in late infancy or adulthood, particularly allergic or metabolic syndromes [28]. Antibiotic exposed prenatal mice resulted in exacerbated asthma following intranasal challenge with ovalbumin [98]. This case is true in children who are administered with antibiotics in the first year of life and may develop asthma during sixth or the seventh year [99]. Early use of marcolids in Finnish children led to the development of asthma and increased BMI associated with a dysbiotic gut microbiota [100]. Effects of antibiotic administration in early life are not limited to development of asthma alone but also to obesity. A low dose of penicillin delivered at birth transiently shifted the microbiota, and this transient shift induced sustained effects in body composition, leading to obesity [101]. All these reports emphasize the detrimental microbiota-associated effects of antibiotics and their implications in health.
Clostridium difficile is perhaps the most characterized pathogen associated with antibiotic associated colitis [102]. With >25,000 annual cases worldwide, C. difficile colitis is almost always associated with prior antibiotic use. The suspicion that microbiota-mediated colonization resistance resisted C. difficile in the gut was finally proven in 2013 [103]. 16S rDNA sequencing alone could distinguish between C. difficile-associated diarrhea and C. difficile-negative diarrhea [104]. Antibiotic treatment reduces secondary bile salt production making the host susceptible to C. difficile infection [105, 106]. Apart from C. difficile, Klebsiella oxytoca also caused antibiotic-associated hemorrhagic colitis (AAHC)—a patchy hemorrhagic colitis usually observed after penicillin therapy typically dominating the right colon. Here, the pathogen is intrinsically resistant to β-lactams and the production of enterotoxin tilivalline can lead to intestinal epithelial apoptosis and colitis [107, 108]. Antibiotic-treated mice had impaired innate and adaptive antiviral immune response, and when the mucosa was exposed to influenza virus, the clearance was substantially delayed. On the other hand, these mice had severe bronchiole epithelial degeneration and increased host mortality when exposed to influenza. This is due to the macrophages from an antibiotic-treated mice had decreased expression of genes associated with antiviral immunity [70].
3.5 Inflammatory bowel disease (IBD)
IBD perhaps is the first diseased condition where alterations in microbiota are studied most extensively. IBD is a term mainly used to describe two disease conditions—Crohn’s disease and ulcerative colitis. Here, intestinal cells play an important role in integrating the interactions among intestinal microbiota, mucosal immune system, and environmental factors [109]. It was observed very early that IBD conditions had a genetic component—there was a 10-fold increase in risk if related closely to the patient [110]. Genome-wide association studies (GWAS) reported many genetic factors that are associated with IBD [111]. As more GWAS based studies began identifying genetic factors associated with IBD, it was soon noted that some IBD genetic factors were also associated with other disease conditions like diabetes [112]. Curiously, GWAS and meta-analysis identified considerable overlap between susceptibility loci for IBD and mycobacterial infections [113]. The genetic associations notwithstanding, alterations in the gut microbiome of IBD patients have always been an interesting topic for microbiome researchers. The most significant alteration in the composition of the gut microbiome associated with IBD is the reduction in the abundance of the protective bacterium Faecalibacterium prausnitzii [114]. However, patterns of gut microbiota dysbiosis was not consistent across different studies. In a large cohort study involving more than 400 pediatric cases, multiple samples obtained from multiple locations of the GI tract before and after the onset of Crohn’s disease were analyzed. Increased abundance of Enterobacteriaceae, Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae and decreased abundance of Erysipelotrichales, Bacteroidales, and Clostridiales were found to be strongly consistent with the diseased condition. Oddly enough, there seems to be prevalence of oral bacteria in IBD and Crohn’s disease patients. For example, the prevalence of oral and stomach-associated C. concisus was very high in both diseased conditions [115]. Furthermore, another Gram-negative oral bacteria Fusobacterium nucleatum was found to be abundant in Crohn’s disease [116]. F. nucleatum was shown to be highly proinflammatory and protumorigenic [117, 118, 119]. The bacterium can activate the epithelial cell proliferation and induce a protomeric microenvironment, while inactivating the immunological tumor surveillance.
3.6 Colorectal cancers (CRC)
CRC is the fourth leading causes of death causing cancer and is the third important cause of malignancy. The CRC incidence is growing fast worldwide in low and middle east countries and is expected to increase by 60% by 2030 worldwide [120]. The transformation from a healthy epithelial cell to a malignant cell requires three steps: (1) induction of oncogenic mutations within Lgr5+ intestinal stem cells, (2) altered β-catenin/Wnt signaling, and (3) proinflammatory cascades such as TNFα-NFκB and IL16-STAT3 catalyzing CRC development (Garret 2015 EN). Initially, there was increasing evidence about the role of bacteria in CRC. Bacteria such as Fusobacterium nucleatum, E. coli, and Bacteroides fragilis were shown to be associated with CRC [117, 121]. F. nucleatum was first shown to be highly enriched in tumors [117, 122]. The bacterium produces the FadA antigen, a ligand of E-cadherin in the intestinal epithelial cells that activate the β-catenin pathway leading to uncontrolled cell growth [119]. Furthermore, F. nucleatum is shown to be overrepresented in the colonic mucosa in the cases where the CRC relapses postchemotherapy. This was shown to be an interplay of intricate mechanisms including TLRs, miRNAs, and autophagy induction [123]. Some strains of E. coli harbor the polyketide synthase (pks) island encoding colibactin, capable of inducing DNA damage and mutation in epithelial cells [121]. A metagenome-wide association study on stools collected from patients with advanced adenomas, CRC, and healthy controls identified that certain Bacteroides species (B. dorei, B. vulgaris, B. massiliensis) and E. coli were overrepresented in the microbiome. Similarly, Parvimonas, Bilophila wadsworthia, Fusobacterium nucleatum, and Alistipes spp. were also overrepresented, suggesting that the gut microbiome signature can be used for early diagnosis and treatment [124].
4. The therapeutic potential of the gut microbiota
Humans have used live bacteria, particularly probiotic bacteria, for therapeutic purposes from time immemorial. We have seen some examples in earlier sections of this chapter. Perhaps, the best example of using live bacteria to cure infectious disease comes from antibiotic-associated CDI illness. Clostridium scindens, an obligate anaerobic bacterial species that inhabits the colon, has the rare ability to convert primary bile salts to secondary bile salts and is highly associated with resistance to C. difficile colitis [125]. Administration of C. scindens to susceptible mice resuscitated the secondary bile salt deficiency and rendered the animal more resistant to CDI. C. scindens and C. difficile have a negative correlation-could be the reason for C. difficile resistance in a healthy human gut microbiota [105]. However, the clinical benefit of using a single bacteria is limited. This is because, as we have seen earlier, many of the disorders are caused by a dysbiotic microbiota. Since a microbiota is very diverse in nature, resuscitation of a healthy gut microbiota cannot be achieved by the administration of a single bacterium. The concept of “putting back the bugs” was demonstrated in 1993 by using a combination of probiotic strains to cure chronic constipations and IBS [126]. Even with CDI, a cocktail of 10 gut commensal bacteria including obligate anaerobes could effect a cure [127]. Since then, many experiments have shown that by replenishing the healthy composition of a normal microbiota, many disease conditions can be controlled. Therefore targeting gut microbiota has gathered much attention and many options are currently being evaluated to achieve this goal of re-establishing the healthy gut microbiota to regain health—leading to the concept of fecal microbiota transplant (FMT).
FMT is the procedure where fecal matter is collected from a tested donor, diluted in an isotonic solution, strained, and transplanted into the patient using colonoscopy, endoscopy, sigmoidoscopy, or enema. The history of using stool of healthy donors to treat human diseases dates back to the fourth century in China, during the Dong Jin dynasty (AD 300–400 years) [128]. Fecal suspensions or “yellow soup” was used to treat serious disorders such as food poisoning, febrile disease, typhoid fever, etc., becoming the first record of the utilization of human feces to treat human diseases. There are striking similarities between the earlier yellow soup and modern day FMT technology—(1) the inoculum originated from human fecal matter, (2) administration route is digestive tract, and (3) the fecal matter re-establishes the microbiota thereby treating the disease. This long tradition might be the reason why FMT is so well accepted in China [129]. In Europe, the first report of using fecal enema to treat pseudomembranous colitis came in 1958 [130]. Currently, FMT stands in the threshold of becoming a great technology to cure many disorders considered incurable in the past.
4.1 In treating diseases associated with gut microbiota-associated dysbiosis
CDI perhaps was the first condition in which a treatment was attempted using FMT. In 1983, it was shown that by re-establishing the healthy gut microbiota using FMT, mitigation of CDI can be achieved (Schwan 1983 EN). Severe CDI cases can lead to intensive care admission, sepsis, toxic megacolon, and can prove fatal. Colectomy is the standard method of treatment, but the mortality rate is 50%. In a study involving 29 patients who underwent FMT plus vancomycin for severe CDI cases, 62% of the patients were cured in a single FMT, while 38% needed multiple FMTs. Taken together, FMT was highly efficient for CDI infections [131]. The primary and secondary cure rates with FMT using fresh fecal sample to cure CDI is 91 and 98% [132]. FMT from frozen fecal sample also gave similar efficacies in treating CDI [133, 134]. By 2013, FMT was made officially the treatment strategy for CDI [103, 135]. Many pharmaceutical firms are actively working to bring easily consumable CDI-targeted drugs based on FMT. A defined microbial ecosystem therapeutics (MET-1 or RePOOPulate) was developed to cure recurrent CDI [136, 137]. The closest enema-based drug that is awaiting clinical approval is RBX2660, which depends upon the microbial suspension provided from the donor and is formulated for therapeutic delivery. With positive results in phase 2, the drug is currently in phase 3.
Similar to CDI, IBD is also a dysbiotic-associated disease where FMT is a potential therapy. However, in IBD, the use of FMT is a bit complicated and less efficient than in CDI. Early studies using FMT to treat IBD showed very promising result with good microbiota remission reported over long-term follow up [138]. With years, the outcomes started to differ depending upon sample size, treatment approaches, and study designs [139]. Even within IBD patients, remission rates were different. Crohn’s disease had a higher remission of 61%, while ulcerative colitis patients had a remission rate of 22%. It is clear that the FMT treatment for IBD is complicated by numerous factors like differences in treatment regimens, stool preparation/formulation, and dosing frequencies. Varied levels of dysbiosis and difference in the microbiota composition between donor and patient also complicate FMT treatments. However, it was reported that FMT with intensive doses and multiple donors induced clinical remission and endoscopic improvement in ulcerative colitis patients, and this treatment had distinctive improvements in the microbiota composition [140]. It was also shown that a second FMT 3 months past the first one greatly improved the efficacy and safety in treating IBD with FMT [141, 142]. Here, the patients received FMT repeatedly in 3 month intervals—in a procedure called step-up FMT. The efficacy of the procedure increased at each step and was best suggested for patients with refractory IBD and immune-related diseases [143, 144]. There are currently 27 ongoing clinical trials using FMT targeting IBD with two additional trials on children with IBD [145].
Cancers like colorectal cancers that are associated with a dysbiotic microbiome opening the possibility for a therapeutic intervention using FMT. It was shown that bacteria like Enterococcus hirae and Barnesiella intestinihominis strengthen cyclophosphamide-induced therapeutic immunomodulatory effects in cancer [146]. This has been highlighted very recently with evidence that microbiome influences with body’s ability to respond to antibody therapy for cancers [147, 148]. A correlation was observed between commensal microbial composition and clinical response to anti-PD-L1 therapy through abundance of bacterial species like Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium [149]. When fecal matter from responding patients were transplanted to germ-free mice, the animals were noted with stronger tumor control, augmented T cell responses, and better efficacy [150]. Gut microbiota could also affect anticancer responses with CTLA-4 [151]. The effects of radiation in gut microbiota and the clinical implications of a modified microbial balance postradiotherapy are now being investigated [152]. The microbiota can be modified to improve its efficacy and reduce the toxic burden of these treatments [153]. FMT can be used to reduce the radiation-induced toxicity and the increase the survival rate in irradiated mice. Here, the WBCs, GI tract function, and intestinal epithelial cell integrity were improved [154]. The research advances notwithstanding, therapeutic approaches associated with FMT is still in its nascent stage. However, considerable progress made in this area of research indicate that the application of FMT based therapy to mitigate mortality associated with diseases like cancer is a near possibility.
FMT is also showing great promise in patients undergoing hematopoietic stem cell transplantation surgery. Administration of a series of prophylactic antibiotics during surgery can result in the loss of microbial gut diversity and antibiotic resistant strains like Streptococcus viridans, Enterococcus faecium, and other Enterobacteriaceae can expand their population in the gut. This loss of microbial diversity during stem cell transplantation is associated with marked increase in mortality [91, 155, 156]. Restoration of a healthy microbiota by eliminating the dominant pathogenic microorganisms therefore becomes very important strategy from a therapeutic point of view. FMT involving a consortium of obligate anaerobic commensal bacteria containing especially Barnesiella is shown to eliminate E. faecium in mice [157], opening up a new therapeutic approach for stem cell transplant patients.
4.2 Collection, preparation, and delivery of FMT samples
Collection and preservation of the stool samples carry the primary importance in FMT. Freshly collected feces can either be immediately used, lyophilized, or cryopreserved. The efficacy of FMT in treating CDI using fresh or frozen feces varied but not significantly [158]. The cure rate was 100% in patients receiving fresh feces, 83% for the lyophilized group, and 78% for patients receiving frozen feces. But the efficacy was more pronounced in treating IBD, and this was demonstrated to be caused due to loss of bacteria in frozen feces [143]. The laboratory preparation methods of FMT is also critical for the success of FMT. Recent studies have reported that some preparation methods can stress the living microbial cells affecting the efficacy of FMT [159] emphasizing the need for extreme care. For example, Faecalibacterium prausnitzii is affected when the fecal sample is exposed to oxygen. Currently, the preparation methods can be classified into “rough filtration” (RF), “filtration plus centrifugation” (FPC), and “microfiltration plus centrifugation” (MPC) [141, 142]. Manual preparation methods takes about 6 hours to complete [160]. With the introduction of automated systems and close cooperation between laboratory scientists and clinicians, the time period of preparation from “defecation to freezing” has been shortened to 1 hour [160]—has effectively increased the efficacy of FMT when tested against IBD patients [143]. Current FMT delivery technologies include delivery of the microbiota to upper, mid, and the lower gut [161]. Oral intake of capsular microbiota delivers it to the upper gut [134, 162]. A suspension of microbiota infusion can be transferred to the small intestine beyond the second duodenal segment through endoscopy [163], nasojejunal tube [143], mid-gut transendoscopic enteral tubing (TET) [164], and percutaneous endoscopic gastro-jejunostomy (PEG-J) [161]. The TET procedure for microbiota transplant is considered very successful [164]. Delivery of microbiota to the lower gut could be through colonoscopy, enema, distal ileum stoma, colostomy, and colonic TET [161]. Colonic TET is recommended for patients needing frequent FMT.
Several groups are developing stool products that can be packaged, transported, commercialized, and easily administered by physicians or consumed by patients. These products range from basic (frozen or freeze-dried stool) to more advanced products like capsules of synthetic stool grown in culture and assembled. The most basic products, from stool banks like OpenBiome and Advancing Bio, provide hospitals with screened frozen material ready for clinical use. More advanced are products like RBX2660, a cryopreserved filtered microbiota derived from stool of selected donors and administered via an enema system. The most advanced is a lyophilized powder that can be reconstituted by rectal infusions developed by CIPAC Therapeutics.
4.3 Precision microbiome reconstitution
The lack of regulatory protocol and stiff resistance from clinicians treating chronically ill patients has dampened efforts to introduce FMT as a viable therapy. This led to the development of the concept of “precision microbiome reconstitution,” where a single bacterium can be used to restore colonization resistance in C. difficile patients [105]—providing a more targeted approach where a consortia of specific bacterial strains are identified to treat a particular diseased condition, and this will enable greater specificity and quality control. In germ-free mice, a murine isolate belonging to the family Lachnospiraceae partially restored colonization resistance against C. difficile [165]. An elaborate study using mouse models, clinical studies, metagenomic analysis, and mathematical modeling identified C. scindens as an intestinal bacterium associated with resistance to C. difficile. C. scindens produces growth inhibitory or spore germination inhibitory secondary bile acids to inhibit C. difficile. Furthermore, colonic induction of anti-inflammatory T regulatory cells can be used to develop immunity against dysbiotic conditions. A community of 17 strains including C. scindens induced the development of anti-inflammatory T regulatory cells, and this reduced colitis [67]. They also identified that the concentration of short-chain fatty acids increased upon the colonization of these 17 isolates. The fact that short-chain fatty acids modulated a Treg cell response suggested a common pathway by which different microbes modulated an induction of Treg cells. This opportunity was utilized to identify many more strains mostly belonging to bacteroides that are capable to induce an immune response that can restore colonization resistance from a dysbiotic condition [68]. However, even though a single strain may be able to resist a single organism of interest, a community of organisms reflecting the diversity of microbiota might be needed to restore baseline colonization resistance. This specific targeted approach is used by pharmaceutical firms to develop targeted drugs—for example, Seres Therapeutics is developing SER-109—comprising bacterial spores enriched and purified from healthy stool and packaged into capsules. The product can restructure a dysbiotic gut to a healthy microbiome. Vedanta Biosciences are identifying and developing bacterial strains that can suppress chronic gut inflammation. Similarly, a microbial assemblage derived from stool and grown in culture called RePOOPulate has been developed to treat CDI infections.
4.4 The importance of SAFE FMT
Safety of the patient should be of prime importance when an FMT procedure is considered, especially if the patient is having a poor immune status [166, 167]. Middle gut FMT procedures can cause vomiting and aspiration [168]. The nasojejunal tube could put the patient at high risk of aspiration and should be conducted with anesthesia [143]. There is enough evidence that the long-term safety of the patient should be considered as well. Generally, a tested donor fecal sample is used for FMT. However, this carries the disadvantage that unwanted or potentially pathogenic bacterial phenotypes maybe carried from donors to recipients. A particular case was reported where the patient developed new onset obesity after obtaining a stool sample from a heterologous donor [169]. Using the patient’s own stool sample can avoid the problems associated with donor stool samples. Here, a fecal sample of the patient is banked in the hospital before any procedure that requires antibiotic treatment. The banked sample may provide the vital resource to avoid hospital-acquired infections and to replenish the patient’s own microbiota. Preservation of the patient’s own or donor feces pose a second challenge [170]. There are reports that fecal matter from patients with colon cancer promoted tumorigenesis in germ-free and carcinogenic mice. Potential cardiometabolic, autoimmune, and neurological disease also have been discussed. All these points to the tough screening and regulations are needed before a donor is selected for fecal sample prior FMT.
However, recent reports suggest that FMT is gaining wide acceptance among patients. A survey showed that among patients of Crohn’s disease who received FMT, 56% showed satisfactory clinical efficacy, 74% showed willingness for a second FMT, and 89% expressed willingness to recommend FMT to other patients [171]. Also, the cost efficacy of FMT has been demonstrated worldwide [172, 173, 174, 175, 176, 177]. FMT is still very far from being implemented into routine therapy. The technique needs to undergo rigorous process of standardization before the therapy becomes applied in daily practice. Nevertheless the importance of gut microbiota in maintenance of a healthy lifestyle is demonstrated without doubt. In future therapeutic approaches including antibiotic therapy should take into consideration the impact it has on the gut microbiota and the clinicians should be mindful of the impact of the devastating secondary effects of these therapeutic approaches on the patient.
\n',keywords:"microbiome, microbiota, gut, antibiotic, IBD, FMT",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64638.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64638.xml",downloadPdfUrl:"/chapter/pdf-download/64638",previewPdfUrl:"/chapter/pdf-preview/64638",totalDownloads:931,totalViews:79,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:46,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"April 9th 2018",dateReviewed:"August 13th 2018",datePrePublished:"December 4th 2018",datePublished:"June 5th 2019",dateFinished:"December 4th 2018",readingETA:"0",abstract:"The gut microbiota is made up of trillion microorganisms comprising bacteria, archaea, and eukaryota living in an intimate relationship with the host. This is a highly diverse microbial community and is essentially an open ecosystem despite being deeply embedded in the human body. The gut microbiome is continually exposed to allochthonous bacteria that primarily originates from food intake. Comprising more than 1000 bacterial species, the gut microbiota endows so many different functions—so many that can be considered as an endocrine organ of its own. In this book chapter, we summarize the importance of gut microbiota in the development and maintenance of a healthy human body. We first describe how the gut microbiota is formed during the birth of a human baby and how a healthy microflora is established overtime. We also discuss how important it is to maintain the microbiota in its homeostatic condition. A discussion is also given on how alterations in the microbiota are characteristic of many diseased conditions. Recent investigations report that reestablishing a healthy microbiota in a diseased individual using fecal microbial transplant can be used as a therapeutic approach in curing many diseases. We conclude this chapter with a detailed discussion on fecal microbial transplants.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64638",risUrl:"/chapter/ris/64638",book:{id:"7534",slug:"role-of-microbes-in-human-health-and-diseases"},signatures:"Shabarinath Srikumar and Séamus Fanning",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Our internal garden—on how gut microbiota is planted and nurtured",level:"1"},{id:"sec_2_2",title:"2.1 The initial colonization",level:"2"},{id:"sec_3_2",title:"2.2 Development of the microbiota",level:"2"},{id:"sec_5",title:"3. Maintain the flora!—on how any alterations could be disastrous",level:"1"},{id:"sec_5_2",title:"3.1 Direct inhibition",level:"2"},{id:"sec_6_2",title:"3.2 Barrier maintenance",level:"2"},{id:"sec_7_2",title:"3.3 Immune maturation and inflammation",level:"2"},{id:"sec_8_2",title:"3.4 Antibiotic-associated colitis",level:"2"},{id:"sec_9_2",title:"3.5 Inflammatory bowel disease (IBD)",level:"2"},{id:"sec_10_2",title:"3.6 Colorectal cancers (CRC)",level:"2"},{id:"sec_12",title:"4. The therapeutic potential of the gut microbiota",level:"1"},{id:"sec_12_2",title:"4.1 In treating diseases associated with gut microbiota-associated dysbiosis",level:"2"},{id:"sec_13_2",title:"4.2 Collection, preparation, and delivery of FMT samples",level:"2"},{id:"sec_14_2",title:"4.3 Precision microbiome reconstitution",level:"2"},{id:"sec_15_2",title:"4.4 The importance of SAFE FMT",level:"2"}],chapterReferences:[{id:"B1",body:'Human Microbiome Project C. A framework for human microbiome research. 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Randomised clinical trial: Faecal microbiota transplantation for recurrent Clostridum difficile infection—Fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Alimentary Pharmacology & Therapeutics. 2017;45(7):899-908'},{id:"B159",body:'Chu ND, Smith MB, Perrotta AR, Kassam Z, Alm EJ. Profiling living bacteria informs preparation of fecal microbiota transplantations. PLoS One. 2017;12(1):e0170922'},{id:"B160",body:'Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569-580'},{id:"B161",body:'Peng Z, Xiang J, He Z, Zhang T, Xu L, Cui B, et al. Colonic transendoscopic enteral tubing: A novel way of transplanting fecal microbiota. Endoscopy International Open. 2016;4(6):E610-E613'},{id:"B162",body:'Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312(17):1772-1778'},{id:"B163",body:'Zhang F, Amateau SK, Khashab MA, Okolo PI 3rd. Mid-gut stents. Current Opinion in Gastroenterology. 2012;28(5):451-460'},{id:"B164",body:'Long C, Yu Y, Cui B, Jagessar SAR, Zhang J, Ji G, et al. A novel quick transendoscopic enteral tubing in mid-gut: Technique and training with video. BMC Gastroenterology. 2018;18(1):37'},{id:"B165",body:'Reeves AE, Koenigsknecht MJ, Bergin IL, Young VB. Suppression of Clostridium difficile in the gastrointestinal tracts of germfree mice inoculated with a murine isolate from the family Lachnospiraceae. Infection and Immunity. 2012;80(11):3786-3794'},{id:"B166",body:'Fischer M, Kao D, Mehta SR, Martin T, Dimitry J, Keshteli AH, et al. Predictors of early failure after fecal microbiota transplantation for the therapy of Clostridium difficile infection: A multicenter study. The American Journal of Gastroenterology. 2016;111(7):1024-1031'},{id:"B167",body:'Fischer M, Kao D, Kelly C, Kuchipudi A, Jafri SM, Blumenkehl M, et al. Fecal microbiota transplantation is safe and efficacious for recurrent or refractory Clostridium difficile infection in patients with inflammatory bowel disease. Inflammatory Bowel Diseases. 2016;22(10):2402-2409'},{id:"B168",body:'Gweon TG, Kim J, Lim CH, Park JM, Lee DG, Lee IS, et al. Fecal microbiota transplantation using upper gastrointestinal tract for the treatment of refractory or severe complicated clostridium difficile infection in elderly patients in poor medical condition: The first study in an Asian country. Gastroenterology Research and Practice. 2016;2016:2687605'},{id:"B169",body:'Alang N, Kelly CR. Weight gain after fecal microbiota transplantation. Open Forum Infectious Diseases. 2015;2(1):ofv004'},{id:"B170",body:'Hale VL, Tan CL, Niu K, Yang Y, Cui D, Zhao H, et al. Effects of field conditions on fecal microbiota. Journal of Microbiological Methods. 2016;130:180-188'},{id:"B171",body:'Xu L, Zhang T, Cui B, He Z, Xiang J, Long C, et al. Clinical efficacy maintains patients\' positive attitudes toward fecal microbiota transplantation. Medicine (Baltimore). 2016;95(30):e4055'},{id:"B172",body:'Konijeti GG, Sauk J, Shrime MG, Gupta M, Ananthakrishnan AN. Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: A decision analysis. Clinical Infectious Diseases. 2014;58(11):1507-1514'},{id:"B173",body:'Varier RU, Biltaji E, Smith KJ, Roberts MS, Kyle Jensen M, LaFleur J, et al. Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection. Infection Control and Hospital Epidemiology. 2015;36(4):438-444'},{id:"B174",body:'Waye A, Atkins K, Kao D. Cost averted with timely fecal microbiota transplantation in the management of recurrent Clostridium difficile infection in Alberta, Canada. Journal of Clinical Gastroenterology. 2016;50(9):747-753'},{id:"B175",body:'Merlo G, Graves N, Brain D, Connelly LB. Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia. Journal of Gastroenterology and Hepatology. 2016;31(12):1927-1932'},{id:"B176",body:'Baro E, Galperine T, Denies F, Lannoy D, Lenne X, Odou P, et al. Cost-effectiveness analysis of five competing strategies for the management of multiple recurrent community-onset Clostridium difficile infection in France. PLoS One. 2017;12(1):e0170258'},{id:"B177",body:'Zhang T, Xiang J, Cui B, He Z, Li P, Chen H, et al. Cost-effectiveness analysis of fecal microbiota transplantation for inflammatory bowel disease. Oncotarget. 2017;8(51):88894-88903'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Shabarinath Srikumar",address:"srikumar.shabarinath@ucd.ie",affiliation:'
UCD-Centre for Food Safety, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Ireland
UCD-Centre for Food Safety, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Ireland
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1. Introduction
Medicine is born from the human need to survive to diseases. At first, someone within the tribe began to realize the constellation of symptoms and signs that defined the diagnosis, for which a proper treatment could make the difference in the course of the disease. The so-defined medical act gave him the mastery over life and death. The awareness of this power has given rise to a set of self-regulating norms, early transmitted to the disciples who applied to learn the noble art of healing. This ethical code became known as the Hippocratic oath of the School of Kos, in honor to Hippocrates, the father of scientific medicine, known for having received himself the knowledge from the hands of Asclepius the Greek god of medicine [1].
Based on a solid knowledge derived from the scientific method, medicine commits itself to the patient and society in simple but basic principles of beneficence, non-maleficence, justice, truth, confidentiality, and respect for the human being. This commitment should be enough to ensure unblemished medical practice, both in the care and, no less important, in the research and experimentation.
But the twentieth century and the horrors exposed by the Holocaust of the Second Great War came to demonstrate that it was not enough.
On August 8, 1945, the countries that formed the Allied Forces in World War II signed the constitution agreement of the International Military Tribunal, to prosecute the Nazi officers on charges of committing peace crimes, war crimes, and crimes against humanity (Control Council Law No. 10: Punishment of persons guilty of war crimes, crimes against peace and humanity). The initial trial in the city of Nuremberg, Germany, was followed by 12 other trials until 1949. The first of these trials became known as the medical case and resulted in the conviction of 16 of the 23 defendants for their involvement, among others, in research projects (high-altitude experiments; freezing experiments; malaria experiments; mustard gas experiments; sulfanilamide experiments; bone, muscle, and nerve regeneration experiments; bone transplantation experiments; seawater experiments; epidemic hepatitis experiments; sterilization experiments; vaccination experiments for yellow fever, smallpox, typhus and other rickettsiosis, paratyphoid A and B, cholera, and diphtheria; poison experiments; and incendiary bomb experiments) [2].
The question wasn’t the possibility of conducting research in human beings but the way and circumstances under which it was done. This court had to define what were the permissible medical experiments, in accordance with ethics, morals, and law. The 10 principles emanating from this court formed the first code of ethical appreciation for research involving humans [2], later developed and extended in its application by the World Medical Association’s Declaration of Helsinki (1964) [3]. Nevertheless, ethical evaluation was still a commitment of the investigators. The case of Tuskegee, USA, syphilis experience (1932–1972) has warned of the need for direct follow-up and the establishment of independent committees able to ensure the appraisal, evaluation, and guidance of research protocols, as proposed by the following Belmont Report [4]. The increasing complexity of ethical problems with the advance of knowledge has dictated the structuring of responses at the national level. In 1983, in France, President François Mitterrand established the “Consultatif National d’Ethique Committee,” the first ethics committee for health and life sciences, with the mission to opine on ethical and social problems arising from progress in the fields of biology, medicine, and health. The increased specificity of experimental research in the new treatments has led to the establishment of research ethics committees with the highest technical capacity to fulfill their mission (US Institutional Review Boards, and the Ethics Committees for Clinical Research in Europe).
2. The ethical principle
The ethics committees are now multidisciplinary boards, including medicine, nursing, social work, law, pastoral care, healthcare administration, and various specialty areas. Their role includes the ethics education, policy formation and review, ethics consultation, and research ethics [5]. In clinical investigation, every protocol must be submitted previously to the beginning of the study for consideration, comment, guidance, and approval. The ethics committees must be independent of the researcher, the promoter, and the sponsor and transparent in their function [6].
The ethics committees for health, especially in the context of clinical research, are thus born not from an internalization of the need for self-regulation but from an external, regulatory, and legal imposition. Since the beginning, they assume a problem-solving police nature that they rarely escape, as their mission includes the laws and regulations as well as applicable international norms and standards. It is common that the ethics committees focus much attention on legal and procedural aspects, answering to this feature, more than applying an individualistic appraisal of the factual project. Consequently, the researchers look at them more as obstacles to the execution of projects than as partners in their implementation.
Ethic must be above the law, respecting it, but discussing it and framing it towards the specific case [7], keeping in mind the protection of the human being. The primacy of ethics, which compromises us all, is certainly not the primacy of the ethics committees, as if they were the exclusive holders of the absolute truth, or its juridical version. The ethical appraisals must return to the Hippocratic matrix of the basic ethical principles to find their guiding path, combining the need for innovation and development in health, through research strategies, with respect for the human being in his or her dignity and vulnerability, in health or in illness, in the daily care they need, or in participating in a research project.
The ethical principles were defined in 1971 by Thomas Beauchamp and James Childress [8]. Beneficence, non-maleficence, justice, and autonomy had become the basis of bioethical decision-making in the last 50 years. Despite the heated discussion about their interpretation, importance, and role of each one, they remain the most internationally accepted. Nevertheless, there’s some controversy about their inability to answer to all the challenges posed by the complexity of current biomedical decisions.
The same principles were adopted by clinical research as a key for ethical evaluation, ensuring the protection of the rights of participants. But there are several differences in their application.
Beneficence refers to the promotion of the best practices to improve the patient. However, many times, the beneficiary of the results in a research project is not the participant but the all other population that will receive the medicine under tests [9]. The principle of non-maleficence derives from the Hippocratic sentence of “primum non nocere,” which means that doctor abstains from practice that put patients under danger. Although we may argue that the risk of harm is under control, we cannot guarantee for certain even in observational research. The principle of justice and equity reminds us to provide the best treatments to those who really need them. The randomization of the sample removes any selective allocation criteria. The autonomy respects the patient’s freedom of choice, based on a sufficient given information. The informed consent freely expressed gives legitimacy to the inclusion of participants. Although the guaranties of the possibility of self-exclusion, no one really wants that to happen, which may compromise the very principle. The definition of autonomy has evolved over the last years, as the boundaries for information and self-determination, leading to structured forms almost widely accepted, but depersonalized and eventually far from the participant.
Over time, other ethical principles have been defined and applied in scientific research. As ethical principles, by definition, require action, new procedures have been adopted to ensure respect for the participants in investigation protocols.
In 1978, the Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research [4] described the ethical principles for research in human beings: beneficence, justice, and the respect for the person. The respect for the participant implies that researcher must recognize the subjects’ autonomy to their own will and assume the duty to protect the most vulnerable.
In the 1998 Barcelona Declaration, a panel of experts defined the principles of autonomy, dignity, integrity, and vulnerability [10]. Autonomy comes up as an ideal to reach. Dignity is an intrinsic value of the individual, meeting himself with others. Integrity is the right to inviolability, implying the respect for privacy, personal ideas and expectations, and for patient’s understanding of his own life and illness. Vulnerability expresses the susceptibility to be hurt. It is commonly understood as the condition of a patient before the threat of disease. In investigation, vulnerability refers to the fragility of participants before the methods. It implies the duty of not to harm the integrity of the participants and, at the same time, to protect their integrity. Classically, we consider children, pregnant women, and elders, but there are many other ways of turning vulnerable, such as the invitation to participate in a research of the doctor to his patient.
More than the statement in the ethical issues of a paper, assuring that the authors were committed with Declaration of Helsinki and Oviedo Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine, researchers should incorporate the ethical principles since the formulation of the research question and in the entire definition of study design and results analysis, in the assumptions they make, and in the decisions they take.
3. Checklist of the ethical appraisal
The ethical appraisal of a research protocol often starts with a descriptive characterization of the study. Checking the presence or absence of certain elements in the protocol may assist this task. Table 1 presents the checklist of ethical appraisal. It does not pretend to be a definitive tool of decision, since the ethical appraisal of a research protocol is not an assignment that may be reduced to a checklist. This table should be perceived as a summary tool to help structure and guide critical thinking regarding ethical research assessment.
Ethical appraisal
Research team
Yes
No
Merit and integrity
Individual researchers curriculum vitae
Research team CVs are expected to demonstrate capacity to develop the study
Relevance and feasibility of the study is expected
Problem
Yes
No
Coherent rationale supported by literature
Questions
Yes
No
Clear and answerable research questions
Design
Yes
No
Appropriate and rigorous
Experimental
Coherence between research questions and research design is expected
Efficient resource allocation is expected
Appropriate bias identification and mitigation strategies are expected
Pre-post intervention
Control group
Observational
Cohort
Case–control
Cross-sectional
Qualitative
Validation (e.g., scale development)
Mixed methodology
Other
Participants enrolment
Yes
No
Non-maleficence
Clear description of the procedure to enroll participants
Consideration of benefits and costs (risks) weighting for individual and for community interests is expected
Commitment to respect the integrity, dignity and autonomy of participants is expected
Appropriate informed consent presentation is expected
Appropriate procedure of data protection is expected
Appropriate procedure for adverse event reporting is expected
Data collection
Yes
No
Gathering data from people
Questionnaire
Individual interview
Group interview (e.g., focus group)
Biological sampling (blood, urine, saliva, sputum, feces, semen, tissue or other bodily fluids)
Gathering data from clinical records
Anonymized or pseudonymized data
Written informed consent from participants
Data storage
Yes
No
Safety measures for database management
Participant safety
Yes
No
Written informed consent from participants
Procedure for reporting of adverse events
Identification of possible risks or harm to participants (e.g., stress or anxiety)
Insurance (intervention studies, if applicable)
Data analysis
Yes
No
Merit and integrity
Exploratory
Detailed explanation of statistical analytical plan is expected (viz., identifying all variables and statistical tests use)
Commitment to report and make results public is expected
Declaration of any conflict of interest is expected
Prespecified
Reporting
Yes
No
Publication or registry of the protocol
Compromise to send a report of the research
Intention to publish the study
Funding
Yes
No
Funding protocol (if applicable)
Table 1.
Checklist of the ethical appraisal.
Overall the research protocol proposal is assessed for its merit and integrity alongside with the description of appropriate and rigorous methods and procedures committed to non-maleficence. The use of sound scientific methods is warranted. Although this is not the main focus of the consideration it is important to assure that the use of resources and enrolment of participants is based on solid scientific grounds. Additionally, appropriate academic conduct in terms of references and authorship authorizations in the use of tools and instruments for research is required. The main focus of attention is usually placed in all the interactions with participants. From first contact where the study is presented to enrollment in the study followed by all the activities required to the end of the study and eventual subsequent follow-up.
4. Common mistakes
The ethics committee of the Northern Regional Health Administration of Portuguese Health Minister was created in 2009 as the first ethical committee in primary care in Portugal. The Northern Regional Health Administration covers a population of about 3.5 million people and have about 9000 collaborators (2776 physicians and 2829 nurses). We have a large experience, counting over 1200 processes evaluated till the end of 2018 (95% research projects in primary care settings). Also we contributed to ethical education among providers implementing several courses on ethical topics, particularly focusing ethics in research.
During this period the discussion on ethical issues increased considerably among physicians and researchers, accompanying Portuguese legislative changes in ethical committees and access and protection of personal data. Ethics does not belong to any one in special: it is a commitment of all. Nevertheless, belonging to an ethical committee forces us to think globally and to decide case by case. In our monthly meeting, we have evolved continuously both in knowledge and in practice. Every project is a challenge for discussion, and every problem is an opportunity to think over about the way to improve ethical awareness, in an increasingly globalized and informed world, but somehow with less time to stop and think. As a result, more than 80% of projects were approved without ethical constraints.
However, many of the projects submitted for appreciation showed ethical constraints, reflecting the distance between research methods and ethical details:
Lack of informed consent. Some researchers think the informed consent is expendable. Others think that informed consent is just a signature in a paper sheet, overlooking the relevance of the information and the explanation to give participants the capacity of accepting consciously and freely [11].
The invitation to participate in the study. It’s hard for a patient assisted in a clinic to refuse the participation in a study when invited by his/her doctor or nurse. It is not forbidden, but this vulnerability forces researchers to be more cautious in the way they include their patients in the study, for example, by asking another member of the team to talk with the patient. This is particularly relevant in the primary care due to the proximity of doctor-patient relationship.
Data collection. Clinical files keep a lot of health data of interest for research. However, these data are available for healthcare and not so much for investigation. The reuse of data implies a legitimacy that does not derive directly from assistance. The free informed consent of the patient or his/her agent is the right way to do it. Nevertheless, under certain circumstances, ethical committee may excuse the explicit consent, but special care must be taken to minimize, anonymize, and secure data.
Variables under study. It’s common to see data collection forms including identification variables such as the patient’s name, birth date, or health system number. This potentially jeopardizes the anonymization and confidentiality of the database. Rarely these variables are relevant for research and should be avoided or duly justified [11].
Use of questionnaires of other authors. Many questionnaires are protected by copyright and must be authorized by their owners. Even if they are on the public domain, the questionnaire has an intellectual property that should be respected. It’s appropriate to obtain prior authorization from the original authors.
Absence of a well-defined statistical analytical plan. Quantitative studies may have an exploratory approach to data with all the limitations that poses for causal inference. Still, an exploratory approach may be helpful for theory generation. For the purpose of theory testing, prespecification of statistical analysis is warranted. Researchers should identify all variables in the study and specify the statistical modeling and testing that will be used. This is an important procedure to mitigate “p-hacking” practices [12].
Lack of feedback to the participants. Researchers should commit with the obligation of informing participants if they identify a health or social problem that needs intervention, during the investigations. Whenever it is appropriate, a definition of adverse event and a procedure for reporting and managing adverse events is expected.
Declaration of conflicts of interest. Although there’s a general acceptance about the definition of conflicts of interest in its several dimensions of financial ties, academic commitments, personal relationships, political or religious beliefs, and institutional affiliations, many times researchers opt by an individual assessment choosing which characteristics are more prone to set up a conflict in the particular case. Everyone has some kind of conflicts of interest [13]. The transparency and truth is also an ethical duty.
5. Weaknesses of ethical review
Current trend of ethical review seems likely to make ethical approval less efficient and less sustainable both in terms of time and money [12]. We can identify potential types of weakness in different places and in different areas of the pathway of ethical review.
Ethics is not an exact science, including several lines of thought, from Aristotelian virtue to Kantian deontology, the deterministic theories, the situational view, the Buberian relational perspective, and many others. Different decisions may arise from different points of view [7].
The most frequent hazards in clinical investigation are the breach of confidentiality, the adequacy of informed consent, and the protection of personal data. Patients are often the weakest link in the research project, unable to control most of the procedures in the protocol. But they may be also the strongest piece as they have the power to drop off, conditioning a potential bias able to weaken the interpretation of the outcomes. It’s crucial to implement good strategies to safeguard voluntary informed consent, allowing the responsible freedom of the participants, based on effective information, especially when researchers are involved in their healthcare assistance [14].
Nowadays, many researchers use a standardized form to submit their study proposals to research ethics committees. The form overcomes the problem of inconsistencies in the paperwork required by different committees or, sometimes, by different members of the same committee. However, this procedure is time-consuming, and many times a work overloads, forcing the researchers to adapt their study protocol to a closed predefined form. Instead of the original idea of simplifying the process, there’s a real risk of increasing the paperwork.
The informed consent is the key to legitimate the inclusion of the participants. However, its necessity may introduce some bias in the research. In primary care, socio-epidemiologic studies are common, and surveys frequently used methodological strategies. The requirement for a written consent will overload the paperwork and may withdraw some participants, leading to lower response rates and conditioning the results [15].
One of the most important fundamental and central aspects of ethical review is the essential information necessary for ethical approval. That information can be written in form of questions [15]:
Can the research protocol be modified to reduce potential hazards, without compromising its ability to answer the research question?
Can the protocol study include solutions to minimize the chances that the remaining hazards result in harms?
Are the hazards or the risk of resulting in harm disproportionately great in comparison to the importance of the new knowledge to be gained?
Another weakness commonly appointed to the ethical committees is the lack of expertise in specific scientific domains or in certain methodological approaches. The deliberations of research ethics committees require knowledge not only of ethical principles but also of different study designs and research topics. It is true that single members of research ethics committees usually do not have expertise in all of these domains for a given application. The way to prevent this weakness is to increase the number and the interdisciplinarity of the members of each research ethical committee. Portuguese health minister made recently an actualization of the regulation of health and research ethical committees, increasing the number of members to a maximum of 11 and imposing the obligation to integrate people from different areas such as medicine, justice, philosophy/ethics, theology, nursing and pharmacy, or even others as necessary [16].
There are also some concerns about the time to answer. One reason is the bureaucratic issues inherent to its internal functioning, not always well understood, many times perfectly expendable, but always present in our experience. The main reason, however, is more relevant. Some projects raise doubts that require further reflection and imply to postpone the decision, giving time to mature each one’s opinions, based on each knowledge, sensitivities, experiences, and values, extended by self-education and, if needed, by consulting other experts.
There is a tendency to normalize the vision of the human being and his nature, leading to preconceived technical decisions, type “ready to wear.” This is more common as the time goes by and the routine settles in. The decision must be always case by case. Each project requires specific consideration, which extends over time in the implementation process.
The most important factor for weakness in ethical committees, as in many other organizations, is the inability to recognize their own limitations. This blindness results in the lack of self-criticism and the affirmation that the decision is so perfect that everyone should accept without reservation. The solution is to maintain a deliberative environment in the ethical committees, with open dialog and real discussion on the different points of view, and the capacity to create consensus more that resorting to the decision by imposed suffrage.
6. Conclusion
Scientific inquiry and the production of new knowledge are central factors in the development of medicine and in improving the quality and quantity of life. It allows the generation of evidence about technologies and procedures offering information useful for health reasoning and decision, whether with and for patients as individuals either for the population.
Thus, the emergence of a research question that does not yet have an established answer (often in the context of the clinical evaluation on medical consultation) is an opportunity to create new knowledge with the potential to improve the current situation.
Methodological strategies for hypothesis testing and for attainment of answers driven by research questions are known. Such procedures are expected to be sufficiently described and structured in the investigation protocol.
Good practices require the submission of a protocol to an ethical committee prior to the start of participants’ inclusion.
Ethical committees are sometimes seen as an obstacle to the work of researchers. The most common criticisms arise from the difficulty in perceiving some scientific concepts due to a lack of training in that specific topic and a tendency to overvalue prejudices that lead to a certain paternalistic attitude towards patients and distrust towards researchers. The historically established police character of ethical committees also contributes to this depreciation.
On the other hand, researchers have a tendency to facilitate processes based on their perception of excellence of the expected results and to forget (or even not know) current regulations and laws.
Ethical committees are a fundamental instrument of self-regulation that seek a balance between the benefit of research and its results (that may be translated into more and better health) and the respect for the participant has a human being in his biopsychosocial dimensions.
In its Greek genesis, ethics derives from ēthikós, which means relating to one’s character. Thus, ethics refers to the ability to live with you and with others respecting individual freedom and its limits by realizing that any act on our part will have a significant influence on the other and therefore must always be weighed.
This may be the key to solve the apparent dilemma. Introducing this consideration in the design and implementation of the research turns it into an ethical investigation that we all agree on.
Acknowledgments
This chapter is based on our experience as members of the ethical committee of Northern Regional Health Administration of Portuguese Health Minister. We thank all other members in which their daily work allowed us to learn and practice the ethical appraisal of a research protocol.
Conflict of interest
The authors declare no conflict of interest regarding the contents of this chapter.
\n',keywords:"ethics, ethics committees, research, ethical analysis, beneficence, personal autonomy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71886.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71886.xml",downloadPdfUrl:"/chapter/pdf-download/71886",previewPdfUrl:"/chapter/pdf-preview/71886",totalDownloads:533,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 11th 2019",dateReviewed:"March 25th 2020",datePrePublished:"April 22nd 2020",datePublished:"May 19th 2021",dateFinished:"April 22nd 2020",readingETA:"0",abstract:"Nowadays, the submission of a research project to an ethical committee and its approval is mandatory. However, researchers often overlook this obligation, because they are too engaged in the design and the process of construction of the study, because of the common tight deadlines, and many times because some devaluation of the role of the committee. Based on our experience of 10 years working in an ethical committee, we propose a way to get close researchers and evaluators, respecting their own aims but bringing them together as partners in the investigation process, protecting patients’ values, at the same time that makes it possible to implement strategies to answer to the research question and to create useful knowledge. Our aim is to smoothen the way researchers look to the ethical committee and, at the same time, to make them understand what really is at stake. Ethics should be a commitment for all and not an obligation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71886",risUrl:"/chapter/ris/71886",signatures:"Paulo Santos, Pedro Teixeira, Helena Beça and Alberto Hespanhol",book:{id:"9566",type:"book",title:"Bioethics in Medicine and Society",subtitle:null,fullTitle:"Bioethics in Medicine and Society",slug:"bioethics-in-medicine-and-society",publishedDate:"May 19th 2021",bookSignature:"Thomas F. 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Introduction",level:"1"},{id:"sec_2",title:"2. The ethical principle",level:"1"},{id:"sec_3",title:"3. Checklist of the ethical appraisal",level:"1"},{id:"sec_4",title:"4. Common mistakes",level:"1"},{id:"sec_5",title:"5. Weaknesses of ethical review",level:"1"},{id:"sec_6",title:"6. Conclusion",level:"1"},{id:"sec_7",title:"Acknowledgments",level:"1"},{id:"sec_10",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Hipocratis opera vera at adscripta. Vol. Quartus. Lausanne; 1771. pp. 197-199'},{id:"B2",body:'Trials of War Criminals before the Nuernberg Military Tribunals under Control Council Law n. 10. Volume II: The medical case; 1949'},{id:"B3",body:'Declaration of Helsinki: Recommendations guiding doctors in clinical research; 1964'},{id:"B4",body:'Sims JM. A brief review of the Belmont report. Dimensions of Critical Care Nursing. 2010;29(4):173-174'},{id:"B5",body:'McGee G, Caplan AL, Spanogle JP, Asch DA. A national study of ethics committees. The American Journal of Bioethics. 2001;1(4):60-64'},{id:"B6",body:'WMA Declaration of Helsinki—Ethical principles for medical research involving human subjects; 2018'},{id:"B7",body:'Sikes P, Piper H. Ethical research, academic freedom and the role of ethics committees and review procedures in educational research. International Journal of Research & Method in Education. 2010;33(3):205-213'},{id:"B8",body:'Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 8th ed. New York: Oxford University Press; 2019'},{id:"B9",body:'Grady C. Chapter 2—Ethical principles in clinical research. In: Gallin JI, Ognibene FP, Johnson LL, editors. Principles and Practice of Clinical Research. 4th ed. Boston: Academic Press; 2018. pp. 19-31'},{id:"B10",body:'Kemp P, Dahl RJ. The Barcelona declaration. Towards an integrated approach to basic ethical principles. Synthesis Philosophica. 2008;23(2):239-251'},{id:"B11",body:'Santos P, Hespanhol A. Informed consent for case reports—An ethical perspective. Acta Bioethica. 2017;23(2):271-278'},{id:"B12",body:'Teixeira PM. p-Hacking—A call for ethics. Pulmonology. 2018;24(3):207-208'},{id:"B13",body:'Cain DM, Detsky AS. Everyone’s a little bit biased (even physicians). JAMA: The Journal of the American Medical Association. 2008;299(24):2893-2895'},{id:"B14",body:'Dekking SA, van der Graaf R, van Delden JJ. Strengths and weaknesses of guideline approaches to safeguard voluntary informed consent of patients within a dependent relationship. BMC Medicine. 2014;12:52'},{id:"B15",body:'Jamrozik K. Research ethics paperwork: What is the plot we seem to have lost? BMJ. 2004;329(7460):286-287'},{id:"B16",body:'Estabelece os princípios e regras aplicáveis às comissões de ética que funcionam nas instituições de saúde, nas instituições de ensino superior e em centros de investigação biomédica que desenvolvam investigação clínica. Decreto-Lei n.° 80/2018. Sect. 198/2018. Série I de 2018-10-15; 2018'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Paulo Santos",address:"psantosdr@med.up.pt",affiliation:'
Department of Medicine of Community, Information and Health Decision Sciences, Faculty of Medicine, University of Porto, Portugal
CINTESIS, Center for Health Technology and Services Research, University of Porto, Portugal
Ethics Committee of the Administração Regional de Saúde do Norte, ARS Norte, Portugal
Department of Medicine of Community, Information and Health Decision Sciences, Faculty of Medicine, University of Porto, Portugal
CINTESIS, Center for Health Technology and Services Research, University of Porto, Portugal
Ethics Committee of the Administração Regional de Saúde do Norte, ARS Norte, Portugal
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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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