\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"2026",leadTitle:null,fullTitle:"Inflammatory Diseases - Immunopathology, Clinical and Pharmacological Bases",title:"Inflammatory Diseases",subtitle:"Immunopathology, Clinical and Pharmacological Bases",reviewType:"peer-reviewed",abstract:'This book is a collection of comprehensive reviews contributed by experts in the diverse fields of acute and chronic inflammatory diseases, with emphasis on current pharmacological and diagnostic options. Interested professionals are also encouraged to review the contributions made by experts in a second related book entitled "Inflammation, Chronic Diseases and Cancer"; it deals with immunobiology, clinical reviews, and perspectives of the mechanisms of immune inflammatory responses that are involved in alterations of immune dynamics during the genesis, progression and manifestation of a number of inflammatory diseases and cancers, as well as perspectives for diagnosis, and treatment or prevention of these disabling and potentially preventable diseases, particularly for the growing population of older adults around the globe.',isbn:null,printIsbn:"978-953-307-911-0",pdfIsbn:"978-953-51-6760-0",doi:"10.5772/2436",price:139,priceEur:155,priceUsd:179,slug:"inflammatory-diseases-immunopathology-clinical-and-pharmacological-bases",numberOfPages:410,isOpenForSubmission:!1,isInWos:1,hash:"55567318dc2901acbc8cdbab9c48feef",bookSignature:"Mahin Khatami",publishedDate:"February 10th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2026.jpg",numberOfDownloads:47448,numberOfWosCitations:17,numberOfCrossrefCitations:8,numberOfDimensionsCitations:24,hasAltmetrics:0,numberOfTotalCitations:49,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 20th 2011",dateEndSecondStepPublish:"February 17th 2011",dateEndThirdStepPublish:"June 24th 2011",dateEndFourthStepPublish:"July 24th 2011",dateEndFifthStepPublish:"November 21st 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"63956",title:"Dr.",name:"Mahin",middleName:null,surname:"Khatami",slug:"mahin-khatami",fullName:"Mahin Khatami",profilePictureURL:"https://mts.intechopen.com/storage/users/63956/images/2341_n.jpg",biography:"Dr. Mahin Khatami was born in Tehran-Iran. She immigrated to USA in 1969 after training in Chemistry (BS) and Science Education (MS). She received her MA in Biochemistry from SUNY at Buffalo (1977) and PhD in Molecular Biology from the University of Pennsylvania (UPA, 1980). Her postdoctoral trainings were in physiology at the University of Virginia, protein chemistry (proteomics) at the Fox Chase Cancer Institute and UPA. She was a Faculty of Medicine at the Department of Ophthalmology, Scheie Eye Institute, UPA, until 1992. In collaboration with a team of scientists, under the direction of John H. Rockey, MD, PhD, at UPA, she quickly earned her supervisory responsibilities on two major projects; cell and molecular biology of diabetic retinopathy/maculopathy and experimental models of acute and chronic ocular inflammatory diseases. In her junior academic career, Dr. Khatami is considered the most productive scientist in USA as she published 39 scientific articles and over 60 abstracts in conference proceedings in the first decade of her research. In 1998, at the National Cancer Institute (NCI), the National Institutes of Health (NIH), she was a Program Director and health scientist administrator, involved in developing molecular concepts for utilization of patient biospecimen for large clinical trials such as Prostate-Lung-Colorectal Ovarian (PLCO) Cancer Screening Trials. Extension of her earlier ‘accidental’ discoveries on models of inflammatory diseases became closely relevant to her duties for developing proposals for molecular diagnosis, prevention and therapy of cancer for PLCO and designs of cohort clinical trials. The results of her pioneering studies in 1980’s on experimental models of inflammatory diseases are suggestive of the first evidence for a direct link between inflammation and tumorigenesis and angiogenesis. She also published the first report on inflammation-induced developmental phases of immune dysfunction that would lead to tumor development. In 2005, she also published an NCI-Invention, in Federal Register for standardizing cancer biomarkers criteria (data elements) as a foundation of developing a cancer biomarkers database; M-CSF, an inflammatory mediator was identified as prototype to test/tailor data elements. Her challenging efforts to promote the role of inflammation in cancer research, which initially met with tremendous resistance by decision makers, have recently paid off as the number of federally funded projects, technologies and drug development and related networks that focus on the role of inflammation and cancer has significantly increased in the last decade within and outside NCI/NIH. \nDr. Khatami has lectured internationally; served as president and VP for Graduate Women In Science (GWIS) Omicron Chapter; scientific judge; founder and president of Medical Education Technologies (HUS); consultant to pharmaceutical companies; member of professional societies and editorial activities; symposia organizer. She is Associate Editor for Cell Biochemistry and Biophysics, lecturer, author and editor. 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This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. 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Genetic polymorphism is the existence of at least two variants with respect to gene sequences, chromosome structure, or a phenotype (gene sequences and chromosomal variants are seen at the frequency of 1% or higher), typical of a polymorphism, rather than the focus being on rare variants [1].
The human genome comprises 6 billion nucleotides of DNA packaged into two sets of 23 chromosomes, one set inherited from each parent. The probability of polymorphic DNA in humans is great due to the relatively large size of human genome. Genomic variability includes a wide range of variations from single base pair change, many base pairs, and repeated sequences [2].
Single nucleotide polymorphisms are the most common type of genetic variations in humans [3], due to their abundance across the human genome; single nucleotide polymorphisms (SNPs) have become important genetic markers for mapping human diseases, population genetics, and evolutionary studies. SNPs have become very important since technologies for DNA sequencing have become feasible and widely available. Advance continues at a rapid rate [4].
A major step forward in genome identification is the discovery of about 30–90% of the genome which is constituted by regions of repetitive DNA which are highly polymorphic in nature [5]. Polymorphic tandem repeated sequences have emerged as important genetic markers and initially, variable number tandem repeats (VNTRs) were used in DNA fingerprinting. In recent years, evidence has been accumulated for the involvement of VNTR repeats in a wide spectrum of pathological states [6].
Throughout the past years, scientists have believed that genes strictly came in two copies in a genome. However, with the recent advancement in molecular technology, discoveries have revealed substantial segments of DNA, ranging in size from thousands to millions of DNA bases that could vary in copy number. Such copy number variations (or CNVs) encompass gene copies, newly discovered CNVs are important sources of genomic diversity [7, 8].
The development and use of DNA-based molecular markers is one of the most significant developments in the field of molecular genetics that facilitate the study of genetic variations in health and diseases [5].
This chapter reviews the DNA-based genetic markers and their application in medicine, with a particular emphasis on common DNA-based genetic markers, including single nucleotide polymorphisms and short tandem repeats (STRs).
Genomic variability at DNA level can be present in many forms including: single nucleotide polymorphisms, variable number of tandem repeats (e.g., mini- and microsatellites), transposable elements (e.g., Alu repeats), structural alterations, and copy number variations. It can occur in the nucleus or mitochondria. Two major sources: (1) mutations that may result as chance processes or have been induced by external agents such as radiation and (2) recombination. Once formed, it can be inherited, allowing its inheritance to be tracked from parent to child [3].
The genomes of humans may be divided into different parts based on known functional properties; the coding and noncoding regions mostly do not code for protein [2, 9]. The coding regions contain DNA sequences which determine primarily the amino acid sequences of the proteins for which they code. Noncoding DNA generally containing DNA sequences with no function has not yet been discovered or possibly no function exists [10]; such sequences may be either single copy or exist as multiple copies called repetitive DNA [10]. Indeed, regions of DNA that do not code for proteins tend to have more polymorphisms. Recently, there has been substantial progress in understanding genome content which centered on discovered protein-coding genes which considered a functional DNA sequence moving away for discoveries of many repeat families, and various copy number variations encompass gene copies leading to dosage imbalance that plays an important role in genome structure, evolution, and diversity [11, 12]. “The Human Genome Project has revealed that humans have only 20,000–30,000 structural genes (protein-coding genes) (International Human Genome Sequencing Consortium, 2004)” [13].
Single base change is “high-density natural sequence variations in human genome” [14]. SNPs are mostly formed when errors occur (substitution, insertion and deletion). SNPs are prominent sources of variation in human genome and serve as excellent genetic markers. Some regions of the genome are richer in SNPs than others. SNPs may occur within gene sequences or in intergenic sequences. SNPs mostly are located in noncoding regions of the genome and have mostly no direct known impact on the phenotype of an individual but their role till now remains elusive, and depending on where SNPs occurs, it might have different consequences at the phenotypic level [3].
It is a type of DNA variation in which a specific nucleotide sequence of various lengths ranging from one to several 100 base pairs is inserted or deleted. Indels are widely spread across the genome. Some authors consider one base pair as SNPs or repeat insertion/deletion as indels.
DNA repeats can be classified as interspersed repeats or tandem repeats. This can comprise over two-thirds of the human genome [15]. Interspersed repeats are dispersed across the genome within gene sequences or intergenic and include retro (pseudo) genes and transposons. Tandem repeats or variable number tandem repeats (≥2 bp in length) that are adjacent to each [16] can involve as few as two copies or many thousands of copies. Centromeres and telomeres largely comprise tandem repeats. Despite increasing evidence on the functionality of DNA repeats, their biologic role is still elusive and under frequent debate [11]. Tandem repeats are organized in a head-to-tail orientation; based on the size of each repeat unit, satellite repeats can be further divided into macrosatellites, minisatellites, and microsatellites [17]. Some of these repeats are described as follows: macrosatellites, with sequence repeats longer than 100 bp, are the largest of the tandem DNA repeats, located on one or multiple chromosomes [11], minisatellites, stretches of DNA, are characterized by moderate length patterns, 10–100 bp usually less than 50 bp [9, 18], and microsatellites also known as short tandem repeats (STRs) repeat units of less than 10 bp, [3].
Structural and copy number variations (CNVs) are another frequent source of genome variability [6, 19, 20]. The term CNVs therefore encompasses previously introduced terms such as large-scale copy number variants (LCVs) [19], copy number polymorphisms (CNPs) [20], and intermediate-sized variants (ISVs) [21]. Some currently used terms are structural variations; a genomic alteration (e.g., an inversion) that involves segments of DNA > 1 kb, copy number polymorphisms; a duplication or deletion event involving >1 kb of DNA [22], intermediate-sized structural variant; and a structural variant that is ∼8–40 kb in size, this can refer to a CNVs or a balanced structural rearrangement (e.g., an inversion) [21].
The development and use of molecular methods for the detection of DNA molecular markers is one of the most significant progresses in the field of molecular genetics. Mapping the human genome requires a set of genetic markers to which we can relate the position of genes. Some of these markers are genes, others SNPs and VNTRs. Molecular markers can be used to mark in genomes for various purposes such as mapping human diseases, pharmacogenetics, and human identification.
Single base pair change leads to single nucleotide variant, probably accounting for many genetic conditions caused by single gene or multiple genes. SNPs represent the major source of human genomic variability. Due to the lack of knowledge on exact SNP number, it is difficult to give a direct estimate of the number of the SNPs in the human genome but in different public and private data bases, more than 5 million have been recorded and about 4 million validated [23]. “The data from the Human Genome project revealed that that human nucleotide sequence differs every 1000-1500 bases from one individual to another” [24]. “The SNP Map working group observed that two haploid genomes differ at 1 nucleotide per 1331 bp”. Over 60,000 however are within genes and some of them associated with diseases [2].
Single nucleotide polymorphisms within protein-coding regions either synonymous polymorphisms; those that do not have any effect on the organism and are said to be selectively silent as the substitution causes no amino acid change in the protein produced (silent mutation) or nonsynonymous substitution results in change in encoded amino acids either missense mutation; change the protein through codon alteration or nonsense mutation results in a chain termination codon [3].
Single nucleotide polymorphisms within a coding sequence cause genetic diseases including sickle cell anemia. SNPs responsible for a disease can also occur in any genetic region that can
Another important group of SNPs is the one that alters the primary structure of a protein involved in drug metabolism; these SNPs are targets for pharmacogenetics studies.
However, some SNPs are not causative, some SNPs are in close association with, and therefore segregate with, a disease-causing sequence so, the presence of SNP correlates with the presence or an increased risk of developing the disease; these SNPs are useful in diagnostics, disease prediction, and other applications [3].
Single nucleotide polymorphisms can be used as genetic markers for constructing high genetic maps and to carry out association studies related to diseases because of their abundance and the availability of high throughput analysis technologies. SNPs have become an important application in the development and research of genetic markers [14].
There are numerous strategies that can be implemented to new single nucleotide variant (SNVs) discoveries; the most common and well-known method is by direct sequencing and in comparison to a puplic or other sequence date base [25, 26] or locus specific amplification of target genomic region followed by sequence comparison [27, 28]; prescreening prior to sequence determination is needed. SNV detection encompasses two broad areas: (1) scanning DNA sequences for previously unknown polymorphisms and (2) screening (genotyping) individuals for known polymorphisms. Scanning for new SNVs can be further classified to two different types of approaches, the first one being the global (or random approach) and the other one being the regional (targeted approach) [14]. There are certain methods which have been developed for using SNVs randomly in the genome; “such as representation shotgun sequencing [14, 29], primer-ligation-mediated PCR [14, 30] and degenerate oligonucleotide–primed PCR” [14, 31].
Haplotypes are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs and may therefore provide increased diagnostic accuracy in some cases [32].
Microsatellites are short tandem repeats (STRs), repeat units, or motifs of less than 10 bp; because of high variability, microsatellite loci are often used in forensics, population genetics, and genetic genealogy. Significant associations were demonstrated between microsatellite variants and many diseases [15].
Depending on the search algorithm, there are approximately 700,000–1,000,000 microsatellite loci which are 2–6 bp long in the human reference genome [33, 34]. Di- and tetra-nucleotides constitute about 75% of microsatellites, with the remaining loci containing tri-, penta, and hexanucleotide. Within genes, STRs are nonrandomly distributed across protein-coding sequences, untranslated regions (UTRs), and introns. STRs containing dinucleotide repeat units that are much more abundant in the regulatory or UTR regions than in other genomic regions. In the coding regions of the genes, repeats mostly have either trimeric or hexameric repeat unit, likely as a result of selection against frameshift mutations [34, 35]. “The mutation rates of STRs often lie between 103 and 106 per cell generation which is 10- to 105-fold higher than the average mutation rates observed in nonrepeated regions of the genome”[36, 37].
“Polymorphism of tandem repeats within protein-coding regions reveals that tandem repeat variation is an important source of variation in many proteins, many of this variation is of significant impact on protein function. Tandem repeats has been associated with a number of diseases and phenotypic conditions, changes in the protein products of genes, leading to diseases, other tandem repeat polymorphisms in noncoding regions are known to modify function through their impact on gene regulation”. “These polymorphisms can arise from events such as unequal crossover, replication slippage or double-strand break repair” [38].
Variations in the STR length play a significant role in modulating gene expression and STRs are likely to be general regulatory elements; regulatory STRs manifest significant polymorphism because of their high intrinsic mutation rate [15].
There are examples for distinctive phenotypic changes and diseases that are directly associated with the increases or decreases of microsatellite repeat arrays; for example, considering Huntington disease gene, triplet nucleotide mutations, the mutation that causes the disease, is an expansion of CAG repeats from the normal range of 11–14 copies to abnormal range of at least 38 copies. The extra CAG repeats that causes extra glutamine is produced [9] and there are more than 40 neurological diseases in humans, such as spinocerebellar ataxia with polyglutamine tracts, which are caused by microsatellite motif length changes in trinucleotide arrays [39].
Testing candidate genes for polymorphisms in exons, promoters, splice sites, or other regulatory regions will have to be done using SNP testing, because it is the most common polymorphisms and more likely responsible for phenotypic variations. For complex phenotypic traits and candidate loci, single-loci SNP analyses present less information due to the bi-allelic nature of the markers, as compared to the multi-allelic microsatellites. However, performing haplotype frequency may improve the accuracy [40]. Recently, polymorphic tandem repeated sequences and coy number variations have emerged as important sources of genomic diversity that facilitate the study of genetic variations in health and diseases.
Different forms of DNA-based molecular markers can be tracked using a variety of techniques. Some of these techniques include RFLPs with Southern blots and polymerase chain reactions (PCRs). Recently great advances in methodology for DNA polymorphisms detection using real time PCR, hybridization techniques using DNA microarray chips, genome sequencing each technique has its own advantage and disadvantage.
DNA digestion with restriction enzyme endonuclease cuts DNA at a specific sequence pattern known as a restriction endonuclease recognition site. Thus, the alleles differ in length and can be distinguished by gel electrophoresis, which can arise from a number of genetic events including point mutation in restriction sites, mutation that creates a new restriction site, insertion, deletion, and repeated sequences. The first polymorphic RFLP was described in 1980. RFLPs were the original DNA targets used for human identification, parentage testing, and gene mapping.
The method of hybridization of DNA with probes is called Southern blotting, after the name of the inventor, Southern [41]. RFLP requires relatively large amounts of DNA. Hence, it cannot be performed with the samples degraded by environmental factors and also takes longer time to get the results [42, 43]. PCR-RFLP is now replaced to avoid using Southern blot.
In-vitro amplification of particular DNA sequences with the help of specifically chosen primers and DNA polymerase enzyme is done. The amplified fragments are separated electrophonically and detected by different staining methods. Real-time PCR useful modification of PCR can detect polymorphisms by various methodologies using real-time PCR chemistries, for example, TaqMan assay or molecular beacons.
Genomic array technology is a type of hybridization analysis allowing simultaneous study of large numbers of targets or samples. In 1987, macroarray evolved into the microarray. Tens of thousands of targets can be screened simultaneously in a very small area. Automated depositing systems (arrayers) can place thousands of spots on glass substrate of the size of a microscope slide (chip) with spotting representative sequences of each gene in triplicate, simultaneous screening of the entire human genome on a single chip. This technique facilitates the process of identifying specific homozygous and heterozygous alleles, by comparing the disparity of hybridization of the target DNA with each redundant probe. Microarray is also used to characterize genetic diversity and drug responses, to identify new drug targets, and to assess the toxicological properties of chemicals and pharmaceuticals [44].
Since technologies for rapid DNA sequencing have become available they are now widely used. There is a great progression for the detection of single nucleotide variants (SNVs) by direct sequencing, but intermediate-sized (from 50 bp to 50 kb) structural variants (SVs) remain a challenge. Such variants are too small to detect with cytogenetic methods but too large to reliably discover with short-read DNA sequencing. Recent high-quality genome assemblies using long-read sequencing have revealed that each human genome has approximately 20,000 structural variants, spanning 10 million base pairs, more than twice the number of bases affected by SNVs. New long-read sequencing approaches are needed to meet this challenge, as short-read sequencing technologies only detect 20% of the SVs present in the human genome [45, 46, 47, 48].
DNA-based molecular markers are such powerful tools for mapping human diseases and discover many multifactorial diseases and disorders.
Genetic mapping and linkage: The mapping of the human genome has made possible to develop a haplotype map in order to better define human SNV variability. The haplotype map or HapMap will be a tool for the detection of human genetic variation that can affect health and diseases [23]. The HapMap project is far more useful because it will reduce the number of SNVs required to examine the entire genome for association with a phenotype or diseases from the 10 million SNPs that are expected to exist to approximately tag 500,000 SNPs [38]. The first large-scale effort to produce a human genetic map was performed mainly using RFLP; other several projects are underway to identify more markers in humans and to make this data publicly available to scientists worldwide. Many groups that are involved in these massive efforts through DNA polymorphisms discovery resource include the SNP consortium (TSC) http://snp.cshl.org [49, 50]. The reason for the current enormous interest in SNPs is the hope that they could be used as markers to identify genes that predispose individuals to common, multifactorial disorders by using linkage disequilibrium (LD) mapping.
“The HapMap Project (http://hapmap.ncbi.nlm.nih.gov/), and other approaches, such as genome wide association studies, have been widely reported for complex polygenic diseases, with some interesting novel genes affecting disease susceptibility now identified. Genome Wide Association; the GWAS has now been used for a large range of traits and diseases e.g. baldness and eye color” [51, 52].
The identification of genes affecting complex trait is a very difficult task. For many complex traits, the observable variation is quantitative, and loci affecting such traits are generally termed quantitative trait loci (QTL). (SNVs) can be used as genetic markers for constructing high-density genetic maps and to carry out association studies related to complex traits and diseases [14].
Individual response to a drug is governed by many factors such as genetics, age, sex, environment, and disease. The influence of genetic factors on the response of a drug is a known fact. Polymorphic STRs, together with SNPs and CNVs, can explain variability in response to pharmacotherapy because of their prevalence in the human genome and their functional role as regulators of gene expression and its applications. Pharmacogenetics is the study of the influence of genetics factors on drug response and metabolism. The science of pharmacogenetics when applied can be used to evade adverse drug reactions, predict toxicity and therapeutic failure, and refine therapeutic efficiency and improve clinical outcomes [53].
Establishing an individual’s identity is one of the uses of DNA sequence information that highlights uniqueness of a particular sample [5], also known as genetic fingerprinting; DNA typing and DNA profiling are molecular genetic methods that enable the identification of individuals using hair, blood, semen, or other biological samples, based on unique patterns in their DNA. This uniqueness in each individual is the basis of human identification at the DNA level, forensic identification, determination of genetic variation, determination of family relationship, and one important instance is identifying good genetic matches for organ or marrow donation. When first described in 1984 by British scientist Alec Jeffreys, the technique used was minisatellites; these sequences are unique to each individual, with the exception of identical twins. Different DNA fingerprinting methods exist, using either restriction fragment length polymorphism (RFLP) or PCR or both. More than 200 RFLP loci have been described in human DNA. Initially, forensic medicine used minisatellite testing; however, this method requires a large amount of material and yield low-quality results especially when only little amount of materials are available. Nowadays, in most forensic samples, the study of DNA is usually performed by microsatellite analysis. The most useful microsatellite for human identification is those with a greater number of alleles, smaller size, higher frequency of heterozygotes (higher than 90%), and low frequency of mutations [43]. Among others, the microsatellite DNA marker has been the most widely used, due to its easy use by simple PCR, followed by a denaturing gel electrophoresis [40]. Each person has some STRs that were inherited from the father and some from mother, useful in paternity testing but however no person has STRs that are identical to those of either parent. The uniqueness of an individual’s STR provides the scientific marker of identity and hence is helpful in forensic identification [54]. Genomic and mitochondrial are two types of DNA which are used in forensic sciences. The genomic DNA is found in the nucleus of each cell in the human body and represents a DNA source for most forensic applications. Mitochondrial DNA (mt DNA) is another source of material that can be used; various biological samples such as hair, bones, and teeth that lack nucleate cellular materials can be analyzed with mt DNA [43, 55].
“Majority of the length of the human Y chromosome is inherited as a single block in linkage from father to male offspring as a haploid entity. DNA genetic markers on the human Y chromosome are valuable tools for understanding human evolution, migration and for tracing relationships among males” [43, 56]. “Chromosome X specific STRs is used in the identification and the genomic studies of different ethnic groups worldwide, because the small size of X-chromosome STR alleles; about 100–350 nucleotides, it is relatively easy to be amplified and detected with high sensitivity” [43].
DNA typing becomes the method of choice for engraftment monitoring, donor cells are examined by following donor polymorphisms in the recipient blood and bone marrow. Although RFLP can efficiently differentiate donor and recipient cells, the detection of RFLP requires the use of southern blot methods, which is too labor intensive and has limited sensitivity for this application, in comparison with small minisatellites or microsatellites that are easily detected by PCR amplification, because of increased rapidity and the 0.5–1% sensitivity achievable with PCR. Sensitivity can be raised to 0.01% using Y-STR, but this approach is limited to that transplant from sex mismatched donor recipient pairs preferably from a female donor to a male recipient [2].
Nowadays, DNA fingerprinting is used as a tool for designing “personalized” medical treatments for cancer patients.
Single nucleotide polymorphisms (SNPs) have become an important application in the development and research of genetic diseases or other phenotypic traits. Haplotypes are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs and may therefore provide increased diagnostic accuracy in some cases.
Polymorphic tandem repeated sequences have emerged as important genetic markers and initially, variable number tandem repeats (VNTRs) were used in DNA fingerprinting; in recent years, evidence has been accumulated for the involvement of VNTR repeats in a wide spectrum of pathological states.
The new global CNV map will transform medical research in four main areas: detection for genes underlying common diseases, study of familial genetic conditions, exclude variation found in unaffected individuals, helping researchers to target the region that might be involved and the data generated will also contribute to a more accurate and complete human genome reference sequence used by all biomedical scientists. Currently, approximately 2000 CNVs have been described; there could be thousands more CNVs in the human population. About 100 CNVs were detected in each genome tested with the average size being 250,000 bases (an average gene is 60,000 bases). With advanced molecular technologies more CNVs will be discovered and more DNA samples from worldwide populations are examined.
Recently, there has been substantial progress in understanding genome content which centered on protein-coding genes which considered a functional DNA sequence moving away for many discoveries, many repeat families, and various copy number variations that play an important role in genome structure, evolution, and diversity. Additional efforts are being placed to develop strategies that would overcome the obstacles in alignment next-generation sequencing data. “Future precision medicine efforts will direct to connect genotypes to phenotypes and distinguish common, from rare or potentially disease linked variants. New long-read sequencing approaches are needed to meet this challenge.”
Other important applications of genetic polymorphism knowledge are improving health care through gene therapy, discovery of new drugs and drug targets, and upgradation of the discovery processes with advanced technologies.
Advances in molecular technologies, DNA sequencing technology, and microarray, coupled with novel, efficient computational analysis tools, have made it possible to analyze sequence-based experimental data, more discoveries, and development at a rapid rate.
The author declares that there is no conflict of interest.
Use of tobacco products will kill you. It does not matter either you smoke tobacco or you use a smokeless tobacco or nicotine patch or smoke e-cigarettes. Last year, 13,500 smokers died of oral cancer. Out of 450,000 new cancer cases diagnosed this year, 37,000 new cases will be diagnosed for 13 different types of oral cancer which include cancer of the lips, salivary glands, buccal cavity, pharynges, oropharyngeal, laryngeal, nasopharyngeal, hypopharyngeal, etc., and respiratory tract and finally lung cancers. It was Professor Ross of London University who developed oral cancer drug called melphalan (phenylalanine moiety is the carrier for the nitrogen mustard) to treat pharyngeal carcinoma [1]. Melphalan cross-links both strands of DNA shutting off genes. Statistics is worst for smokers. Over 155,700 Americans died of lung cancer last year and over 222,500 will be diagnosed this year. Compare the US mortality, the worldwide figure is ten times as high. While squamous cell carcinoma is responsible for causing oral cancer, adenocarcinoma is one of the deadliest forms of lung cancers. Most patients die within 5 years of their diagnosis. Tobacco smoking kills faster.
\nFor years, we have been trying to answer three important questions: What is cancer? What causes cancer? And how could we diagnosed treat and prevent cancer. For this chapter, I have divided my presentation in three parts. First, I will provide some historical background; second, I will describe how efforts are being made to develop novel drugs to treat cancer; and finally, I will share some ethical problems we are facing today.
\nToday, we must tell all smokers in the world that tobacco smoking whether it is the regular cigarette or e-cigarette or nicotine patch or the use of smokeless tobacco, and all tobacco modifications contains nicotine, and it is the nicotine which causes oral and lung cancers. If you are diagnosed with lung cancer, you are most likely to die within 5 years. Tobacco companies have known this fact for more than half a century. In the late 1930s
The tobacco companies have flooded so much money in the Congressional and Senatorial election campaign, in the US alone, the US senate had voted not to ban tobacco sale to school-aged teenagers. Greedy tobacco executives won the day and needy millions around the world lost the day. Now, tobacco companies will be exporting over 150 billion cigarettes per year to the Asian continent particularly targeting India and China where almost half of the world’s population live. It is a sad day for all of us. The young people, who are getting addicted to smoking today, will start dying 20 years from now. Of all cancers, tobacco smoking remains the single major preventable cause of cancer deaths in the world.
\nCancer is a very ancient disease. The early Greek coined the term cancer. They thought that this unusual disease spread like a crab so they were the first to call it a cancer or crab. The answer to the first question is that cancer is the abnormal growth of the normal cells due to accumulation of mutations over lifetime.
\nOur body is made of about 100 trillion cells. These cells are constantly being replaced by similar young fresh cells. For example, your white blood cells (WBCs) live for about 120 days. They are replaced by other white blood cells. Liver cells make more liver cells and replace old liver cells with new liver cells; lung cells make new lung cells. When this normal cell regulation breaks down, liver cells do not produce liver cells; they produce altered cells called mutant cells. Mutation is caused by exposure to radiations, chemical pollutions, viral infection, or genetic inheritance. The changed cells grow much faster than the normal cells and they form a lump, we call it a tumor. As tumor grows, it spreads over to the nearby blood circulating vessels. When tumor grows over these vessels, it draws more nourishment than the normal cells. Some of the tumor cells break off and split and plunge in the blood stream. These live tumor cells flow in the blood stream and travel wherever the blood goes. If the blood goes to the brain, the free floating tumor cells deposit in the brain and start growing as the brain tumors called metastasized cells. Although the cancer may have started in the lungs from smoking, it may spread to the brain or to other organs of our body. Only cancer cells spread this way; we call these migratory deposits metastasized cells, and only metastasized cells invade neighboring organs causing spread of cancer. We have no cure against metastasized cancers.
\nHow many kinds of cancers do we have? There is a cancer for every tissue type in our body. There are 220 types of tissues in our body. Every tissue type in our body can suffer from cancer because every tissue in our body is replaced cells by cells with younger cells; they can either be replaced by normal cells in healthy people or they can also be replaced by abnormal or mutated cells when we get cancer. Would you believe that even your bones are being replaced? You could also get bone cancer.
\nShort answer is exposure to radiations, chemical pollutants like smoking, viral infection, or genetic inheritance. This is the most important question and I want to spend more time explaining the causes of cancer. This is where we spent most of the $30 billion during the lasts 30 years trying to understand how normal cells become abnormal. If we understand how they become abnormal, we should be able to treat them.
\nIn 1971, President Richard Nixon declared war on cancer and released hundreds of millions of dollars for cancer research. He challenged Americans, the way President John Kennedy had challenged Americans a decade earlier to land men on the moon and bring them back safely. Although both presidents had great ideas, but there was a major difference.
\nAt the time President Kennedy made that famous speech in the US congress, most of the engineering problems had already been worked out. For example, we already knew the engine thrust and its lift off power needed to leave Earth’s gravity. It was calculated to be 7 miles/minute or burning fuel in the absence of air to excel the spacecraft. These engineering problems had already been solved and the knowledge was already available. Only money and trained men power were needed to build the spacecrafts. Within 10 years of that speech, President Kennedy’s dream was turned to reality. On July 20, 1969, Americans landed men on the moon and brought them back safely.
\nBut when President Nixon declared war on cancer, money was made available, but the knowledge was not there. We did not exactly know the inner working of a single living cell and how a normal cell functions, and we did not know why the normal cell becomes abnormal or cancerous. Some basic knowledge was available. In 1953, the big discovery was made in Cambridge University, England. Crick and Watson had determined the double helical structure of the genetic material DNA and postulated how the living cells divide and cells grow, and they were awarded Nobel Prize for their discovery [3]. Armed with this knowledge, we were ready to understand how a normal cell functions. Crick and Watson also opened the doors for the Nobel Prize Club. Every year, since then, a new Nobel Laureate was added to the genetic club. Soon after, Marshall Nirenberg broke the genetic code and unlocked the secret of life by showing that only three nucleotides code for an amino acid, the building block of protein. The remaining codes were deciphered by Salvador Ochoa, followed by an Indian Scientist, Govind Khorana who shared the Nobel Prize with Walter Gilbert.
\nAfter President Nixon’s speech, it had taken about 20 years to understand how a normal cell functions and how it becomes abnormal by exposure to radiations, chemical pollutants, viral infection, or genetic inheritance. Let me summarize below the work of a dozen Nobel Laureates: To understand cancer, you have to understand how a normal cell functions and how it becomes abnormal. We made step by step progress over the past 30 years. First, you might ask why we study a single cell and why a single cell is so important. The fact is our life begins with a single cell. You and I are the loving union of our parents. Both parents contribute half the genetic material to each cell. Our father contributed one sperm and our mother contributed one egg. When the egg and sperm join together, we were conceived. We grow as a single cell in our mother’s womb. This single cell has a set of complete instructions to construct us within in 9 months. By the time we are grown up to adulthood, that single cell makes over 100 trillion copies of itself.
\nDuring replication, if we introduce slight error in the nucleotide sequence called mutation by exposing to radiations or chemical pollutants including nicotine, viral infection, or genetic inheritance, the error is copied in every other cell. At this stage, pregnant mothers should be extremely careful what they eat and what they drink and to avoid exposing the fetus from the secondhand smokers and should stay away from smokers as far as they could. Every cell in our body has a complete library of our genome and carries complete instructions to make our brain, our nose, our ears, our arms, and our legs. Although each cell carries complete instructions to make all the organs, not all cells make all organs, but each cell begins to receive specific instructions to take a different role as it begins to make more copies. We call this process the cell differentiation.
\nDamage to DNA nucleotide called mutations produces disastrous change in the information molecules. As I said above, mutations are caused by exposure to radiations, chemical pollution, viral infection, or genetic inheritance. In addition to hundreds of chemicals isolated from tobacco tar, the most potent carcinogen is nicotine N-oxide. As mutation begins in a single biological molecule, it is called a point mutation. To study changes in genetic profile of a single cell, we examine the entire genome of the same single cell. As cells grow rapidly, other mistakes in DNA replications are most likely to occur such as deletion, insertion, or inversions of nucleotide sequence. Such additional mutations are responsible for causing major diseases. Before the completion of Human Genome Project, NCI screened thousands of chemicals, plant extracts, and animal extracts for their antitumor activity. By trial and error, one in several thousand turned out to be useful. There was a need to make a rational approach to design drugs.
\nIn 1990, United State Congress authorized 3 billion dollars to NIH to decipher the entire human genome within 15 years that is the total genetic information that makes us human called the Human Genome Project. Thousands of scientists from 6 industrialized nations and 20 biomedical centers joined our effort, and within 13 years, the entire human genome was deciphered and published in the scientific journal
On April 3, 2003, we read the Human Genome, the entire book of life. We found that less than 2% of the genome codes for proteins and the rest is the noncoding region which contains switches to turn the genes on or off. We can cut and paste genetic letters in the noncoding region which could serve as markers and which has no effect, but a slight change in the coding region makes a normal cell abnormal or cancerous.
\nA single cell is so small that we cannot even see with our naked eyes. We have to use a powerful microscope to enlarge its internal structure. Under an electron microscope, we can enlarge that one cell up to nearly a million times of its original size. Under the electron microscope, a single cell looks as big as our house. There is a good metaphor with our house. For example, our house has a kitchen, the cell has a nucleus. Imagine for a moment that our kitchen has 23 volumes of cookbooks which contain 24,000 recipes to make different dishes for our breakfast, lunch, and dinner. The nucleus has 23 pairs of chromosomes which contain 24,000 genes which carry instructions to make proteins. Proteins interact to make cells; cells interact to make tissues; and tissues interact to make an organ and several organs interact to make a man, a mouse, or a monkey. In every cell of our body, we carry 16,000 good genes, 6000 mutated genes responsible for 6000 diseases, and 2000 pseudogenes that have lost their functions, during evolutionary time.
\nOur entire book of life is written in four letters, and they are A (adenine), T (thymine), G (guanine), and C (cytosine). These four chemicals are called nucleotide and they are found in the nucleus of all living cells including humans, plants, and animals. Instruction in a single gene is written in thousands of AT/GC base pairs that are linked together in a straight line and we call them DNA (deoxyribonucleic acid—Nobel prize was awarded to Crick and Watson for describing the double helical nature of the DNA structure). When thousands to millions of AT/GC base pairs contain information to make a single protein, we call that portion of AT/GC base pairs a gene (Nobel Prize was awarded to Khorana and Gilbert for making a functional gene). The genes begin to function with a start codon (AUG) and stop working at the following three stop codon: UGA, UGG, and UAG. After the stop codon, no more amino acids are added and DNA synthesis stops. If we count all the AT/GC base pairs in a single cell of our body, we will find that there are 3.2 billion pairs present in every cell. The entire AT/GC sequence of 3.2 billion base pair is called the human genome or the book of our life which carries total genetic information to make us.
\nWe deciphered all 46 chromosomes. What surprises us most is that our genome contains 6,400,000,000 nucleotide bases, half from our father and half from our mother. Less than 2% of our genome contains genes which code for proteins. The other 98% of our genome contains switches, promoters, terminators, etc. The 46 chromosomes present in each cell of our body are the greatest library of the human book of life on planet Earth. The chromosomes carry genes which are written in nucleotides. Before sequencing (determining the number and the order of the four nucleotides on a chromosome), it is essential to know how many genes are present on each chromosome in our genome. The Human Genome Project has identified the following genes on each chromosome. We found that the chromosome (1) is the largest chromosome carrying 263 million A, T, G, and C nucleotide bases and has only 2610 genes. The chromosome (2) contains 255 million nucleotide bases and has only 1748 genes. The chromosome (3) contains 214 million nucleotide bases and carries 1381 genes. The chromosome (4) contains 203 million nucleotide bases and carries 1024 genes. The chromosome (5) contains 194 million nucleotide bases and carries 1190 genes. The chromosome (6) contains 183 million nucleotide bases and carries 1394 genes. The chromosome (7) contains 171 million nucleotide bases and carries 1378 genes. The chromosome (8) contains 155 million nucleotide bases and carries 927 genes. The chromosome (9) contains 145 million nucleotide bases and carries 1076 genes. The chromosome (10) contains 144 million nucleotide bases and carries 983 genes. The chromosome (11) contains 144 million nucleotide bases and carries 1692 genes. The chromosome (12) contains 143 million nucleotide bases and carries 1268 genes. The chromosome (13) contains 114 million nucleotide bases and carries 496 genes. The chromosome (14) contains 109 million nucleotide bases and carries 1173 genes. The chromosome (15) contains 106 million nucleotide bases and carries 906 genes. The chromosome (16) contains 98 million nucleotide bases and carries 1032 genes. The chromosome (17) contains 92 million nucleotide bases and carries 1394 genes. The chromosome (18) contains 85 million nucleotide bases and carries 400 genes. The chromosome (19) contains 67 million nucleotide bases and carries 1592 genes. The chromosome (20) contains 72 million nucleotide bases and carries 710 genes. The chromosome (21) contains 50 million nucleotide bases and carries 337 genes. Finally, the sex chromosome of all female called the (X) contains 164 million nucleotide bases and carries 1141 genes. The male sperm chromosome (Y) contains 59 million nucleotide bases and carries 255 genes.
\nIf you add up all genes in the 23 pairs of chromosomes, they come up to 26,808 genes and yet we keep on mentioning 24,000 genes. The remaining genes are called the pseudogenes. For example, millions of years ago, humans and dog shared some of the same ancestral genes; we both carry the same olfactory genes. Since humans do not use these genes to smell for searching food, these genes are broken and they lose their functions in humans, but we still carry them. We call them pseudogenes. Recently, some Japanese scientists have activated the pseudogenes; this work may create ethical problem in future as more and more pseudogenes are activated.
\nThe above DNA nucleotide bases constitute the genetic map of the normal human being; what makes them abnormal and makes us sick is the mutation in the coding regions of the genome. Now, we can examine the tumor genome of the oral cancer patients to identify specific mutations responsible for causing the disease. As I said above, less than 2% of the genome codes for amino acids. Slightest damage to the coding regions of the four nucleotides A, T, G, and C either by radiations, chemical pollution (from tobacco tar), genetic inheritance, or viral infection or by insertion, deletion, or inversion of the nucleotide bases code for wrong or abnormal amino acids resulting in diseases.
\nAlthough you and I are both human and yet no two individuals look the same because the AT/GC base pairs in each of us are arranged slightly differently, a difference of one nucleotide in a thousand base pair. The amazing fact is that out of 3,000,000,000 AT/GC base pairs, only 3 pairs of AT/GC code for a single amino acid, the building blocks of protein, called a codon (Nobel Prize was awarded to Nierenberg and Ochoa). Codons are the most important collections of AT/GC base pairs because they have correct instructions to make the right amino acids (there are only 20 amino acids; they randomly combine to make a protein). Thousands of amino acids make a protein and thousands of proteins make a cell; billions of cells make a tissue and hundreds of tissues make an organ and several organs make an individual such as you and me. This is how normal cell functions and we begin to grow.
\nAs I said above, the old cells begin to die and they are constantly being replaced by healthy cells. Why do the normal cells become abnormal or become cancerous? Any factor that disrupts the 2% of the coding region of our genome will alter its function by slightly altering its code; an altered codon will code for a wrong amino acid and a wrong amino acid will give a wrong protein and it will make normal cell abnormal. When the functions of codons are disrupted intentionally or unintentionally, we alter the codon’s function. For example, intentionally we alter a codon by smoking and unintentionally by exposure to environmental pollution such as chemicals or radiations. Altered codons have wrong information to make wrong amino acids. Wrong amino acids make wrong proteins and wrong proteins make wrong cells and wrong cells grow much faster than the normal cells and become abnormal or cancerous and they form a lump, we call these lumps tumors.
\nFour factors will disrupt a codon’s function. Two are minor such as viruses and inherited oncogenes, and two are major such as radiations and chemical pollutants in our environment. Let me explain how a codon is altered:
\nHPV causes more than 32,000 cases of cancer including oral cancer every year in the US. It is also very preventable by giving HPV vaccine for children at ages 11–12 which can protect them.
\nViruses are not considered germ in the classical sense because they lack the ability to reproduce its progeny independently. To reproduce their own kind, viruses attack DNA of living cells, whether they are humans, animals, or plant cells. Viruses are also fragments of DNA that have the ability to merge in the host cell DNA and become integrated and invisible. They infect (merge) host’s DNA and alter its functional machinery in such a way as to make protein and progeny for themselves. Not all viruses are bad. If all viruses kill their host cells, they will die too. Only a handful of virulent viruses destroy host cells. For example, AIDS viruses in human disrupt the codons and cause a unique cancer in AIDS patients called Kaposi carcinoma. Hardly anyone survives that cancer.
\nOncogenes are also fragments of mutated DNA, but they are always bad. They are complete genes that have the instructions to make a specific bad protein. Such genes are called oncogenes (cancer-causing genes). Our institute\'s, NIH\'s, past Director, Dr. Harold Varmus, was the first man to identify an oncogene in humans. For his work, Dr. Varmus shared a Nobel Prize with Dr. Michael Bishop.
\nFrom here begins one of the most exciting stories that explain the causes of cancer. In the early 1990s, some scientists in England were studying cancer-causing viruses. When scientists injected cancer-causing viruses to animals, they found that sometimes viruses grow and other times they do not. On close examination, they detected a background protein in all cells. Whenever the background protein is absent, cancer-causing viruses grow and the animal develops cancer. Whenever the background protein is present, cancer-causing viruses will not grow. They called it the background Protein 53 or (P53). They identify the gene that makes P53 protein and they named P53 gene. Since cancer is suppressed in the presence of P53, scientists named P53 as cancer suppressor proteins. When a normal cell is damaged, the surrounding cells grow to make P53 protein to repair the damage. When healing is complete, the P53 protein stops the cells from further growth. If there is a mutation in the P53 gene, P53 loses its function and the cell growth will not stop and grow continuously and become cancerous.
\nAs I said above, that gene is a collection of codons and each codon is made of three pairs of AT/GC. Hundreds of thousands to millions of AT/GC base pairs combine to form gene-53. Now, we know that the codon in P53 is sensitive to mutation by chemicals, radiations, viruses, and oncogenes. If you cause a slight defect in the codon by altering one letter of AT/GC base pair, the entire P53 gene becomes defected. Defected P53 cannot produce background protein that suppresses cancer. In the absence of P53 protein, patients develop cancer. The lesson we learn is that if a single letter of this four-letter AT/GC base pairs is altered by virus or by chemicals or by gene or by radiation, first a single normal cell becomes abnormal or cancerous. Over many replications, the mutated cell becomes cancerous. Repeated exposure to chemicals such as smoking tobacco several times a day, you could alter a single letter of AT/GC base pairs. If a single cell becomes defected, it will multiply and accumulate and an entire organ becomes cancerous. When the defected organ cannot function, we become ill.
\nUnfortunately, cancer is not localized at one place for long (we could have cut out the defected organ and throw it away); it spreads or metastasizes as I described above. Once it is metastasized, the other organs lose their function; with too many defected organs, a patient cannot survive for long. When we examine the internal structure of tumors of a dead patient, we find it mostly consists of abnormal cells that have been altered.
\nLet me tell you what you can do to protect yourselves and what we can do to help you? If you want to protect yourselves from oral or lung cancers, stop taking tobacco in any form and in any kind. The best way we can help you is to pursue as vigorously as we could do to find other sensitive genes and try to replace them with healthy genes by a method called gene therapy. Gene therapy could work if a single gene is mutated. Unfortunately, several genes are mutated in oral lung cancers. Gene therapy fails, but drug therapy works. From here my work begins. Professor Ross and I design drugs to shut off multiple defected genes.
\nAs I said above, although the book of life is written in 3.2 billion AT/GC base pairs, about 2% of the AT/GC base pairs contain 24,000 genes (specific instructions to make proteins), the rest of DNA is called the junk DNA. As I said above, it is not garbage that we throw away; it contains important gene switches, promoters, enhancers, etc. We keep it because someday we might be able to find out what additional information it may provide about us. We carry all 24,000 genes in every cell of our body, but less than 6000 genes are probably bad genes (mutated) that are linked to a variety of genetic defects leading to 6000 different diseases. Each of us does not carry all 6000 bad genes, but we do carry a single copy of at least 4–5 bad genes in our genome. They remain dormant because only one parent carries a single copy of a mutated gene. We need both bad copies of bad genes, one from each parent to get sick. We have inherited these bad genes from our parents. Our parents inherited these genes from their parents. One ancestor can pass on the same bad genes to her children and children’s children. Therefore, it is a wise idea not to marry within the same family tree. The more intermarriages among the same family members, the more bad genes tend to concentrate among fewer and fewer children of that family.
\nI could take tobacco extract samples to the lab and analyze its ingredients. First, I soak the tobacco in ammonia and extract with chloroform. All nitrogen bases are extracted in chloroform. I could wash the extract with water to remove all water-soluble impurities and dry the extract and distill off the chloroform. I place the residue in long glass column filled with silica gel. I pour a solvent mixture which carries the residue down the column. It is called the separation of different components by chromatography. I shine the UV light on the glass column as the solvent flows down. Hundreds of different bands appear in different colors, corresponding to hundreds of components present in the tobacco tar. The largest band is nicotine. To confirm, I take a little sample from the band and inject in the MS (mass spectrometer: the largest peak corresponds to the molecular weight of the nicotine). I could make the radiolabeled nicotine by adding C-14 diazomethane in sodium hydroxide. The reaction adds a radiolabeled methyl group to nicotine molecule. I inject the radiolabeled methyl nicotine to half a dozen mice. I collect their urine samples separately. Analysis of the urine sample shows that some mice produce no change and others produce a new chemical called nicotine N-oxide. All those mice in which the gene that produces monoamine oxidase was activated developed cancer. If you inject nicotine N-oxide to another set of a dozen mice, they all come down with various cancers. All aromatic N-oxides are carcinogens.
\nNow, you know why Sir Winston Churchill, who smoked cigar all his life, never developed cancer, but film actor Yul Brenner smoked cigarettes and died of lung cancer. If you were to analyze their urine samples, you will find that Mr. Brenner urine contains nicotine N-oxide. The gene monoamine oxidase is activated in Brenner to make nicotine N-oxide not in Sir Winston. While Sir Winston lived, Brenner died.
\nWhile I was busy designing drugs, such as AZQ, to shut off genes which cause brain cancers, my colleagues in the other labs at NCI (National Cancer Institute) have isolated hundreds of chemicals from the tobacco tar which contains dozens of carcinogenic chemicals. If you would apply the tobacco tar on the skin of mice, within a few weeks, tumor develops on the skin surface. The major culprit is nicotine which is considered as one of the most addictive chemicals. Some studies showed that it is even more addictive than many known narcotics such as marijuana, opiates, and heroin. Oral cancer (OC) is caused by chemicals released by chewing tobacco. Most football players chew tobacco; they call it smokeless tobacco. Smoking burns tobacco generating even more aromatic amines which are known carcinogens. Nitrosoamines bind to DNA producing mutations.
\nAfter the completion of the Human Genome Project, we have identified specific mutations responsible for a specific disease. Now, we design drugs to attack that specific mutation to shut off that gene. The completion of the Human Genome Project has the greatest impact on developing drugs on a rational basis and for treating various cancers including the oral cancer. The technologies developed during the completion of the Human Genome Project (the tool kits which contain hundreds of restrictions enzymes to cut DNA ligase to join DNA pieces; using these tool kits, we can cut, paste, and copy genes) could be used to treat and prevent oral cancer. The recently completed Thousand Genome Project will pinpoint with precision and accuracy the specific damage to DNA nucleotides responsible for causing various oral cancers. Once the mutated genes on a specific chromosome are identified, we can design drugs to shut off those genes like we designed AZQ (US Patent 4,146,622) to attack brain tumor (for structure, see Figure 1).
\nNIH Scientific Achievement Award. Aziridines as single strand DNA binding agent.
Once the mutation sites and chromosome numbers are identified, we can diagnose, prevent, and treat the oral cancer either by gene therapy if a single gene mutation is responsible for causing any of the above cancers or by drug therapy if multiple mutations are involved. As I stated above, French Anderson and his colleagues have successfully developed gene therapy for treating SCID (severe combined immunodeficiency) syndrome; we could use the same method to cut and paste and replace the bad gene with the good gene in a virus which is used to infect the WBC obtained from the same patient. After harvesting the infected WBC, the transgenic WBC was injected back in the same patient to treat SCID. It worked and patients fully recovered. Several thousand SCID children are living a normal life. Gene therapy works with a single gene mutation, but not if the multiple mutations are responsible for causing diseases.
\nOn the other hand, if cancer is caused by multiple mutations, we could use drug therapy by preventing malignant cell replication developed by Ross by cross-linking both strands of DNA. Using dyes specific to OC cells as carriers for nitrogen mustard, as done by Ross in making Melphalan, we could also develop new class of drugs to attack cancer cells in the other parts of the oral cavity. The bad news is that there have been 13 different forms of oral cancer identified. The good news is that for designing a drug, we have to find a dye which colors one of these tumors. There are hundreds of dyes available for testing. Once we succeed in finding a dye, we could design drugs by using our method by attaching aziridines to attack that specific oral cancer by shutting off mutated genes by binding to a single strand of DNA. What would happen if we succeed and when next-generation sequencers produce inexpensive and fast sequencing genomes is that we could identify all mutated genes on all 13 oral cancers with precision and accuracy and design drugs to shut off those genes.
\nIn the laboratory of the Sir Walter Ross at the Royal Cancer Hospital of London University, England, I was trained to design drugs to attack mutated DNA shutting off mutated genes. Professor Ross had spent all his life working on “Biological Alkylating Agents” and published a series of paper including a book [9, 10, 11, 12, 13]. Using the same rationale, I worked with Professor Ross for almost 10 years at London University developing anticancer drugs. Instead of cross-linking DNA with nitrogen mustards, I used aziridines to bind to a single strand of DNA shutting off the genes.
\nDuring 10-year period in the Professor Ross’ Lab, I made over 120 such drugs to attack a solid tumor called the Walker carcinoma 256 in rats. The most effective drug was called CB 1954 (2-4, dinitrophenyl aziridinyl benzamide) (see structure in Figure 1). It was 70 times more toxic to the tumor cell [14]. It is the most effective drug ever made against the solid experimental tumor for which I was honored with the Royal Cancer Hospital’s Institute Cancer Research postdoctoral award. Why mutated DNA must be attacked is because mutated DNAs code for wrong amino acids which produce wrong protein and cause abnormal growth leading to cancers. The reason why we work on mouse model is that if you would compare the genome of man, mouse, and monkey, they are all mammalians and their genomes are very similar. Once you succeed in attacking mouse tumor, it opens gate to attack human tumors. Now, you know how challenging it is to shutting off a mutated gene and how easy it is to introduce mutations in the same gene by smoking.
\nThe good news about smokers is that they could see their own genome on their computers and could also see the progress of mutations of their own genomes before and after smoking. Now, I do not have to tell my best friends not to smoke. All I have to do is to give the two CDs of their genomes and let them see for themselves. Let them see on their own computers and compare the two genomes. First, CD taken soon after their birth and second taken after they become smokers. Before I talk about the sequence-specific tumors of oral and lung cancers, let me share with you how our genome, the book of our life, looks like before you smoke.
\nThe basis of OC is that people who are chewing tobacco or inhaling burning tobacco by smoking (as in India) or chewing betel quid, betel nut, etc. (as in Taiwan) causing major mutations in their genomes producing a host of chemicals which damage the normal function of the cell causing them to become abnormal or cancerous. To understand the molecular basis of cancers, we have to sequence the normal as well as cancer cell genomes for comparison.
\nTo refresh your memory, I repeat. Carcinoma is the most common type of cancer. It begins in the epithelial tissue of the skin, or in the tissue that lines the internal organs, such as mouth, oral cavity, reparatory tract, and lungs. There are 220 different types of tissues in the normal human being. We have sequenced (read letter by letter the entire script of nucleotides, their numbers, and their orders in which they are arranged). After genome sequencing, we can compare with the sequence of oropharynx carcinoma with normal cell from nonsmokers. I am happy to inform you that we just completed the Thousand Genome Project. Now, we can compare thousands of the same mutated sequence a time. We can locate the specific mutations with precision and accuracy. To locate specific mutations, in all oral cavity cancers, similar comparison can be studied in several types of salivary gland cancers including adenoid cystic carcinoma, mucoepidermoid carcinoma, and polymorphous low-grade adenocarcinoma. Tonsils and base of the tongue tissues also develop lymphomas.
\nOnce a mutation is identified in a specific oral cancer, my job begins trying to find a dye which colors these tumors. Once a dye is found, I could attach the toxic groups to shut off their genes. There are hundreds of dyes and there are hundreds of their combinations. With AT and GC, four nucleotides of DNA, I get 64 combinations; imagine how many combinations I get from hundreds of dyes. Fortunately, there are finite combinations. I could find it. Suppose I want to design drugs to treat cancers of the oral cavity. The cancer begins in the epithelial tissue of the skin, or in the tissue that lines the internal organs, such as mouth, oral cavity, reparatory tract, and finally reaching lungs. We have been designing drugs to attack toughest solid tumor like Walker carcinoma 256 in rats or glioblastoma in humans. It would be much easier to attack carcinoma. And also suppose that I find a single dye which specifically colors a specific carcinoma cell. Now, my work begins to attach aziridines or carbamate or both as we succeeded in making AZQ for attacking brain tumor. Nowadays, I have to submit the research proposal to the Safety Committee (IRB: Institutional Review Board) for their approval. Since I will be using highly toxic nerve gases and nitrogen mustard, the proposal will be rejected.
\nFirtz Heber, a German Army officer, worked on the development of chemicals as a weapon of war. He was responsible for making deadly nerve gases and nitrogen mustards. Before the WWI, he was honored with a Nobel Prize for capturing nitrogen directly from the atmosphere by burning the element magnesium in the air forming its nitride. Upon hydrolysis, nitride is converted to its nitrate which is used as a fertilizer. Using this method, we could make unlimited amount fertilizer. Nitrate is also used for making explosive. Soon after the WWI, Heber was charged with a crime against humanity for releasing hundreds of cylinders of chlorine gas on the Western front killing thousands of soldiers in the trenches. When allied forces reached his residence, his son shot himself and his wife committed suicide. Heber went in hiding in Switzerland. After the war, German government got his release as a part of the peace negotiations. Heber returned home to hero’s welcome. Although he promised never to work on the nerve gases again, secretly he continued to develop more lethal analogs of highly toxic nitrogen mustards. It was Heber who first made the notorious bis-dichloroethyl methyl amine. Because it smells like mustard seeds, it is called as nitrogen mustard. During the next 20 years, before the beginning of the WWII, hundreds of more toxic analogs of nitrogen mustard were developed. The bad news is that they are highly toxic and the good news is that they shut off genes.
\nNitrogen mustard was mercilessly used during the WWII by both German and Italian armies against allied forces. Most soldiers exposed to nitrogen mustard were frozen to death. Their blood analysis showed a sharp decline in white blood cell (WBC). Since patients with the cancer of the blood called leukemia showed a sharp increase of WBC, Professor Ross and his group wondered if minimum amount of nitrogen mustard could be used to control leukemia in cancer patients. It was a success. For the following 30 years, Ross developed hundreds of derivatives of nitrogen mustard to treat a variety of cancers. His most successful drugs are chlorambucil, melphalan, and merophan [2, 3, 4, 5, 6, 14].
\nRadiolabeled study showed that nitrogen mustard shut off genes by binding to DNA by cross-linking. At London University, I work for Professor Ross for almost 10 years first as his graduate student, then his post-doctoral fellow, and then as his special assistant. I worked with the deadliest nerve agents such as nitrogen mustards, carbamates, and aziridines developed during Hitler’s time for evil purposes. We are converting evil into good. These agents easily pass through various layers of our skin from ectoderm to mesoderm to endoderm. They easily enter the cell nucleus destroying the beta and gamma cell which develop immunity. Then they enter the nuclear membrane where they find the stem cells. Stem cells differ from say skin cells. In stem cells, all 24,000 genes are functioning and they have not yet differentiated, but skin cells are differentiated and they have shut off all other genes except the skin cell genes.
\nTo the above toxic agents, I attach dyes to attack one of the carcinoma cells. The toxic group is activated by cell’s enzyme to produce a positive carbon ion called carbonium ion. It is extremely reactive; it binds to all four nucleotides (AT and GC) which form the DNA. But it preferentially binds to N-7 of guanine killing the stem cells. Professor Ross and I have demonstrated the attack on N-7 of guanine using the radiolabeled study.
\nIf I am accidentally exposed to any of the above toxic agents, I do not die of mustard poisoning; I would be frozen to death. What happens is the following: each cell carries hundreds of mitochondrial cells (mitochondria are foreign cells called prokaryotes without nuclear membrane captured by human cells during the evolutionary period, millions of years ago; they live in symbiotic relationship; to perform daily function, mitochondria provide energy to human cells and human cells provide free food and free housing to the mitochondria) which carry energy-rich phosphate bonds. They produce energy by breaking phosphate bonds in which a chemical called ATP (adenosine triphosphate) is broken down to ADP (adenosine diphosphate) which is further broken down to AMP (adenosine monophosphate). As normal cell grows, an enzyme attaches inorganic phosphate to the AMP regenerating ATP. If mitochondrial cells die, there is no energy available.
\nAs I said above, NIH is the largest biomedical center in the world. It has unlimited facilities (chemicals, equipment, and personnel). Twenty-one thousand best and brightest scientists selected from Ivy League schools work in 26 institutes in more than 3000 labs. I had sent NIH over 120 drugs for NCI screening program [14, 15, 16]. During the 3-year period at NIH labs, I made AZQ (US Patent 4,146,622) and 45 patentable analogs [17, 18, 19]. Years later, I was honored for my work on developing AZQ. Almost 20 years later, for translating my work from mouse to man and making AZQ (US Patent 4,146,622) for treating brain cancer, I was honored with the “2004 NIH Scientific Achievement Award,” one of the America’s highest awards in medicine (Figure 2). I was also honored by the Government of India with Vaidya Ratna (Gold Medal) (Figure 3).
\n2004 NIH Scientific Achievement Award presented to Dr. Hameed Khan by Dr. Elias Zerhouni, the Director of NIH during the NIH/APAO award ceremony held on December 3, 2004. Dr. Khan is the discoverer of AZQ (US Patent 4,146,622), a novel experimental drug specifically designed to shut off a gene that causes brain cancer for which he receives a 17-year royalty for his invention (License Number L-0I9-0I/0). To this date, more than 300 research papers have been published on AZQ. The award ceremony was broadcast live worldwide by the Voice of America (VOA). Dr. Khan is the first Indian to receive one of the America’s highest awards in Medicine.
His excellency, Dr. A.P.J. Abdul Kalam, the President of India greeting Dr. A. Hameed Khan, discoverer of anticancer AZQ, after receiving 2004, Vaidya Ratna, the Gold Medal, one of the India’s highest awards in medicine at the Rashtrapathi Bhavan (Presidential Palace), in Delhi, India, during a reception held on April 2, 2004.
In spite of all the risks, fear, and challenges, the zeal and the enthusiasm that I had to design drugs to attack brain cancer like AZQ is not there to treat oral or lung cancers. Do you know why because I know in my heart, the patient once cured will go back to smoking again. He cannot help it; it is an addiction (Figure 4) [20, 21].
\nGold Medal for Dr. Khan. Dr. A. Hameed Khan, a scientist at the National Institutes of Health (NIH), USA, and an American Scientist of Indian origin, was awarded on April 2, 2004. Vaidya Ratna, the Gold Medal, one of the India’s highest awards in medicine for his discovery of AZQ (US Patent 4,146,622) which is now undergoing clinical trials for treating brain cancer.
Firtz Haber was a hero to some for getting a Nobel Prize for capturing nitrogen directly from atmosphere by burning magnesium metal in the air and hydrolyzing magnesium nitride to produce nitrate the fertilizer. To others, he was the greatest criminal because he released hundreds of cylinders of chlorine gas at the Western front killing thousands of soldiers in the trenches. It was Haber who made the nitrogen mustard and its deadly analogs which were used during WWII. Soldiers exposed to nitrogen mustard burns died of a sharp drop in the white blood cell (WBC) count. Since all cancers showed a sharp increase in WBC count, Ross decided to use modified derivatives of nitrogen mustard to control the cancer growth. Ross was successful. He attached amino acid phenylalanine as a carrier for the nitrogen mustard moiety to make melphalan for treating pharyngeal carcinoma. Over a 10-year period, I made dozens of analogs of nitrogen mustards for Ross. The deadliest among them was the phenylenediamine mustard. We use these compounds to check the sensitivity of the tumors in the tumor bank. If tumors in the tumor bank become resistant, we have to replace them with fresh more sensitive tumors for testing other compounds.
\nProteins in our body are made of 20 amino acids. When Ross made melphalan by using 1 amino acid out of 20, most of my colleagues thought that they could use the following 19 amino acid to treat all 13 forms of oral cancers including lung cancer: alanine, arginine, aspartic acid, asparagine, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine (Ross used this amino acid to make melphalan for treating pharyngeal carcinoma), proline, serine, threonine, tryptophan, tyrosine, and valine.
\nAliphatic nitrogen mustards are deadlier than aromatic nitrogen mustards. They decided not to proceed because they do not want to risk their life to save the life of nicotine addicts. If you want to save smokes’ life by risking your own, you are welcome to it. I will show you how to make the nitrogen mustard by describing Haber’s crudest method. Haber reacted methylamine with ethylene oxide to make 2-bis dihydroxy ethylene methyl amine. It was chlorinated by heating with phosphorus pentachloride in the phosphoric acid. If you noticed a faint smell of mustard seed, Congratulations, you got nitrogen mustard; you are dead. No matter how much precaution you take, after the experiment, if you take an alcohol swab of walls, doors, and knobs and run mass spectra of alcohol extract, you find a line corresponding to nitrogen mustard. If you are exposed to nitrogen mustard and cross the threshold level, your WBC drops sharply and the energy-providing mitochondria die and you are most likely to freeze to death.
\nWill anyone approve this study, probably no one. Your IRB will reject your proposal; your safety committee will reject it and who will provide the funds for such study. No one.
\nTobacco companies are rich and can afford to invest money in curing cancers. Since most of their work is conducted behind closed doors, why not make nitrogen mustard analogs of all other 19 amino acids. Like melphalan, they might find some of these analogs of amino acids of nitrogen mustard to cure oral to lung cancers. They could make money not only by giving cancers by selling tobacco products but also by treating some cancers.
\nSome of my best friends smoke and most of them are not scientists. Do I tell them not to smoke and keep their friendship? Not a chance. So I tell them experimental facts as gently as possible. My readers are my best friends. All I want is to make them think. If they think, my job as a friend is done.
\nScientists in our group are working on different kinds of cancers. As I stated above, there are more than 220 different types of tissues and they could all become cancerous if they are exposed to radiations or chemical environmental pollution. We are all working to cure those cancers. Unfortunately, there is no great enthusiasm for working on either oral cancer or lung cancer. Such diseases are considered self-inflicting wounds. The users of tobacco products are addicted and frequently developed these types of cancers. Many scientists believe that all of us have a free will. We have a right to live and we have a right to die. If you do not smoke or chew tobacco, you will not expose yourself to a host of carcinogens. Some of us believe that you are addicted to nicotine if we cure your oral cancer, you will go back and chew tobacco again. How can we protect you from yourself? If we protect you from yourself, we create a monster. On the other hand, if you are one of those unfortunate persons who inherit a mutated gene, or exposed to secondhand smoking or exposed to radiations or heavy metal particles, you deserve all our help and many of us have been designing drugs for treating oral and lung cancers for these innocent victims.
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\\n\\nAs a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 128,000 international scientists and researchers.
\n\nThe Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
\n\nOAPF Publishing Options
\n\n*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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\n\nYour Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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